Synthesis method and synthesis device of lipidosome

Abstract

The invention provides a synthesis method and a synthesis device of lipidosome, and the method comprises the following steps: respectively introducing two liquids of an organic phase and a water phase into two sample introduction channels of a Y-shaped flow channel; the Y-shaped flow channel comprises the two sample introduction channels and a synthesis channel communicated with the convergence position of the two sample introduction channels; and driving a regular pentagonal special ultrasonic device arranged at the bottom of the synthesis channel to work, and mixing the two liquids in the synthesis channel at least through micro vortexes which are generated in the liquids in the synthesis channel and are distributed at the positions of the edges of the regular pentagon when the special ultrasonic device works, so as to generate the target liposome. Through collaborative design of the micro-channel structure and the special ultrasonic device, the synthesis efficiency of the lipidosome can be remarkably improved, and the average particle size and uniformity of a product in the synthesis process of the lipidosome are optimized.

Description

Technical Field

[0001] The present application relates to the technical fields of biomedicine and molecular biology, and in particular to a method and apparatus for synthesizing liposomes. Background Art

[0002] Liposomes (also known as lipid globules, liquid crystal microcapsules) use phospholipids, cholesterol and other lipids as membrane materials and have a cell membrane-like structure. Therefore, they can be used as drug carriers to achieve the delivery of multiple drugs, thereby effectively solving the problems of poor bioavailability of free drugs, low plasma solubility, and high clearance rate. However, the delivery effect and pharmacokinetic circulation half-life of drugs are strongly affected by the size of liposomes. Some studies have shown that liposomes with a size greater than 200nm can cause severe toxicity, liposomes with a size less than 50nm will accumulate in the liver, and liposomes with a size of around 100nm can maintain good stability in the blood circulation, so that they exhibit better biodistribution characteristics in the body. Therefore, in the synthesis process of liposomes, precise control of liposome size and uniformity is crucial to optimizing its drug properties.

[0003] Microfluidics is a technology for precisely controlling and manipulating microscale fluids. It can be applied to medicine, biotechnology, chemical engineering and other technical fields. For example, microfluidics can be used to mix two or more liquids together at high speed for rapid reaction to generate liposomes.

[0004] When synthesizing liposomes using microfluidics, controlling liposome size is highly dependent on flow rate, and there are also problems such as long mixing distances and times. Therefore, how to effectively control the size (particle size and uniformity) of liposomes to produce liposomes with controllable and uniform particle size remains a technical challenge to be solved. Summary of the Invention

[0005] In view of this, the present application proposes a liposome synthesis method and synthesis device, which can significantly improve the synthesis efficiency of liposomes and optimize the average particle size and uniformity of the products during the liposome synthesis process through the coordinated design of microfluidic channel structure and ultra-ultrasonic device.

[0006] The first aspect of the present application provides a method for synthesizing liposomes, comprising:

[0007] The organic phase and the aqueous phase are respectively introduced into the two injection channels of the Y-shaped flow channel; the Y-shaped flow channel includes the two injection channels and a synthesis channel connected to the confluence of the two injection channels;

[0008] The ultra-sonic device in the shape of a regular pentagon disposed at the bottom of the synthesis channel is driven to operate, and at least when the ultra-sonic device is in operation, micro-vortices generated in the liquid in the synthesis channel and distributed at the positions of the respective sides of the regular pentagon are used to mix the two liquids in the synthesis channel to generate target liposomes.

[0009] From the above, in a method for synthesizing liposomes provided by the present application, an organic phase and an aqueous phase are respectively introduced into the two inlet channels of the Y-shaped flow channel, so that the two liquids converge into the synthesis channel of the Y-shaped flow channel, and then a regular pentagonal supersonic device is set at the bottom of the synthesis channel and driven to work. The micro-vortices generated by the device during operation and distributed at the positions of the sides of the regular pentagon can generate local strong disturbances and flow field changes, promote molecular diffusion and convection mixing between the liquids, and significantly enhance the mixing effect of the organic phase and the aqueous phase in the synthesis channel, thereby generating target liposomes. In addition, the design of the Y-shaped flow channel enables the two liquids to flow into the synthesis channel according to a predetermined ratio and flow rate, and the working parameters of the supersonic device (such as frequency, power, etc.) can be precisely adjusted to achieve precise control of the mixing process, thereby improving the synthesis efficiency of liposomes of different sizes.

[0010] Optionally, the ultra-ultrasonic device is arranged at the confluence of the two sampling channels and the synthesis channel, wherein two adjacent sides of the regular pentagonal ultra-ultrasonic device are respectively oriented towards the two sampling channels.

[0011] From the above, the confluence of the two injection channels and the synthesis channel is where the liquids of the two injection channels converge. At the confluence, the liquids of the two injection channels collide with each other at a certain angle and speed. By setting the ultra-ultrasonic device here, the liquids can be mixed as soon as they come into contact and begin to converge. The momentum and energy of the liquids when converging can be fully utilized, combined with the effect of micro-vortices, to make the mixing process more efficient.

