Device and method for realizing particle modification

Abstract

The invention provides a device and a method for realizing particle modification, the device comprises a first flow channel and an acoustic resonator capable of acting on liquid in the first flow channel, the acoustic resonator is fusiform, and the acoustic resonator is used for generating an acoustic fluid effect in the liquid in the first flow channel to capture first particles in the first liquid, the captured first particles are distributed and flow along the fusiform profile of the acoustic resonator, so that the first particles distributed to the side edge of the fusiform profile are controllably mixed with the second liquid in the side edge area, and the controllable mixing is used for controllably combining the second particles in the second liquid with the first particles; the first particles combined with the second particles flow to a fourth flow channel along the tip of the rear end of the fusiform profile of the acoustic resonator; and the first liquid flowing through the first flow channel flows to the two fifth flow channels.

Description

Technical Field

[0001] The present application relates to the technical fields of micro-electromechanical, biomedical technology, chemical engineering, etc., and in particular to a device and method for realizing particle modification. Background Art

[0002] In the technical fields of medicine, biotechnology, chemical engineering, etc., it is common to encounter scenarios where other targets are modified on a particle, such as using a particle as a carrier to modify other particles. How to improve the controllability of the modification process, improve the effect of the modification (such as strong uniformity, etc.), and be able to easily separate the modified particles to improve the efficiency of the overall modification process are technical issues that have always been concerned in research and development. The following is an example of modifying nanoparticles (NPs) on red blood cells (RBC):

[0003] Red blood cells can be used as carriers for the delivery of drug-loaded nanoparticles. Compared with free drugs, drug-loaded nanoparticles show significant advantages in targeting and sustained release, but they are easily cleared by the mononuclear phagocyte system in the spleen and liver, which leads to a reduction in the dose at the site of action, thereby reducing its therapeutic effect. In order to solve this problem, loading (i.e., modifying) drug-loaded NPs onto the surface of red blood cells can allow the drug to circulate in the blood for a long time, thereby improving the efficiency of drug delivery, effectively extending the circulation time of drug-loaded NPs in the body, and solving the common problem of premature clearance in the delivery of drug-loaded NPs. This form of administration is also called "red blood cell hitchhiking."

[0004] At present, most of the methods for loading NPs on the surface of red blood cells are to change the interaction with the red blood cell membrane by adjusting the properties of NPs (including size, surface charge, surface structure, etc.), thereby generating different adhesion forces and the number of adhered NPs to be loaded on the surface of red blood cells. This process usually involves an incubation process (a process for modifying NPs and loading them into red blood cells) and multiple centrifugation processes (for removing excess unbound NPs to obtain red blood cells modified with NPs). The overall scheme is complex and time-consuming, with poor controllability and a low level of automation, resulting in low production efficiency.

[0005] Therefore, how to improve the controllability of particles used as carriers to modify other particles (such as red blood cells modified with drug-loaded NPs), reduce the overall complexity, and improve production efficiency are technical problems that need to be solved. Summary of the invention

[0006] In view of the above problems in the prior art, the present application provides a device and method for realizing particle modification to solve the technical problems mentioned in the background technology.

[0007] To achieve the above-mentioned purpose, the first aspect of the present application provides a device for realizing particle modification, comprising: a first flow channel; a second flow channel and two third flow channels connected to the upstream of the first flow channel, wherein the two third flow channels are located on both sides of the second flow channel, the second flow channel is used to pass a first liquid containing first particles, and the two third flow channels are used to pass a second liquid containing second particles, and the second liquid passed through the two third flow channels forms a sheath flow; a fourth flow channel and two fifth flow channels connected to the downstream of the first flow channel, wherein the two fifth flow channels are located on both sides of the fourth flow channel; an acoustic resonator that can act on the liquid in the first flow channel, the acoustic resonator being shuttle-shaped, with its front end and The tip of the rear end faces the direction of the second flow channel and the fourth flow channel respectively; the acoustic resonator is used to generate an acoustic fluid effect in the liquid in the first flow channel to capture the first particles in the first liquid, so that the captured first particles flow along the shuttle-shaped contour of the acoustic resonator, so that the first particles distributed to the side of the shuttle-shaped contour can be controllably mixed with the second liquid in the side area, and the controllable mixing can achieve controllable combination of the second particles in the second liquid with the first particles; the first particles combined with the second particles flow toward the fourth flow channel along the rear end tip of the shuttle-shaped contour of the acoustic resonator; the first liquid after flowing through the first flow channel flows toward the two fifth flow channels.

[0008] Optionally, the caliber of the fourth flow channel inlet is smaller than the caliber of the fifth flow channel inlet.

[0009] Optionally, it also includes: adjusting the pressure of the fourth flow channel to control the flow distribution between the fourth flow channel and the two fifth flow channels, so as to facilitate the first particles combined with the second particles to flow into the fourth flow channel, and facilitate the first liquid after flowing through the first flow channel to flow to the two fifth flow channels.

[0010] Optionally, it also includes at least one of the following: the upstream of the second flow channel is connected to a first inlet; the upstream of the two third flow channels are connected to a second inlet; the downstream of the fourth flow channel is connected to a third outlet; the downstream of the two fifth flow channels is connected to a fourth outlet.

[0011] Optionally, the selection of the height of the first flow channel and the selection of the power of the acoustic resonator are related to the first particles and the second particles.

[0012] Optionally, the particle size of the first particle is larger than the particle size of the second particle; at the current height of the first flow channel, the power of the acoustic resonator is controlled so that it can capture the first particle, so that the captured first particle flows along the shuttle-shaped contour of the acoustic resonator, and the first particle combined with the second particle flows to the downstream fourth flow channel at the rear end tip; and the power of the acoustic resonator is such that the second particle is not concentrated at the rear end tip and flows downstream.

[0013] Optionally, the acoustic-fluid effect generated by the acoustic resonator also induces the second particles to flow along the periphery of the shuttle-shaped profile of the acoustic resonator, so that the first particles distributed to the sides of the shuttle-shaped profile can be controllably mixed with the second liquid flowing in the side areas and around the shuttle-shaped profile.

[0014] Optionally, the controllable mixing is achieved by at least one of: by controlling the power of the acoustic resonator; by controlling the flow rate of the first liquid, the flow rate of the second liquid, the flow rate ratio of the first liquid to the second liquid, or the total flow rate of the first liquid and the second liquid.

[0015] Optionally, the first particle includes a carrier, and the carrier includes at least one of the following: cells, red blood cells, T cells, NK cells, stem cells, liposomes, and microspheres; the second particle includes nano- or micron-particles, and the nano- or micron-particles contain at least one of the following: drug-loaded nanoparticles, polymer nanoparticles, inorganic nanoparticles, metal nanoparticles, composite nanoparticles, magnetic nanoparticles, proteins, polypeptides, molecules, and supramolecules.

[0016] The second aspect of the present application provides a method for achieving particle modification, using any device for achieving particle modification described in the first aspect, the method comprising: passing a first liquid containing a first particle into a second flow channel; passing a second liquid containing a second particle into two third flow channels, the second liquids passed into the two third flow channels forming a sheath flow; driving an acoustic resonator to work, generating an acoustic-fluid effect in the liquid in the first flow channel, capturing first particles in the first liquid based on the acoustic-fluid effect, causing the captured first particles to flow along the shuttle-shaped contour of the acoustic resonator, causing the first particles distributed to the side of the shuttle-shaped contour to be controllably mixed with the second liquid in the side area to achieve the combination of the second particles in the second liquid with the first particles; the first particles combined with the second particles flow to the fourth flow channel along the rear end tip of the shuttle-shaped contour of the acoustic resonator; the first liquid after flowing through the first flow channel flows to the two fifth flow channels.

[0017] Among them, the scheme of the embodiment of the present application can be applied to load NPs onto the surface of RBCs. For example, RBCs and 200 nanometer positively charged fluorescent particles are selected as experimental models. The surface of RBC is negatively charged, while the surface of NPs is positively charged. Due to electrostatic interaction, this promotes their binding. In this embodiment, the distribution and movement of RBCs and NPs under the acoustic flow effect are studied, and the appropriate flow rate and input power are determined to control the NPs loading process. By adjusting the contact time between red blood cells and NPs, the loading amount of NPs can be adjusted to ensure that the loading of NPs on the surface of red blood cells is uniform and controllable. On the other hand, in the embodiment of the present application, the design of the size and structure of the microchannel matches the resonator, so that the RBC sample after modification of NPs can be directly obtained, eliminating the steps of repeated centrifugation and washing required in the traditional method. The scheme of this embodiment has the characteristics of high uniformity of RBC modified with NPs, controllability and automation of the modification process. BRIEF DESCRIPTION OF THE DRAWINGS

[0018] Figure 1 It is a schematic diagram of the structure of a device for realizing particle modification provided in the first embodiment of the present application;

[0019] Figure 2 2 are graphs showing the capture effects of two particles provided in the embodiments of the present application at different channel heights and powers, wherein (a) is a graph showing the capture effects of 200 nm particles at different channel heights and powers, and (b) is a graph showing the capture effects of 5 μm particles at different channel heights and powers;

[0020] Figure 3 Schematic diagram of the characterization of particle manipulation provided by the embodiment of the present application, wherein (a) is a schematic diagram of the microchannel structure, (i) is a local enlarged view of the position within the red dotted line frame, (ii) is a top view of the assembled resonator and microchannel, (b) is a distribution diagram of two particles at different powers, (c) is a result diagram of NPs removal rate, the vertical axis represents the concentration ratio between the fourth outlet and the second inlet, and the horizontal axis represents the input power of the resonator;

[0021] Figure 4 : The present application provides a comparative diagram, wherein (a), (b) and (c) are diagrams of flow cytometry of microfluidics and incubation methods at different particle concentrations (from left to right: 0.04 mg / mL, 0.1 mg / mL and 0.2 mg / mL), (d) is a diagram of loading efficiency of nanoparticles (concentration: 0.04 mg / mL) at different input powers, (e) is a diagram of the percentage of positive cells, and (f) is a diagram of statistical data of fluorescence intensity;

[0022] Figure 52 are graphs of biocompatibility characterization provided in the embodiments of the present application, wherein (a) shows CLSM images of erythrocytes loaded with NPs displayed in (i) bright field, (ii) erythrocyte fluorescence field, (iii) NPs, and (iv) merge (captured at a power of 1360 mW and a NPs concentration of 0.2 mg / mL), (b) is a confocal layer scanning image of a single erythrocyte, (c) is a SEM image of natural erythrocytes and erythrocytes loaded with NPs, and (d) is a graph of hemolysis results at different input powers;

[0023] Figure 6 It is a schematic diagram of the structure of a device for realizing particle modification provided in another embodiment of the present application.

[0024] It should be understood that the size and shape of each block diagram in the above structural diagram are for reference only and should not constitute an exclusive interpretation of the embodiment of the present invention. The relative position and inclusion relationship between the blocks presented in the structural diagram are only schematic representations of the structural association between the blocks, and do not limit the physical connection method of the embodiment of the present invention. DETAILED DESCRIPTION

[0025] The technical solution provided by the present 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 the present application are mainly to illustrate the possible implementation methods of the technical solution of the present application and should not be interpreted as the only limitation on the technical solution of the present application. It is known to those of ordinary skill in the art that with the evolution of the system structure and the emergence of new business scenarios, the technical solution provided by the present application is also applicable to similar technical problems.

[0026] It should be understood that the embodiments of the present application provide a solution for implementing particle modification, including a device and method for implementing particle modification, and applications thereof. Since the principles of solving the problems in these technical solutions are the same or similar, some repetitions may not be repeated in the following specific embodiments, but it should be considered that these specific embodiments have been referenced to each other and can be combined with each other.

[0027] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by technicians in the technical field of this application. In the event of any inconsistency, the meaning described in this specification or the meaning 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 the present application and are not intended to limit the present 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 to the terms used in this specification before describing the specific embodiments:

[0028] 1) Sheath flow focusing, a flow cytometer fluid system that uses fluid dynamics to focus cells in a liquid. The principle is to use a faster-moving sheath fluid to force the sample into a smaller core flow (also called a hydrodynamic core, i.e., laminar flow near the axis), where each particle in the core flow travels along the same axis at approximately the same speed. Once the sample enters the core flow, it can be detected by a laser detection point.

[0029] Two-dimensional sheath flow focusing refers to the sheath flow focusing function based on micro-electromechanical systems (MEMS), such as microfluidics. Since the sheath flow and the sample flow are located in the same plane, it is called two-dimensional sheath flow focusing.

[0030] It should be noted that, in the present application, structures that can realize laminar flow in a microchannel are collectively referred to as two-dimensional sheath flow structures.