[0012] Optionally, the shape of the ultra-sonic wave device forms a regular pentagonal ring structure with a hollow interior, and an outer vertex of the regular pentagonal ring structure is located on the boundary line of the two liquids flowing into the synthesis channel;

[0013] At least when the ultra-sonic device is working, micro-vortices generated in the liquid in the synthesis channel and distributed at the inner and outer sides of the regular pentagonal ring mix the two liquids in the synthesis channel to generate target liposomes.

[0014] Optionally, the shape of the ultra-sonic wave device forms a regular pentagonal ring structure with a hollow interior, an outer vertex of the regular pentagonal ring structure is located on the boundary line of the two liquids flowing into the synthesis channel; a second regular pentagon or a second regular pentagonal ring structure is nested in the regular pentagonal ring structure;

[0015] At least when the ultra-sonic device is operating, micro-vortices generated in the liquid in the synthesis channel and distributed at the positions of the inner and outer sides of the regular pentagonal ring, the positions of the sides of the nested second regular pentagon, or the positions of the inner and outer sides of the second regular pentagonal ring mix the two liquids in the synthesis channel to generate target liposomes.

[0016] From the above, the shape of the ultra-ultrasonic device can adopt a regular pentagonal ring structure, or a smaller regular pentagonal structure or regular pentagonal ring structure can be nested in the regular pentagonal ring structure, which can form a multi-level sound field distribution so as to act on a larger range in the synthetic channel, generate more micro-vortex positions, and have more acoustic fluid tunnels. When applied to the mixing of different liquids or different particles in the liquid in the flow channel or reactions based on mixing, it has more mixing areas, or equivalently longer acoustic fluid tunnels, and a better mixing effect.

[0017] In a second aspect, the present application provides a liposome synthesis device for implementing the above-mentioned liposome synthesis method, comprising:

[0018] A Y-shaped flow channel, the Y-shaped flow channel comprising two injection channels and a synthesis channel connected to the confluence of the two injection channels, the two injection channels being used to inject two liquids, an organic phase and an aqueous phase;

[0019] The ultra-sonic device in the shape of a regular pentagon is arranged at the bottom of the synthesis channel. When it is working, micro-vortices distributed at the positions of each side of the regular pentagon generated in the liquid in the synthesis channel mix the two liquids in the synthesis channel to generate target liposomes.

[0020] Optionally, the ultra-ultrasonic device is arranged at the confluence of the two sampling channels and the synthesis channel, wherein two adjacent sides of the regular pentagonal ultra-ultrasonic device are respectively oriented towards the two sampling channels.

[0021] Optionally, the shape of the ultra-sonic wave device forms a regular pentagonal ring structure with a hollow interior, and an outer vertex of the regular pentagonal ring structure is located on the boundary line of the two liquids flowing into the synthesis channel;

[0022] At least when the ultra-sonic device is working, micro-vortices generated in the liquid in the synthesis channel and distributed at the inner and outer sides of the regular pentagonal ring mix the two liquids in the synthesis channel to generate target liposomes.

[0023] Optionally, the shape of the ultra-sonic wave device forms a regular pentagonal ring structure with a hollow interior, an outer vertex of the regular pentagonal ring structure is located on the boundary line of the two liquids flowing into the synthesis channel; a second regular pentagon or a second regular pentagonal ring structure is nested in the regular pentagonal ring structure;

[0024] At least when the ultra-sonic device is operating, micro-vortices generated in the liquid in the synthesis channel and distributed at the positions of the inner and outer sides of the regular pentagonal ring, the positions of the sides of the nested second regular pentagon, or the positions of the inner and outer sides of the second regular pentagonal ring mix the two liquids in the synthesis channel to generate target liposomes.

[0025] Optionally, the synthetic channel is linear in shape, has a width of 100 micrometers to 160 micrometers, and a length of 500 micrometers to 6 millimeters.

[0026] From the above, the linear channel structure is simple. In the linear channel, the flow velocity distribution of the liquid is relatively uniform, which helps to ensure that the mixing process of the liquid in the channel is relatively stable and reduce the fluctuation of the mixing effect caused by uneven flow velocity.

[0027] Optionally, the ultra-ultrasonic device adopts a continuous working mode or a pulsed working mode, and the power is 250 mW-400 mW;

[0028] The flow ratio of the organic phase to the aqueous phase is 1:1-1:9.