[0031] 2) Acoustic resonator: refers to a resonator that can emit sound waves, wherein the vibration frequency of the acoustic resonator in the present application is about 0.5-30 GHz, preferably about 1-10 GHz, and more preferably about 1-5 GHz. The acoustic resonator can be a bulk acoustic wave resonator (BAW), a surface acoustic wave resonator (SAW), etc. The bulk acoustic wave resonator has a higher vibration frequency than the surface acoustic wave resonator.

[0032] Bulk acoustic wave resonator: under the stimulation of input signals, it generates ultra-high frequency vibrations and emits bulk acoustic waves. The propagation of bulk acoustic waves in the fluid induces directional movement of the fluid and forms fluid vortices. One of the phenomena is that a number of tiny fluid vortices can be generated in the fluid at the edge of the chip contour of the bulk acoustic wave resonator. These fluid vortices can capture particles in the liquid. Combined with the position distribution of these fluid vortices, the particles in the liquid are distributed at the edge of the chip contour of the bulk acoustic wave resonator. Since the particles in the fluid will flow through these fluid vortices distributed at the edge of the chip contour, the flow path of the particles formed by these fluid vortices is referred to as an acoustic fluid tunnel in this application. The particles flowing through the acoustic fluid tunnel under the combined action of the fluid and the vortex can take a spiral path.

[0033] The first embodiment of the present application provides a device for implementing particle modification, which can be seen in Figure 1 or Figure 6 In the example shown in a, the device may include:

[0034] First flow channel;

[0035] A second flow channel and two third flow channels connected to the upstream of the first flow channel, wherein the two third flow channels are located on both sides of the second flow channel, the second flow channel is used to pass a first liquid containing first particles, and the two third flow channels are used to pass a second liquid containing second particles, and the second liquid passed through the two third flow channels forms a sheath flow;

[0036] A fourth flow channel and two fifth flow channels connected to the downstream of the first flow channel, wherein the two fifth flow channels are located on both sides of the fourth flow channel;

[0037] An acoustic resonator capable of acting on the liquid in the first flow channel, wherein the acoustic resonator is in a shuttle shape, and the tips of the front end and the rear end thereof are respectively directed toward the second flow channel and the fourth flow channel;

[0038] The acoustic resonator is used to generate an acoustic fluid effect in the liquid in the first flow channel to capture first particles in the first liquid, so that the captured first particles flow along the shuttle-shaped profile of the acoustic resonator, so that the first particles distributed to the side of the shuttle-shaped profile are controllably mixed with the second liquid in the side area, and the controllable mixing is used to controllably combine the second particles in the second liquid with the first particles;

[0039] The first particles combined with the second particles flow toward the fourth flow channel along the rear end tip of the shuttle-shaped profile of the acoustic resonator; and the first liquid flowing through the first flow channel flows toward the two fifth flow channels.

[0040] In some embodiments, the caliber of the inlet of the fourth flow channel is smaller than the caliber of the inlet of the fifth flow channel. Since the first particles combined with the second particles are released downstream along the rear end tip of the acoustic resonator, the caliber of the inlet of the fourth flow channel facing the rear end tip of the acoustic resonator can be smaller, and the caliber of the inlet of the fifth flow channel can be larger, which can facilitate the liquid containing the unreacted second particles to carry the second particles to flow to the fifth flow channel.

[0041] In some embodiments, the pressure of the fourth flow channel can be adjusted to control the flow distribution between the fourth flow channel and the two fifth flow channels, so as to facilitate the first particles combined with the second particles to flow into the fourth flow channel, and facilitate the first liquid flowing through the first flow channel to flow to the two fifth flow channels. In some embodiments, the third outlet of the fourth flow channel is externally connected to a flexible tube, and the flexible tube has a flow regulating device (such as an adjustable clamping device, etc.) to regulate the pressure of the fourth flow channel.

[0042] In some embodiments, Figure 1 As shown, it also includes at least one of the following: the upstream of the second flow channel is connected to a first inlet; the upstream of the two third flow channels are connected to a second inlet; the downstream of the fourth flow channel is connected to a third outlet; the downstream of the two fifth flow channels is connected to a fourth outlet.

[0043] In some embodiments, the selection of the height of the first flow channel and the selection of the power of the acoustic resonator are related to the first particle and the second particle. In some embodiments, when the height of the first flow channel and the power of the acoustic resonator are certain selected values, the acoustic resonator has different capture capabilities for the first particle and the second particle, for example, the capture capability of the first particle or the first particle combined with the second particle is stronger than the capture capability of the second particle.

[0044] In some embodiments, the particle size of the first particle is larger than the particle size of the second particle; at the current height of the first flow channel, the power of the acoustic resonator is controlled so that it can capture the first particle, so that the captured first particle flows along the shuttle profile distribution of the acoustic resonator and combines with the first particle, and the first particle combined with the second particle flows to the downstream fourth flow channel at the rear end tip; and the power of the acoustic resonator is such that the second particle is not concentrated at the rear end tip and flows downstream. That is, the acoustic resonator at this power has a stronger ability to capture the first particle, or the first particle combined with the second particle, than the second particle.

[0045] In some embodiments, the acoustic fluid effect generated by the acoustic resonator also induces the second particles to flow along the periphery of the shuttle-shaped contour of the acoustic resonator, so that the first particles distributed to the side of the shuttle-shaped contour are controllably mixed with the second liquid distributed and flowing in the side area and around the shuttle-shaped contour. Among them, the acoustic resonator at this power has a stronger ability to capture the first particles, or the first particles combined with the second particles, than the second particles. Therefore, the second particles are distributed around the contour and have a larger distribution range than the first particles. Since the acoustic resonator also has an inducing effect on the second particles, the second particles are also distributed around the shuttle-shaped contour of the acoustic resonator, increasing the probability of contact and collision with the first particles, thereby enhancing the binding effect.

[0046] In some embodiments, the controllable mixing is achieved by at least one of: by controlling the power of the acoustic resonator; by controlling the flow rate of the first liquid, the flow rate of the second liquid, the flow rate ratio of the first liquid to the second liquid, or the total flow rate of the first liquid and the second liquid.

[0047] In some embodiments, the first particle comprises a carrier, and the carrier comprises at least one of the following: cells, red blood cells, T cells, NK cells, stem cells, liposomes, and microspheres; the second particle comprises nanoparticles, and the nanoparticles contain at least one of the following: drug-loaded nanoparticles, polymer nanoparticles, inorganic nanoparticles, metal nanoparticles, composite nanoparticles, magnetic nanoparticles, proteins, polypeptides, molecules, and supramolecules.

[0048] In some embodiments, the nanoparticles may also be micron particles. In some embodiments, the carrier-modified particles may be, for example, drug-loaded nanoparticles modified on cells (such as red blood cells, T cells, etc.), small molecules modified on the cell surface, proteins or polypeptides modified on the microsphere surface, and the like.

[0049] In some embodiments, the acoustic resonator includes a single BAW resonator, a single SAW resonator, or a combination of two or more acoustic resonators, such as a combination of two BAW resonators, or a combination of an integrated SAW resonator and a SAW resonator. The combination described herein includes a parallel combination or a series combination.

[0050] For example, the parallel combination includes: acoustic resonators are arranged in parallel in the first flow channel, and the width of the first flow channel can accommodate the parallel acoustic resonators. Such a structure can achieve a higher flux. Correspondingly, multiple fourth flow channels corresponding to the rear ends of the multiple acoustic resonators can be set, and the downstream of these fourth flow channels can converge into one outlet. Alternatively, another acoustic resonator for particle capture is set downstream of the first flow channel to capture the first particles combined with the second particles flowing upstream, and then release the captured particles to the corresponding fourth flow channel through the other acoustic resonator.

[0051] For example, the series combination includes: acoustic resonators are sequentially arranged upstream and downstream in the first flow channel, and the length of the first flow channel can accommodate the parallel acoustic resonators. Such a structure can realize sequentially controllable reactions through multiple acoustic resonators, and can extend the controllable mixing reaction time to achieve a mixing reaction of the required time. According to actual needs, there can be multiple parallel and series connections, or they can be mixed and used.

[0052] For example, a plurality of acoustic resonators may be sequentially arranged along the extension direction of the first flow channel, so as to further prolong the reaction time between the first liquid and the second liquid.

[0053] In some embodiments, Figure 6 As shown in b, the third flow channel connected to the upstream of the first flow channel and the fifth flow channel connected to the downstream of the first flow channel can also be one, wherein the third flow channel forms a single-sided sheath flow. In this solution, the utilization rate of the acoustic resonator will be lower than Figure 1 or Figure 6 The a plan.

[0054] In some embodiments, the acoustic resonator is disposed on the channel wall of the first flow channel, and its position covers the first liquid and the second liquid, and the mixing of the two liquids is completed in the area covered by the acoustic resonator. For example, the front end of the contour of the acoustic resonator covers the first liquid at a position on the fluid channel wall, and at least one side covers the second liquid at a position on the fluid channel wall, thereby achieving the above-mentioned controllable mixing of the first liquid inducing the second liquid in the sheath flow layer. Figure 6 FIG. a shows an embodiment in which a portion of both sides of the acoustic resonator extends into the laminar flow region of the sheath flow (i.e., the second liquid) to induce the first liquid in the laminar flow to flow along both sides and react with the second liquid in the two sheath flow layers in a controllable manner. Figure 6 b shows another embodiment, in which the two-dimensional sheath flow and the first liquid form two layers of laminar flow, and the first liquid is confined to one side of the sheath flow laminar flow (i.e., the laminar flow formed by the second liquid). The front end of the acoustic resonator profile is located in the laminar flow region of the first liquid, and a portion of one side of the acoustic resonator extends into the laminar flow region of the sheath flow (i.e., the second liquid) to induce the first liquid in the laminar flow to flow along the above-mentioned side distribution and controllably mix and react with the second liquid in the sheath flow layer.

[0055] In some embodiments, the vibration frequency of the acoustic resonator is about 0.5-30 GHz, preferably about 1-10 GHz, and more preferably about 1-5 GHz. When the vibration frequency is above 1 GHz, the effect of inducing the first liquid in the laminar flow to flow from the front end of the acoustic resonator contour along the side of the acoustic resonator is very obvious, and the thermal effect is low. When the vibration frequency is below 5 GHz, it is easier to control, so the above is more preferably about 1-5 GHz. On the other hand, the bulk acoustic wave resonator has a higher vibration frequency than the surface acoustic wave resonator, so when the vibration frequency is to be higher, the bulk acoustic wave resonator can be preferably used.

[0056] The acoustic resonator is preferably in a shuttle shape, for example, a shuttle shape with smooth sides includes an angular front end, two side edges extending along the two sides of the angle, and a rear end with the two side edges closed at the downstream side to form a pointed tip. In other embodiments, acoustic resonators with pointed or acute angles at the front and rear ends can also be applied to the embodiments of the present application, such as a rhombus, a polygonal shape similar to a shuttle shape, a spindle-shaped structure, etc.

[0057] A second embodiment of the present application provides a method for implementing particle modification, using any of the above-mentioned devices for implementing particle modification, the method comprising:

[0058] Passing a first liquid containing first particles into a second flow channel;

[0059] Passing a second liquid containing second particles into two third flow channels, wherein the second liquid passed into the two third flow channels forms a sheath flow;

[0060] The acoustic resonator is driven to work, an acoustic fluid effect is generated in the liquid in the first flow channel, first particles in the first liquid are captured based on the acoustic fluid effect, the captured first particles are distributed and flow along the shuttle-shaped profile of the acoustic resonator, and the first particles distributed to the side of the shuttle-shaped profile are controllably mixed with the second liquid in the side area, so as to realize the combination of the second particles in the second liquid and the first particles;

[0061] The first particles combined with the second particles flow toward the fourth flow channel along the rear end tip of the shuttle-shaped profile of the acoustic resonator; and the first liquid flowing through the first flow channel flows toward the two fifth flow channels.

[0062] In some embodiments, controllable mixing of the first particles and the second particles is achieved by controlling the power of the acoustic resonator, controlling the flow rate of the first liquid, the flow rate of the second liquid, the flow rate ratio of the first liquid to the second liquid, or the total flow rate of the first liquid and the second liquid, thereby achieving controllable binding (modification) of the second particles to the first particles.

[0063] In order to better understand the present application, the experimental process of the third embodiment provided in the present application is described in detail below. In this embodiment, red blood cells (RBC) are used as the first particles, and drug-loaded NPs are used as the second particles, and the NPs are modified to RBC through the scheme of the present application.