[0029] As shown above, in the continuous operating mode, the ultra-ultrasonic device continuously generates sound waves, which can form a stable acoustic field environment within the synthetic channel. The continuous action of the sound waves can generate a continuous driving force on the liquid, helping to stably control the flow speed and direction of the liquid in the synthetic channel. The pulsed operating mode can precisely control the action time and interval of the sound waves as needed to produce special flow field effects, such as transient vortices and jets. These special flow fields can be used for some special microfluidic operations, opening up new application areas for microfluidic technology. In addition, by adjusting the flow ratio of the organic phase and the aqueous phase, the degree of mixing can be precisely controlled. For example, when the flow ratio is close to 1:1, the amount of liquid in the two phases is relatively balanced, and the sound wave action can be more evenly dispersed in the two phases, forming a more stable mixed system. At a flow ratio of 1:9, the aqueous phase accounts for a larger proportion, and the sound waves can more effectively disperse the organic phase in the large amount of aqueous phase, achieving uniform emulsification or dissolution of the organic phase in the aqueous phase.

[0030] These and other aspects of the present application will become more apparent from the following description of the embodiment(s). BRIEF DESCRIPTION OF THE DRAWINGS

[0031] Figure 1a Schematic diagram of the jet phenomenon and secondary flow phenomenon generated by the ultra-ultrasonic device provided in the embodiment of the present application;

[0032] Figure 1b is a schematic diagram of an acoustofluidic tunnel provided in an embodiment of the present application;

[0033] Figure 2 A flow chart of a method for synthesizing liposomes provided in an embodiment of the present application;

[0034] Figure 3a A schematic diagram of a first implementation of the liposome synthesis device provided in an embodiment of the present application;

[0035] Figure 3b Schematic diagram of a second implementation of the liposome synthesis device provided in the examples of the present application;

[0036] Figure 3c Schematic diagram of a third implementation of the liposome synthesis device provided in the examples of the present application;

[0037] Figure 4a Provided in the embodiments of this application Figure 3a A schematic diagram of a synthesis simulation result of the liposome synthesis device;

[0038] Figure 4b Provided in the embodiments of this application Figure 3b A schematic diagram of a synthesis simulation result of the liposome synthesis device;

[0039] Figure 4c Provided in the embodiments of this application Figure 3c A schematic diagram of a synthesis simulation result of the liposome synthesis device;

[0040] Figure 5 Provided in the embodiments of this application Figure 4a-4c Schematic diagram of the mixing frequency comparison of the synthetic simulation.

[0041] It should be understood that the sizes and shapes of the blocks in the above structural diagrams are for reference only and should not constitute an exclusive interpretation of the embodiments of this application. The relative positions and inclusion relationships between the blocks presented in the structural diagrams are only schematic representations of the structural relationships between the blocks, and do not limit the physical connection methods of the embodiments of this application. DETAILED DESCRIPTION

[0042] The technical solution provided by this application is further described below with reference to the accompanying drawings and examples. It should be understood that the system structure and business scenarios provided in the examples of this application are mainly for illustrating possible implementation methods of the technical solution of this application and should not be interpreted as the sole limitation of the technical solution of this application. It is known to those skilled in the art that with the evolution of the system structure and the emergence of new business scenarios, the technical solution provided by this application is also applicable to similar technical problems.

[0043] It should be understood that the liposome synthesis schemes provided in the embodiments of this application, including liposome synthesis devices and methods, as well as applications thereof, are provided. Because these technical solutions solve the same or similar problems, some repetitions may not be repeated in the following specific embodiments. However, these specific embodiments should be considered as cross-references and can be combined with each other.

[0044] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art to which this application belongs. In the event of any inconsistency, the meanings described in this specification or the meanings derived from the contents recorded in this specification shall prevail. In addition, the terms used herein are only for the purpose of describing the embodiments of this application and are not intended to limit this application. In order to accurately describe the technical content in this application and to accurately understand the present invention, the following explanations or definitions are given for the terms used in this specification before describing the specific embodiments:

[0045] 1) Ultrasonic device: A high-frequency resonator can be a device that generates mechanical vibrations by applying voltage based on the piezoelectric effect. In this application, a piezoelectric resonator that generates ultrasonic waves of not less than 0.5 gigahertz (GHz) when in operation is used. Preferably, a piezoelectric resonator that generates ultrasonic waves of not less than 1 GHz and not more than 30 GHz when in operation is used. For example, it can be 2G-2.5 GHz. Such piezoelectric resonators can be, for example, surface acoustic wave (SAW) devices, bulk acoustic wave (BAW) devices, etc. For example, when it is a BAW, it can be a film bulk acoustic wave resonator (FBAR), a solid-state mounted resonator (SMR), or a Lamb wave resonator (LWR). For the sake of convenience, the piezoelectric resonator that can generate ultrasonic waves of not less than 0.5 GHz will be referred to as an ultrasonic device in the following.

[0046] 2) Jet phenomenon: This phenomenon occurs when the sound waves of a super-ultrasonic device act on a liquid. The regional vibrations generated by the working interface of the super-ultrasonic device can form traveling waves in the liquid, exerting a continuous thrust on the liquid in the liquid environment, causing at least a portion of the liquid to move linearly along the direction of sound wave propagation. This linear motion phenomenon is called jet phenomenon.

[0047] Secondary flow phenomenon: including eddy currents and heat reflux, is another phenomenon produced when ultra-ultrasonic devices act on liquids. It includes eddy currents (or micro-vortices) caused by the local circulation of liquids driven by the jet, and heat reflux caused by the heat generated by the ultra-ultrasonic devices.

[0048] The jet phenomenon and secondary flow phenomenon can be found in Figure 1aThe images and schematics are shown. Figure 1a Schematic diagram of using eddy currents (ie micro-vortices) to capture particles is shown in FIG.

[0049] 3) Acoustic fluid tunnel: Under the stimulation of input signal, the ultra-ultrasonic device generates ultra-high frequency vibration and emits body acoustic wave, which propagates in the fluid and induces the directional motion of the fluid (jet phenomenon), further forming fluid micro-vortex. One of the phenomena is, Figure 1b As shown in the simulation diagram, several tiny fluid micro-vortices (such as Figure 1a As shown in the figure, these fluid micro-vortices can capture particles in the liquid. Combined with the position distribution of these fluid micro-vortices, it is shown that the particles in the liquid are distributed at the edge of the chip of the ultra-ultrasonic device. Since the particles in the fluid will flow through these fluid micro-vortices distributed at the edge of the chip, the paths formed by these fluid micro-vortices for the particles to flow through (as shown in the figure) Figure 1b As shown), this application refers to the acoustic fluid tunnel.

[0050] 4) The shape of the super-ultrasonic device: for example, pentagonal, leaf-shaped, spindle-shaped, etc. The shape of the super-ultrasonic device in the embodiment of the present application refers to the shape of the resonance area of ​​the super-ultrasonic device. The bottom electrode layer, the piezoelectric layer and the top electrode layer (these three layers can be called resonance layers) respectively form the resonance area in the overlapping area of ​​the orthographic projection on the substrate. For example, one structure of the resonance layer of the above-mentioned pentagonal super-ultrasonic device can be composed of a pentagonal bottom electrode layer, a piezoelectric layer and a top electrode layer of the same shape and overlapping orthographic projections. Another structure can be composed of bottom electrode layers, piezoelectric layers and top electrode layers of different shapes, such as including: a quadrilateral bottom electrode layer, the projection of the piezoelectric layer and the top electrode layer covering the quadrilateral is a pentagon located within the quadrilateral. Thus, the overlapping area of ​​the orthographic projections of the bottom electrode layer, the piezoelectric layer and the top electrode layer on the substrate is the pentagon, forming the pentagonal super-ultrasonic device. The definition of the shape of the ultra-ultrasonic device in this application is merely used to illustrate the definition and does not limit the ultra-ultrasonic device to include other layer structures. For example, a reflective layer (such as a Bragg reflector layer or a cavity reflector layer) may be provided below the resonant layer, and aluminum nitride may be provided as a protective layer above the resonant layer. Similarly, unless otherwise specified, the area of ​​the ultra-ultrasonic device mentioned in this application refers to the area of ​​the resonant region of the ultra-ultrasonic device.

[0051] For another example, a super ultrasonic device with a regular pentagonal ring structure may have a top electrode that is a regular pentagonal ring, a bottom electrode layer and a piezoelectric layer that are pentagons, and a resonance region formed by projection that is a regular pentagonal ring.

[0052] For another example, a second regular pentagon is nested in a regular pentagonal ring structure, and the top electrode may be configured to have the second regular pentagon nested in the regular pentagonal ring structure, and the regular pentagonal ring structure of the top electrode is electrically connected to the second regular pentagon ( Figure 3c The electrical connection is not shown in the figure, and the electrical connection between the regular pentagonal ring structure and the second regular pentagon has little effect on the overall mixing. For another example, the electrical connection position of the bottom electrode corresponding to the top electrode can be hollowed out, so that the resonant area formed by the projection does not include the electrical connection (matching Figure 3c shape in the ).

[0053] The definition of the shape of the ultra-ultrasonic device in this application is merely used to illustrate the definition and does not limit the ultra-ultrasonic device to include other layer structures. For example, a reflective layer (such as a Bragg reflector layer or a cavity reflector layer) may be provided below the resonant layer, and aluminum nitride may be provided as a protective layer above the resonant layer. Similarly, unless otherwise specified, the area of ​​the ultra-ultrasonic device mentioned in this application refers to the area of ​​the resonant region of the ultra-ultrasonic device.

[0054] The solution provided in this application is described in detail below with reference to the accompanying drawings and embodiments.

[0055] The embodiments of the present application propose a method for synthesizing liposomes and a liposome synthesis device for implementing the method. Through the coordinated design of the microfluidic structure and the ultra-ultrasonic device, the synthesis efficiency of the liposomes can be significantly improved, and the average particle size and uniformity of the products during the liposome synthesis process can be optimized.