[0064] In this embodiment, the proposed acoustofluidic platform (i.e. Figure 1 The device shown in the figure not only realizes the loading of NPs onto the RBC surface, but also integrates the structure of removing unbound NPs into one device. Among them, the working mechanism of the acoustic resonator is that high-frequency vibration reduces the attenuation distance of sound waves in the liquid, resulting in rapid attenuation inside the liquid, thereby increasing the body force to drive the fluid flow, forming an acoustic streaming effect, and at the same time, due to the constraint effect of the microchannel structure, the liquid in the microchannel presents a vortex flow pattern. At the same time, the pressure applied by the inlet generates a velocity along the positive x-axis, which ultimately causes the liquid to flow in a spiral in the microchannel. Studies have shown that cells or particles flowing through microchannels are affected by both the acoustic radiation force and the resistance caused by the acoustic field. The intensity of the acoustic radiation force acting on the particle is closely related to its size, and larger particles are subjected to greater forces. This size-related force leads to different distribution patterns of particles of different sizes in the microchannel. Therefore, the unique edge orientation of the resonator can control the distribution and direction of fluids and objects.

[0065] The PDMS microchannel is designed with two inlets and two outlets ( Figure 1). The second inlet is divided into two branches for sheath flow of NPs, while the first inlet is used to inject the pretreated RBC suspension. The third outlet is used as a collection port for the modified RBC sample, and the fourth outlet merges the two outlet branches into one for flowing out excess free NPs. This structure of the present application realizes the direct collection of red blood cell samples from the third outlet, while transferring excess unbound NPs to the fourth outlet. This allows NPs to be loaded onto the surface of RBC without the centrifugation mentioned in the background technology.

[0066] In a low Reynolds number microfluidic system, the RBCs and NPs suspensions form a three-phase laminar flow device working area in the microfluidic system, with RBCs occupying the middle phase and the sheath flow of NPs maintained on both sides. When entering the acoustic resonator, the first and second particles show different behaviors in the microchannel due to the difference in size and position in the first flow channel. Larger RBCs are subject to greater acoustic radiation forces in the resonance region, causing them to exhibit a spiral flow along the edge of the acoustic resonator and eventually release at the end of the acoustic resonator. On the other hand, smaller NPs are subject to very small acoustic radiation forces, causing them to move with the fluid. During this process, NPs adhere to the surface of RBCs through electrostatic interactions. In addition, the number of rotations of RBCs along the edge of the device determines the length of the motion path, which can be adjusted by changing the input power of the acoustic resonator. This adjusts the contact time between RBCs and NPs and controls the loading amount of NPs on RBCs.

[0067] The experimental process of this embodiment is described in detail below:

[0068] 1. Introduction to the Experimental Process

[0069] 1.1. Determine the parameters of the microfluidic chip

[0070] First, the “fixed” geometric parameters (the height of the first flow channel) are determined by simulation, and then variable parameters such as power and flow rate are determined by experiments.

[0071] In this platform, we expect that the acoustic flow will exert stronger manipulation on particles of larger size and move them along the edge of the device. At the same time, the capture of smaller particles is minimized, ensuring that a large number of larger particles can flow out from the third outlet while minimizing the doping of small particles. Therefore, the RBC sample loaded with nanoparticles can be collected directly from the third outlet without further purification steps such as centrifugation. Studies have shown that for the acoustic fluidic platform, the input power and the height of the microchannel are the main factors that determine whether particles will be captured at the edge of the device. Therefore, in order to determine the optimal height of the microchannel (i.e., the first flow channel) of our microfluidic chip, we studied the movement and distribution of particles in microchannels with heights of 20, 40, 80, and 100 μm under different input power conditions. Figure 2Figure a shows the results of 200nm particles in microchannels of different heights with powers ranging from 460mW to 1660mW. The 200nm particle suspension was injected into both the second and first inlets, where the flow rate of the second inlet was 5μL / min and the flow rate of the first inlet was 0.5μL / min. He showed that reducing the height of the microchannel and increasing the input power can enhance particle capture. For example, the capture effect of 200nm particles in a 20μm microchannel is very obvious. However, when the microchannel height is 40μm and the power is lower than 760mW, or when the height is 80μm or 100μm and the power is lower than 1660mW, there is no significant capture of 200nm particles. Therefore, we further studied microchannels with heights of 40, 80, and 100μm, for a total of 5μm particles. As Figure 2 As shown in b, the second inlet is injected with ultrapure water (UP water) at a flow rate of 5 μL / min, while the first inlet is injected with a 5 μm particle suspension at a flow rate of 0.5 μL / min. However, for the 40 μm high microchannel, although there is no significant capture of 200 nm particles at low power (460 mW), the capture of 5 μm particles is also unsatisfactory. Similarly, for the 100 μm high microchannel, when the power is lower than 1660 mW, there is no obvious capture of 200 nm particles, but the manipulation of 5 μm particles is also ineffective. After comprehensive consideration, we finally decided to use a microchannel height of 80 μm and powers of 760, 1060, and 1360 mW for further research, because these conditions can effectively capture 5 μm particles, while there is almost no obvious capture on 200 nm particles. It can be seen that the conditions for the capture of particle size are related to the height of the microchannel (i.e., the first flow channel) and the input power of the acoustic resonator. Based on this, when it is necessary to capture particles of different sizes, the microchannel height and input power conditions for capturing particles of different sizes can be obtained through experiments, and then the appropriate microchannel height and input power can be selected.

[0072] 1.2. Characterization of sample collection

[0073] In order to investigate the performance of the platform in removing small particles while recovering large particles, polystyrene spheres with diameters of 5 μm and 200 nm were first used as model particles for the experiment. Figure 3 As shown in a, 200nm and 5μm polystyrene microsphere suspensions are injected from the second inlet and the first inlet respectively. The third outlet is used to collect 5μm particles and the fourth outlet is used to collect 200nm particles. During the experiment, the height of the collection tube is adjusted to adjust the pressure at the outlet, thereby controlling the flow distribution between the two outlets to ensure that as many 5μm particles as possible flow out of the third outlet and 200nm particles flow out of the fourth outlet. The video snapshot shows the particle flow distribution at different input powers in the resonator working area ( Figure 3b), where orange is 5μm particles and green is 200nm particles. The results show that when the device is turned off, the 200nm particle suspensions on both sides are sandwiched by the 5μm particle suspension in the middle, forming a three-phase laminar flow. In this case, almost all 5μm particles are able to flow out of the middle outlet, while 200nm particles flow out of the side branches. Once the device is activated, the trajectory of the particles changes significantly due to the acoustic streaming effect. After entering the working area, the 5μm particles initially spiral along the edge of the resonance area, then converge toward the middle branch, and finally flow out through the third outlet. At the same time, the 200nm particles also flow in a spiral shape with the fluid, flow into the side branch, and flow out through the fourth outlet. The spiral motion path of the 5μm particles enhances their interaction with the 200nm particles.

[0074] In addition, we calculated the concentration ratio between the fourth outlet and the second inlet. This ratio is defined as the 200nm particle removal rate of the platform (calculation details in the Experimental section). The results show that the removal rate is as high as 90% or higher under all power conditions ( Figure 3 c). In conclusion, the two types of particles treated by acoustic streaming flow out from different outlets without the need for post-treatment like centrifugation.

[0075] 1.3. Loading NPs onto RBCs

[0076] To prove this concept, we investigated the loading of NPs onto the RBC surface based on the flow parameters obtained from the above particle experiments. We injected a suspension of 200 nm positively surface charged NPs into the second inlet at a rate of 5 μL / min and a suspension of RBCs into the first inlet at a rate of 0.5 μL / min, respectively. Figure 4 Figures ac show the flow cytometry fluorescence intensity distributions of NPs at concentrations of 0.04, 0.1, and 0.2 mg / mL obtained using the microfluidics method (blue histogram) and batch incubation method (red histogram), respectively. The results show that the fluorescence distribution range of erythrocytes modified with NPs obtained by the microfluidics method is narrow, but the fluorescence intensity is relatively low. This indicates that the microfluidics-based loading method effectively enhances the uniformity of the product, while the loading capacity is slightly reduced.

[0077] To investigate the effect of input power on loading NPs onto RBCs, we analyzed the loading efficiency of NPs under different power conditions (0 mW, 760 mW, 1060 mW, and 1360 mW) with a NPs concentration of 0.04 mg / mL. In these experiments, we only adjusted the input power of the resonator while keeping other experimental conditions unchanged. Figure 4As shown in the figure, the flow cytometry results showed that the loading efficiency of RBCs increased with the increase of power. In addition, the fluorescence intensity of RBCs modified with NPs increased with the increase of power ( Figure 4 f), which shows that the loading amount of NPs can be easily adjusted by controlling the input power of the resonator. We analyzed that this is due to the increase in the input power, which leads to an increase in the acoustic streaming velocity. In addition, since RBC and NP exhibit spiral flow in the working area of ​​the device, this lengthens the contact path between them as they flow through the resonance area at a fixed length, providing more opportunities for the particles to assemble on the RBC surface. Figure 4g shows snapshots of the moving images of 5-micron particles at powers of 760, 1060, and 1360 mW. By counting the number of circles the particles rotate from point A to point B, it is found that as the power increases, the number of circles the particles rotate within a certain distance also increases. This shows that the length of the path that the particles move in the microchannel in the platform can be adjusted by power. It also further demonstrates the controllability of this platform in terms of the loading amount of red blood cell nanoparticles.

[0078] To verify the biocompatibility of the platform, we visualized the nanoparticle-loaded erythrocytes using confocal laser scanning microscopy (CLSM) and scanning electron microscopy (SEM). Here, the erythrocyte membrane was stained to achieve 3D visualization using confocal imaging. Figure 5 As shown in ac, both CLSM and SEM images confirmed that the NPs were effectively loaded onto the RBCs. At the same time, the red blood cells basically maintained their natural structure, presenting a concave disc shape with a diameter of approximately 6-8 μm. This indicates that this method causes only minimal damage to the red blood cells. In addition, the hemolysis rate of the red blood cell samples treated under different power conditions was further measured using a microplate reader. After centrifuging the obtained NPs-loaded RBCs suspension, the absorption intensity of hemoglobin in the supernatant was measured to calculate the hemolysis rate (the calculation details are in the Materials and Methods section). The results confirmed that the hemolysis rates of the samples obtained in this experiment were all below 5%, indicating that this method did not cause significant damage to the red blood cells.

[0079] In conclusion, we proposed a microfluidics-based strategy for loading NPs onto RBCs in this work. Although there is potential to further improve the loading efficiency, this microfluidic chip-integrated approach excels in the controllability, integration, and automation of RBC carrier preparation, effectively reducing contamination issues during handling.

[0080] 2. Conclusion

[0081] In this study, we introduced a platform for surface loading of NPs onto RBCs by integrating high-frequency piezoelectric acoustic resonators into a microfluidic structure with multiple inlet and outlet branches. The resonators were used to regulate the flow distribution and interaction between RBCs and NPs in the microchannel. Compared with the traditional bulk phase incubation method, the microfluidic system enhanced the control of the uniformity of micro / nano-objects. In addition, the loading of NPs onto RBCs can be controlled by adjusting the input power of the resonator, especially under low particle concentration conditions. This allows the control of the contact opportunity and duration between RBCs and NPs. In addition, the unique edge orientation of the resonator guides the RBCs to focus in the middle of the microchannel. This, combined with the matched design of microfluidic size and structure, facilitates the direct collection of modified RBCs loaded with NPs from the designated sample outlet, while the excess free NPs are guided to the waste outlet, eliminating the need for tedious post-processing steps to obtain the final sample. This greatly improves the automation level of the RBC loading process. As a versatile platform technology, the proposed platform has the potential to be used in various applications, including particle or cell modification and washing studies.

[0082] 3. Introduction to the Experimental Part

[0083] Reagents and materials

[0084] 200 nm polystyrene NPs with positively charged surface groups labeled with fluorescein isothiocyanate (FITC) were purchased from Xi’an Qiyue Biotechnology Co., Ltd. (Xi’an, China). Ltd. 5 μm red uniform polystyrene microspheres were purchased from Shanghai MacLean Biochemical Co., Ltd. (Shanghai, China). 200 nm non-functionalized polystyrene microspheres were purchased from Shanghai Huizhi Biotechnology Co., Ltd. (Shanghai, China). Hank’s buffer was purchased from Beijing Sorabio Technology Co., Ltd. (Beijing, China). Red fluorescent cell membrane dye in the neurite outgrowth staining kit was purchased from Thermo Fisher Scientific (USA). Glutaraldehyde fixative (2.5%) was purchased from Shanghai Yuanye Biotechnology Co., Ltd. (Shanghai, China). Analytical grade ethanol was purchased from Tianjin Yuanhua Company (Tianjin, China). Ultrapure water (UP water, Millipore filtration system, resistivity higher than 18.2 MΩ). Polydimethylsiloxane (PDMS, Sylgard184) was purchased from Dow Chemical Company. Negative photoresist (SU-8) was purchased from Suzhou Scientific Research Materials Microtechnology Co., Ltd. (Suzhou, China). All reagents were not further purified.