[0056] like Figure 2 As shown, the present invention provides a method for synthesizing liposomes, which comprises:

[0057] S110: introducing the organic phase and aqueous phase into the two injection channels of the Y-shaped flow channel respectively;

[0058] S120: driving the ultra-sonic device in the shape of a regular pentagon disposed at the bottom of the synthesis channel of the Y-shaped flow channel to operate, at least when the device is operating, to generate micro-vortices in the liquid in the synthesis channel distributed at the positions of the respective sides of the regular pentagon to mix the two liquids in the synthesis channel to generate target liposomes.

[0059] In the embodiment of the present application, an organic phase and an aqueous phase are respectively introduced into two injection channels of a Y-shaped flow channel, so that the two liquids converge into the synthesis channel of the Y-shaped flow channel. Then, a regular pentagonal ultra-sonic device is set at the bottom of the synthesis channel and driven to work. The micro-vortices generated by the device during operation and distributed at the positions of the sides of the regular pentagon can generate local strong disturbances and flow field changes, promote molecular diffusion and convective mixing between the liquids, and significantly enhance the mixing effect of the organic phase and the aqueous phase in the synthesis channel, thereby generating target liposomes.

[0060] In some embodiments, the height of the synthesis channel also has a certain impact on the mixing results. For example, when the channel height is reduced from 140μm to 40μm, the particle size is further reduced under the same power and pulse conditions, with an average particle size of 110nm. At a low flow channel (40μm), the effect of different pulse conditions on particle size generation is more significant. The high flow channel (140μm) is compatible with the device's pulsed operating mode at powers of 1W and 2W; while at a low flow channel (40μm), the device is best operated in pulsed mode at 1W.

[0061] Reference Figure 3a As shown, a liposome synthesis device proposed in an embodiment of the present application includes:

[0062] A Y-shaped flow channel having two injection channels and a synthesis channel connected to the confluence of the two injection channels, the two injection channels being used to inject two liquids, an organic phase and an aqueous phase;

[0063] The ultra-sonic device in the shape of a regular pentagon is arranged at the bottom of the synthesis channel. When it is working, micro-vortices distributed at the positions of each side of the regular pentagon generated in the liquid in the synthesis channel mix the two liquids in the synthesis channel to generate target liposomes.

[0064] In some embodiments, the synthetic channel is linear in shape, with a width of 100 to 160 microns and a length of 500 to 6 mm. In a linear channel, the flow rate of the liquid is relatively uniform, which helps ensure a relatively stable mixing process within the channel and reduces fluctuations in the mixing effect caused by uneven flow rates.

[0065] In some embodiments, the ultra-sonic device operates in either continuous or pulsed mode, with a power of 250 to 400 milliwatts. In continuous mode, the ultra-sonic device continuously generates sound waves, creating a stable acoustic field within the synthesis channel. The continuous action of the sound waves exerts a continuous driving force on the liquid, helping to stably control the flow velocity and direction of the liquid within the synthesis channel. In pulsed mode, the duration and interval of the sound waves can be precisely controlled as needed to produce special flow field effects, such as transient vortices and jets. These special flow fields can be used for specialized microfluidic operations, such as particle capture, separation, and manipulation, opening up new application areas for microfluidic technology. Experimental simulation results show that, at the same power, the particle size synthesized in the continuous mode is smaller than or equal to that synthesized in the pulsed mode. Furthermore, when using the pulsed mode, for the same pulse duration, a shorter period results in a smaller particle size; for the same pulse duration, a longer pulse duration results in a smaller particle size.

[0066] In some embodiments, an organic phase and an aqueous phase are introduced through two inlet channels of a Y-shaped flow channel. The organic phase can be a mixture of DPPC (dipalmitoylphosphatidylcholine) and cholesterol, a mixture of DSPC (distearoylphosphatidylcholine) and cholesterol, or POPC (palmitoyloleoylphosphatidylcholine). The aqueous phase can be pure water. An ultra-sonic device is then used to generate an acoustofluidic tunnel in the liquid within the synthesis channel, corresponding to the edge of the contour of the ultra-sonic device. The two liquids within the synthesis channel are mixed through the acoustofluidic tunnel to generate a target liquid (e.g., a liposome solution).