[0085] 3.2. Platform manufacturing

[0086] The core components of the platform include a high-frequency acoustic resonator and a PDMS microfluidic structure with two inlets and two outlets. The resonator is manufactured using microelectromechanical system (MEMS) technology. In short, the alternating deposition of aluminum nitride (ALN) and silicon dioxide (SiO2) forms a reflective layer on a silicon wafer. Molybdenum (Mo) is deposited as the bottom electrode, then ALN ​​is deposited as the piezoelectric layer, and then another layer of Mo is deposited as the top electrode. Each layer is patterned accordingly through an etching process. This leads to the formation of a "sandwich" structure of the resonator with the desired resonator area.

[0087] The microfluidic structure was fabricated using standard photolithography. In short, the pattern of the photomask was first designed using Layout software and fabricated by mask lithography. SU-82025 or SU-82050 negative photoresist was spin-coated onto a clean 4-inch silicon wafer with the desired thickness. Subsequently, a pre-bake was performed on a hot plate, and the patterned structure was transferred from the photomask to the photoresist using a UV photolithography machine. After photolithography, post-baking, and development, reheating was performed to further strengthen the microstructure, and a wafer with a SU-8 photoresist structure was obtained. To replicate the microchannel structure, the PDMS-based agent and curing agent were completely mixed in a mass ratio of 10:1 and vacuumed to remove bubbles. To ensure smoothness, the PDMS mixture was poured into the silicon wafer mold produced above and pre-cured on a flat hot plate at 90°C for 20 minutes. Then, additional curing was performed in a constant temperature oven for 90 minutes to achieve complete curing. Microchannel structures of different heights were obtained. It consists of two inlets and two outlets, where the width of the main channel is 500 μm, including three inlet branches and three outlet branches. The width of the inlet branches is 300 μm. The width of the middle outlet branch is 60 μm, and the width of the outlet branches on both sides is 600 μm. Finally, after creating the liquid inlet and outlet holes, the PDMS microfluidic channel is assembled with the resonator using a 3D printed fixture.

[0088] 3.3. Particle experiments for evaluating the platform

[0089] The optimal microchannel height was investigated using surface-uncharged particles and the non-centrifugal capability of the platform was verified. 200 nm green fluorescent particles and 5 μm red fluorescent particles were injected from the second inlet and the first inlet through a polytetrafluoroethylene tube, respectively. Fluorescence microscopy was used to observe the flow and distribution of particles in real time. The concentration of samples collected from the fourth outlet was measured by NTA (NS-300, Malvern, UK).

[0090] 3.4. Loading NPs into RBCs

[0091] Whole blood was collected from healthy mice and centrifuged at 300 g for 3 times at 4 °C to wash the serum and resuspended in Hank's buffer. Different concentrations of positive surface charge NPs were obtained by diluting with Hank's buffer. For the microfluidic method, positive surface charge NPs were injected into the microchannel from the second inlet at a flow rate of 5 μL / min, while RBCs were injected into the microchannel from the first inlet at a flow rate of 0.5 μL / min. After loading by acoustic flow, the RBCs loaded with NPs were collected from the third outlet using a centrifuge tube containing Hank's buffer, while the excess NPs flowed out from the fourth outlet. For the incubation method, the NPs and RBC suspension were mixed and incubated at a volume ratio of 10:1, and then Hank's buffer was added and centrifuged 3 times to wash the excess NPs. The obtained samples were stored at 4 °C for flow cytometric analysis.

[0092] Flow cytometry

[0093] Flow cytometry (CytoFLEXLX, BeckmanCoulter, USA) was used to analyze the fluorescence intensity and loading of NPs, using a 488 nm laser for excitation and a 525 nm emission filter to detect FITC. Before flow cytometry, red blood cell samples were filtered through a 300 mesh filter to prevent instrument clogging. Data were processed using FlowJo 10.8.1.

[0094] SEM characterization

[0095] After centrifugation of natural erythrocytes and erythrocyte samples loaded with NPs, they were fixed with 2.5% glutaraldehyde for 30 min. Subsequently, gradient dehydration was performed using 30%, 50%, 70%, 95% and 100% ethanol, and each concentration was applied for 10 minutes. Finally, the erythrocytes were resuspended in 95% ethanol. The prepared samples were spotted onto a clean glass slide and left to dry overnight. After gold sputtering, the samples were prepared for SEM imaging (ApreoS, ThermoScientific, USA).

[0096] 3.7. Characterization of erythrocyte hemolysis

[0097] The hemolysis rate of red blood cells treated with the NPs surface loading platform was determined using a microplate reader (Varioskan LUX Multimode Microplate Reader, Thermofisher, USA). First, the absorption wavelength of hemoglobin was determined. A 2.5 μL sample of the original concentration RBC suspension was diluted in 1 mL of UP water. It was then refrigerated at 4 ° C for 1 hour and gently mixed every 20 minutes to ensure complete release of hemoglobin. After centrifugation (3000g, 5 minutes, 4 ° C), a supernatant containing hemoglobin was obtained. Then 200 μL of the supernatant sample was aspirated and diluted twice and then added to a standard 96-well plate. The UV absorbance intensity was measured in the range of 350nm to 750nm to determine the peak absorbance wavelength, which was found to be 415nm.

[0098] To measure the hemolysis level of the experimental group (EG), we collected the supernatant after centrifugation (300g, 5 min, 4°C) of the RBC sample suspension treated with the platform. 200 μL of each sample under different power conditions was dispensed into a 96-well plate for measuring the UV absorbance intensity at 415 nm. Similarly, to measure the hemolysis level of the positive control group (PCG) and the negative control group (NCG), we suspended an equal amount of red blood cells in UP water to completely release hemoglobin, which theoretically would not be hemolyzed, but released hemoglobin in Hank's buffer. Then, we measured the absorbance peak at a wavelength of 415 nm using the same method. The hemolysis rate (HR%) was calculated using the following formula:

[0099]

[0100] Among them, Absorbance values ​​are the absorbance values, EG is the experimental group, NCG is the negative control group, and PCG is the positive control group.

[0101] In the several embodiments provided in the present application, it should be understood that the disclosed devices and methods are not limited to the above embodiments, and can also be implemented in other ways. For example, the device embodiments described above are only schematic. For example, the division of the units is only a logical function division. There may be other division methods in actual implementation, such as multiple units or components can be combined or integrated into another system, or some features can be ignored or not executed. Another point is that the mutual coupling or direct coupling or communication connection shown or discussed can be through some interfaces, indirect coupling or communication connection of devices or units, which can be electrical, mechanical or other forms.