[0067] In some embodiments, as Figure 3a As shown, the regular pentagonal super-ultrasonic device can be placed at the confluence of the two sampling channels and the synthesis channel, wherein the adjacent two sides of the regular pentagonal super-ultrasonic device face the two sampling channels respectively. The confluence of the two sampling channels and the synthesis channel is where the liquids from the two sampling channels converge. At this confluence, the liquids from the two sampling channels collide with each other at a certain angle and speed. Placing the super-ultrasonic device there can generate micro-vortices that can fully cover the liquid streams entering the synthesis channel, enabling mixing as soon as the liquids come into contact and begin to converge. This can fully utilize the momentum and energy of the liquids as they converge, and combined with the action of the micro-vortices, produce a uniform disturbance in the liquid, greatly shortening the start-up time of mixing and making the mixing process more efficient. In addition, one outer vertex of the regular pentagonal super-ultrasonic device is located on the boundary line of the two liquids in the synthetic channel (that is, the regular pentagonal structure is symmetrically arranged at the boundary line of the two liquids in the synthetic channel), so that the acoustic fluid effect generated by the super-ultrasonic device can be directly focused on the liquid boundary area. This precise positioning can effectively break the interfacial tension between the two liquids, promote the mutual penetration and diffusion between molecules, and significantly enhance the mixing effect.

[0068] Generally speaking, the area of ​​a hypersonic device is negatively correlated with its resonant frequency (natural frequency): the larger the area, the lower the resonant frequency. However, the resonant frequency of a hypersonic device is positively correlated with its ability to manipulate particles and microfluids. The higher the resonant frequency, the greater the device's ability to mix microfluids at the same drive power. Therefore, a smaller hypersonic device typically has a higher resonant frequency, generating stronger vortices and improving its ability to mix microscale fluids. For example, the mixing process can produce smaller particles. However, a smaller hypersonic device also reduces its effective range within the flow channel, which is disadvantageous for microfluidics that require mixing within a larger area. Furthermore, a smaller hypersonic device also results in a shorter acoustofluidic tunnel, which also negatively impacts the spatial range of microfluids that can be mixed. For example, for mixing high-throughput, multiphase fluids within a flow channel, a hypersonic device with a small area may result in insufficient mixing efficiency to generate nanoscale products due to the aforementioned two factors.

[0069] Based on this, Figure 3b As shown, in some embodiments of the present application, the ultra-sonic device may adopt an internal hollow regular pentagonal ring structure, wherein the internal hollow shape is a regular pentagon, and an outer vertex of the regular pentagonal ring structure is located at the boundary line of the two liquids flowing into the synthesis channel. Alternatively, as Figure 3c As shown, a smaller regular pentagon or regular pentagonal ring structure can be nested in the above-mentioned internally hollowed regular pentagonal ring structure.

[0070] based on Figure 3b-Figure 3c , this application adopts a regular pentagonal ring structure with internal hollowing or a regular pentagonal ring structure with large and small nesting, compared with Figure 3a The regular pentagonal structure shown has the same total area as a regular pentagonal structure, but the internal hollow or nested regular pentagonal ring structure can form a multi-level acoustic field distribution, with a larger effective range acting on the flow channel, and more locations where micro-vortices can be generated (with more acoustic fluid tunnels). When applied to the mixing of different liquids or reactions based on mixing, it also has a relatively good effect. For example, when different liquids flowing into different branches upstream of the flow channel flow through the ultra-ultrasonic device provided in the embodiments of the present application, the liquid in a larger range, under the action of more micro-vortices, forms turbulence or turbulence in more spaces, or passes through longer acoustic fluid tunnels, thereby achieving a better mixing effect, thereby generating target liposomes with a smaller average particle size and better uniformity.

[0071] based on Figure 3a-3c The present application also provides simulation results of related experiments based on the above embodiments of the present application. Figure 4a-4c and Figure 5As shown, under the same experimental conditions (same flow ratio, same power 400mW), using Figure 3a-3c The liposome synthesis device shown conducts synthesis experiments on two liquids, organic phase and aqueous phase, to evaluate the influence of ultra-sonic devices with different geometric structures on the liquid mixing effect in the liposome synthesis device, so as to further optimize the average particle size and uniformity (monodispersity coefficient) of the product during the liposome synthesis process.

[0072] in Figure 4a For use Figure 3a A schematic diagram of the simulation results of the synthesis experiment of the liposome synthesis device is shown. The simulation results show that the mixing area is concentrated near the pentagon vertices, but the overall mixing uniformity is average. Figure 4b For use Figure 3b A schematic diagram of the simulation results of the synthesis experiment of the liposome synthesis device is shown. The simulation results show that the internal hollow regular pentagonal ring structure helps to expand the range of the sound field and improve the local disturbance intensity. Figure 4c For use Figure 3c A schematic diagram of the simulation results of the synthesis experiment conducted by the liposome synthesis device shows that the nested structure of 20μm pentagonal rings and small pentagons exhibits the best mixing effect and the highest mixing frequency, indicating that this nested structure can more effectively promote mixing during the liposome synthesis process and help to achieve the generation of small-particle liposomes.

[0073] Figure 5 for Figure 4a-4c Schematic diagram of the mixing frequency comparison of the synthetic simulation, where the mixing frequency of the regular pentagonal structure is about 58%, the mixing frequency of the regular pentagonal ring structure with internal hollowing is about 82%, and the mixing frequency of the nested structure of pentagonal rings and small pentagons is about 96%, which is the optimal mixing frequency.

[0074] The simulation experiment results provided in the present application show that the total area of ​​the ultra-ultrasonic device with an internal hollow or nested regular pentagonal ring structure provided in the embodiment of the present application is unchanged compared with the ultra-ultrasonic device with a regular pentagonal structure, so the resonant frequency does not decrease significantly, and thus a relatively high resonant frequency can still be maintained. However, the overall area formed by the pentagons of the internal hollow or nested structure is larger than that of the regular pentagonal structure, and the number of locations where micro-vortices can be generated is increased. When applied to liquid mixing or mixing-based reactions, since more acoustic fluid tunnels can be generated, a larger space of turbulent or turbulent flow or a longer acoustic fluid tunnel can be formed as a whole, which is beneficial to the mixing or mixing reaction of different liquids or different particles in the liquid.

[0075] In some embodiments, when the organic phase and the aqueous phase flow into the synthesis channel in a certain ratio, the acoustic wave action generated by the ultra-sonic device can break the interfacial tension between the two phases, allowing the two phases of liquid to fully contact and mix. By adjusting the flow ratio of the organic phase and the aqueous phase, the degree of mixing can be precisely controlled. For example, when the flow ratio is close to 1:1, the amount of liquid in the two phases is relatively balanced, and the acoustic wave action can be more evenly dispersed in the two phases, forming a more stable mixed system. As the flow ratio increases from 1:1 to 1:9, the same power (250mW to 400mW) is applied, and the particle size decreases. When the flow ratio is 1:3 or 1:4, the water-alcohol interface is located in the middle, and the effective mixing area of ​​the device is the largest. When 400mW is applied, the average particle size is reduced to 120nm. When the flow ratio is increased to 1:9, the water-alcohol interface deviates from the center, and the minimum particle size reaches 58nm, but a miscellaneous peak appears at 500-1000nm, resulting in a large PDI (Polydispersity Index).

[0076] In summary, the liposome synthesis device provided in the embodiment of the present application, by setting a super ultrasonic device at the bottom of the synthesis channel of the Y-shaped flow channel, utilizes the micro-vortex generated by the super ultrasonic device during operation to generate local strong disturbances and flow field changes, promote molecular diffusion and convection mixing between liquids, and can significantly enhance the mixing effect of the two liquids in the synthesis channel. The design of the Y-shaped flow channel enables the two liquids to flow into the synthesis channel according to a predetermined ratio and flow rate, and the working parameters of the super ultrasonic device (such as frequency, power, etc.) can be precisely adjusted, thereby achieving precise control of the mixing process, thereby improving the mixing efficiency of the liquids.

[0077] It should be noted that the embodiments described in this application are only a part of the embodiments of this application, rather than all of the embodiments. The components of the embodiments of the present application generally described and shown in the accompanying drawings can be arranged and designed in various different configurations. Therefore, the above detailed description of the embodiments of the present application provided in the accompanying drawings is not intended to limit the scope of the application for protection, but merely represents selected embodiments of the present application. Based on the embodiments of the present application, all other embodiments obtained by those skilled in the art without making creative work are within the scope of protection of this application.

[0078] The words "first, second, third, etc." or module A, module B, module C and other similar terms in the specification and claims are only used to distinguish similar objects and do not represent a specific ordering of the objects. It is understandable that the specific order or sequence can be interchanged where permitted so that the embodiments of the present application described herein can be implemented in an order other than that illustrated or described herein.

[0079] In the above description, the numbers representing the steps involved do not necessarily mean that the steps must be executed. Intermediate steps may also be included or replaced by other steps. If permitted, the order of the previous and next steps may be interchanged or executed simultaneously.

[0080] The term "comprising" as used in the specification and claims should not be construed as limiting to what is listed thereafter; it does not exclude other elements or steps. Thus, it should be interpreted as specifying the presence of the features, integers, steps, or components mentioned, but not excluding the presence or addition of one or more other features, integers, steps, or components, or groups thereof. Thus, the expression "a device comprising means A and B" should not be limited to a device consisting solely of components A and B.

[0081] The term "one embodiment" or "an embodiment" mentioned in this specification means that the specific features, structures, or characteristics described in conjunction with the embodiment are included in at least one embodiment of the present application. Therefore, the phrases "in one embodiment" or "in an embodiment" appearing in various places in this specification do not necessarily refer to the same embodiment, but may refer to the same embodiment. In addition, in the various embodiments of the present application, unless otherwise specified or there is a logical conflict, the terms and / or descriptions between different embodiments are consistent and can be referenced to each other. The technical features in different embodiments can be combined to form new embodiments based on their inherent logical relationships.