[0102] The units described as separate components may or may not be physically separated, and the components shown as units may or may not be physical units, that is, they may be located in one place or distributed on multiple network units. Some or all of the units may be selected according to actual needs to achieve the purpose of the solution of this embodiment.

[0103] In addition, 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 can be understood 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.

[0104] In the above description, the numbers representing the steps, such as S10, S20, etc., do not necessarily mean that the steps will be executed in this manner. If permitted, the order of the steps can be interchanged or they can be executed simultaneously.

[0105] The term "comprising" as used in the description and claims should not be interpreted as being limited to what is listed thereafter; it does not exclude other elements or steps. Therefore, it should be interpreted as specifying the presence of the features, integers, steps or components mentioned, but does not exclude the presence or addition of one or more other features, integers, steps or components and groups thereof. Therefore, the expression "a device comprising means A and B" should not be limited to a device consisting of components A and B only.

[0106] References to "one embodiment" or "an embodiment" in this specification mean that a particular feature, structure, or characteristic described in conjunction with the embodiment is 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 one or more embodiments, the particular features, structures, or characteristics can be combined in any appropriate manner, as would be apparent to one of ordinary skill in the art from this disclosure.

[0107] 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 application 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 application. Therefore, although the present application is described in more detail through the above embodiments, the present application is not limited to the above embodiments, and may also include more other equivalent embodiments without departing from the concept of the present application, all of which belong to the scope of protection of the present application.

Claims

1. A device for particle modification, characterized in that: include: First flow channel; A second flow channel and two third flow channels connected to the upstream of the first flow channel, wherein the two third flow channels are located on both sides of the second flow channel, the second flow channel is used to pass a first liquid containing first particles, and the two third flow channels are used to pass a second liquid containing second particles, and the second liquid passed through the two third flow channels forms a sheath flow; A fourth flow channel and two fifth flow channels connected to the downstream of the first flow channel, wherein the two fifth flow channels are located on both sides of the fourth flow channel; An acoustic resonator capable of acting on the liquid in the first flow channel, wherein the acoustic resonator is in a shuttle shape, and the tips of the front end and the rear end thereof are respectively directed toward the second flow channel and the fourth flow channel; The acoustic resonator is used to generate an acoustic fluid effect in the liquid in the first flow channel to capture first particles in the first liquid, so that the captured first particles flow along the shuttle-shaped profile of the acoustic resonator, so that the first particles distributed to the side of the shuttle-shaped profile are controllably mixed with the second liquid in the side area, and the controllable mixing is used to controllably combine the second particles in the second liquid with the first particles; The first particles combined with the second particles flow toward the fourth flow channel along the rear end tip of the shuttle-shaped profile of the acoustic resonator; and the first liquid flowing through the first flow channel flows toward the two fifth flow channels.

2. The device according to claim 1, characterized in that The diameter of the fourth flow channel inlet is smaller than the diameter of the fifth flow channel inlet.

3. The device according to claim 1 or 2, characterized in that: Also includes: The pressure of the fourth flow channel is adjusted to control the flow distribution between the fourth flow channel and the two fifth flow channels, so as to facilitate the first particles combined with the second particles to flow into the fourth flow channel and facilitate the first liquid flowing through the first flow channel to flow to the two fifth flow channels.

4. The device according to any one of claims 1 to 3, characterized in that: Also includes at least one of the following: The upstream of the second flow channel is connected to a first inlet; The upstream of the two third flow channels are connected to a second inlet; The downstream of the fourth flow channel is connected to a third outlet; The downstream of the two fifth flow passages are connected to a fourth outlet.

5. The device according to any one of claims 1 to 4, characterized in that: The selection of the height of the first flow channel and the selection of the power of the acoustic resonator are related to the first particles and the second particles.

6. The device according to any one of claims 1 to 5, characterized in that: The particle size of the first particles is larger than the particle size of the second particles; At the current height of the first flow channel, the power of the acoustic resonator is controlled so that it can capture the first particle, so that the captured first particle flows along the shuttle-shaped profile of the acoustic resonator, and the first particle combined with the second particle flows to the downstream fourth flow channel at the rear end tip; and the power of the acoustic resonator is such that the second particle is not concentrated at the rear end tip and flows downstream.

7. The device according to any one of claims 1 to 6, characterized in that: The acoustic-fluid effect generated by the acoustic resonator also induces the second particles to flow along the periphery of the shuttle-shaped profile of the acoustic resonator, so that the first particles distributed to the side of the shuttle-shaped profile can be controllably mixed with the second liquid distributed and flowing in the side area and around the shuttle-shaped profile.

8. The device according to any one of claims 1 to 7, characterized in that: The controllable mixing is achieved by at least one of the following: This is achieved by controlling the power of the acoustic resonator; This is achieved by controlling the flow rate of the first liquid, the flow rate of the second liquid, the flow rate ratio of the first liquid to the second liquid, or the total flow rate of the first liquid and the second liquid.

9. The device according to any one of claims 1 to 8, characterized in that: The first particle includes a carrier, and the carrier includes at least one of the following: cells, red blood cells, T cells, NK cells, stem cells, liposomes, and microspheres; The second particle comprises a nanoparticle or a microparticle, and the nanoparticle or the microparticle comprises at least one of the following: a drug-loaded nanoparticle, a polymer nanoparticle, an inorganic nanoparticle, a metal nanoparticle, a composite nanoparticle, a magnetic nanoparticle, a protein, a polypeptide, a molecule, and a supramolecule.

10. A method for particle modification, characterized in that: Using the device for particle modification according to any one of claims 1 to 9, the method comprises: Passing a first liquid containing first particles into a second flow channel; Passing a second liquid containing second particles into two third flow channels, wherein the second liquid passed into the two third flow channels forms a sheath flow; The acoustic resonator is driven to work, an acoustic fluid effect is generated in the liquid in the first flow channel, first particles in the first liquid are captured based on the acoustic fluid effect, the captured first particles are distributed and flow along the shuttle-shaped profile of the acoustic resonator, and the first particles distributed to the side of the shuttle-shaped profile are controllably mixed with the second liquid in the side area, so as to realize the combination of the second particles in the second liquid and the first particles; The first particles combined with the second particles flow toward the fourth flow channel along the rear end tip of the shuttle-shaped profile of the acoustic resonator; and the first liquid flowing through the first flow channel flows toward the two fifth flow channels.

Images