[0082] Note that the above are only preferred embodiments of the present application and the technical principles used. Those skilled in the art will understand that the present invention is not limited to the specific embodiments described herein, and that various obvious changes, readjustments, and substitutions can be made by those skilled in the art without departing from the scope of protection of the present invention. Therefore, although the present application has been described in more detail through the above embodiments, the present invention is not limited to the above embodiments, and may include many other equivalent embodiments without departing from the concept of the present invention, all of which fall within the scope of protection of the present invention.

Claims

1. A method for synthesizing liposomes, characterized in that: include: The organic phase and the aqueous phase are respectively introduced into the two injection channels of the Y-shaped flow channel; the Y-shaped flow channel includes the two injection channels and a synthesis channel connected to the confluence of the two injection channels; The ultra-sonic device in the shape of a regular pentagon disposed at the bottom of the synthesis channel is driven to operate, and at least when the ultra-sonic device is in operation, micro-vortices generated in the liquid in the synthesis channel and distributed at the positions of the respective sides of the regular pentagon are used to mix the two liquids in the synthesis channel to generate target liposomes.

2. The method according to claim 1, characterized in that The ultra-ultrasonic device is arranged at the confluence of the two sampling channels and the synthesis channel, wherein two adjacent sides of the regular pentagonal ultra-ultrasonic device face the two sampling channels respectively.

3. The method according to claim 1 or 2, characterized in that The shape of the ultra-sonic wave device forms a regular pentagonal ring structure with a hollow interior, and an outer vertex of the regular pentagonal ring structure is located on the boundary line of the two liquids flowing into the synthesis channel; At least when the ultra-sonic device is working, micro-vortices generated in the liquid in the synthesis channel and distributed at the inner and outer sides of the regular pentagonal ring mix the two liquids in the synthesis channel to generate target liposomes.

4. The method according to claim 3, characterized in that The shape of the ultra-sonic wave device forms a regular pentagonal ring structure with a hollow interior, wherein an outer vertex of the regular pentagonal ring structure is located at the boundary line of the two liquids flowing into the synthesis channel; a second regular pentagon or a second regular pentagonal ring structure is nested within the regular pentagonal ring structure; At least when the ultra-sonic device is operating, micro-vortices generated in the liquid in the synthesis channel and distributed at the positions of the inner and outer sides of the regular pentagonal ring, the positions of the sides of the nested second regular pentagon, or the positions of the inner and outer sides of the second regular pentagonal ring mix the two liquids in the synthesis channel to generate target liposomes.

5. A liposome synthesis device for implementing the liposome synthesis method according to any one of claims 1 to 4, characterized in that: include: A Y-shaped flow channel, the Y-shaped flow channel comprising two injection channels and a synthesis channel connected to the confluence of the two injection channels, the two injection channels being used to inject two liquids, an organic phase and an aqueous phase; The ultra-sonic device in the shape of a regular pentagon is arranged at the bottom of the synthesis channel. When it is working, micro-vortices distributed at the positions of each side of the regular pentagon generated in the liquid in the synthesis channel mix the two liquids in the synthesis channel to generate target liposomes.

6. The device according to claim 5, characterized in that The ultra-ultrasonic device is arranged at the confluence of the two sampling channels and the synthesis channel, wherein two adjacent sides of the regular pentagonal ultra-ultrasonic device face the two sampling channels respectively.

7. The device according to claim 5 or 6, characterized in that The shape of the ultra-sonic wave device forms a regular pentagonal ring structure with a hollow interior, and an outer vertex of the regular pentagonal ring structure is located on the boundary line of the two liquids flowing into the synthesis channel; At least when the ultra-sonic device is working, micro-vortices generated in the liquid in the synthesis channel and distributed at the inner and outer sides of the regular pentagonal ring mix the two liquids in the synthesis channel to generate target liposomes.

8. The device according to claim 5, characterized in that The shape of the ultra-sonic wave device forms a regular pentagonal ring structure with a hollow interior, wherein an outer vertex of the regular pentagonal ring structure is located at the boundary line of the two liquids flowing into the synthesis channel; a second regular pentagon or a second regular pentagonal ring structure is nested within the regular pentagonal ring structure; At least when the ultra-sonic device is operating, micro-vortices generated in the liquid in the synthesis channel and distributed at the positions of the inner and outer sides of the regular pentagonal ring, the positions of the sides of the nested second regular pentagon, or the positions of the inner and outer sides of the second regular pentagonal ring mix the two liquids in the synthesis channel to generate target liposomes.

9. The device according to claim 5, characterized in that The synthetic channel is linear in shape, has a width of 100 micrometers to 160 micrometers, and a length of 500 micrometers to 6 millimeters.

10. The device according to claim 9, characterized in that The ultra-ultrasonic device adopts a continuous working mode or a pulsed working mode, and the power is 250 mW-400 mW; The flow ratio of the organic phase to the aqueous phase is 1:1-1:9.

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