Method for generating microscale columnar high velocity acoustic jet in a liquid environment and applications thereof

Abstract

A method for generating a microscale columnar high-speed acoustic jet in a liquid environment and applications thereof, the method comprising: a liquid environment; a high-frequency resonator, which, when in operation, generates a specific ultrasonic wave with a frequency of 0.5-30 GHz to act on the liquid environment, and generates a directional fluid motion along the direction of propagation of the acoustic wave in the liquid at the solid-liquid interface, i.e. a columnar focused acoustic jet; driving the high-frequency resonator to operate at a first power in at least one driving cycle, each driving cycle comprising a first stage and a second stage, the high-frequency resonator being driven to operate in the first stage, and being stopped from driving in the second stage; the first power being such that the high-frequency resonator generates the acoustic jet in the first stage; and the duration of the first stage at the first power being less than a second threshold value or the duty cycle of the first stage in one driving cycle being less than a first threshold value.

Description

Method for generating micro-scale cylindrical high-speed acoustic beam in liquid environment and its application Technical Field

[0001] The present application relates to the field of microfluidics technology, and in particular to a method for generating a microscale columnar high-speed acoustic beam in a liquid environment and its application. Background Art

[0002] In the field of acoustofluid technology, acoustofluid is a stable flow caused by sound waves. This phenomenon manifests itself as momentum transfer from sound waves to fluid motion. When ultrasonic waves propagate in a sound-absorbing fluid, they cause the medium to move as a whole. Among them, since the special sound waves generated by the high-frequency resonator are absorbed faster in the fluid and have a shorter propagation distance, their acoustofluid effect is more obvious. The regional vibration generated by the working interface of the high-frequency resonator forms a traveling wave in the liquid, and exerts a continuous thrust on the local liquid in the liquid environment, thereby driving the local liquid to move in the direction of the traveling wave propagation. At the same time, based on the viscosity of the fluid, the surrounding liquid of the local liquid will be driven to move together, thereby forming a flow effect of the liquid in the direction opposite to the working interface. Among them, the local liquid refers to the part of the liquid facing the working interface of the high-frequency resonator. As the high-frequency resonator continues to work, the liquid continues to flow, which will further generate secondary fluids such as liquid vortices and convection in the liquid environment.

[0003] In addition to driving liquid flow, generating eddies, and generating convection, the ultrasonic waves of high-frequency resonators can, in certain scenarios, also be used to generate a focused acoustic beam within the liquid, specifically a high-speed, cylindrical jet of fluid, aligned with the direction of the acoustic wave propagation. This beam is characterized by its alignment with the direction of the acoustic wave propagation within the liquid, its thin, cylindrical shape, and minimal mixing with the surrounding liquid, resulting in a distinct flow pattern between the beam and the surrounding liquid. This relatively stable flow allows for better momentum transfer. This characteristic of the acoustic beam can be used to manipulate the directional movement of a portion of liquid or the directional movement of materials contained within it.

[0004] Therefore, how to provide a solution to enable ultra-ultrasonic devices to generate acoustic beams in liquids, as well as corresponding applications, are technical problems that need to be solved. Summary of the Invention

[0005] In view of the above problems in the prior art, the present application provides a method for generating a micro-scale cylindrical high-speed acoustic beam in a liquid environment and its application.

[0006] In a first aspect, the present application provides a method for generating a microscale columnar high-speed acoustic beam flow in a liquid environment, comprising: a liquid environment; a high-frequency resonator, which, when in operation, generates 0.5-30 GHz ultrasonic waves acting on the liquid environment to generate directional fluid motion at a solid-liquid interface along the direction of propagation of the acoustic wave in the liquid, wherein the directional fluid motion is a focused columnar acoustic beam flow; driving the high-frequency resonator with a first power to operate in at least one driving cycle, each driving cycle including a first stage and a second stage, driving the high-frequency resonator to operate in the first stage to generate 0.5-30 GHz ultrasonic waves, and stopping driving the high-frequency resonator in the second stage; wherein the magnitude of the first power enables the high-frequency resonator to generate the acoustic beam flow within the first stage.

[0007] As described above, the present application drives the high-frequency resonator with the first power of the above magnitude through each driving cycle including the first stage and the second stage, thereby generating a focused columnar acoustic beam in a liquid environment.

[0008] As a possible implementation of the first aspect, the duration of the first stage at the first power is less than a second threshold or the duty cycle of the first stage in one driving cycle is less than the first threshold, so that the temperature of the high-frequency resonator is within a third threshold.

[0009] As described above, by limiting the duration or duty cycle of the first stage, the temperature of the high-frequency resonator device or the liquid environment in which the device is located can be controlled to be within the third threshold when generating the above-mentioned acoustic beam flow, thereby avoiding overheating.

[0010] As a possible implementation of the first aspect, when the duty cycle of the high-frequency resonator during the duration of the first stage is less than a first threshold, or when the duration is less than a second threshold, the high-frequency resonator is suppressed from generating a secondary flow in the liquid environment.

[0011] As described above, by limiting the duration or duty cycle of the first stage, the generation of eddies or convection in the liquid environment can be suppressed when the above-mentioned acoustic beam is generated, so as to facilitate the control of the liquid or particles in the liquid through the acoustic beam.

[0012] The present application also provides some applications of a method for generating micro-scale columnar high-speed acoustic beam flow in a liquid environment based on the first aspect, including: a method for directional transport based on acoustic beam flow, a method for particle control based on acoustic beam flow, a method for particle sorting based on acoustic beam flow, a method for processing cells based on acoustic beam flow, a method for achieving micro-water hammer effect based on acoustic beam flow, a method and device for continuous droplet generation based on acoustic beam flow, a droplet ejection component based on acoustic beam flow, a printing device and a printing method, etc. BRIEF DESCRIPTION OF THE DRAWINGS

[0013] FIG1a is a schematic diagram of the jet phenomenon and the secondary flow phenomenon in a liquid environment, and FIG1b is a photograph of the acoustic beam flow generated in a liquid environment using the method of the present application;

[0014] FIG2 is a continuous frame diagram of the process of generating an acoustic beam flow in the present application;

[0015] FIG3 is a graph of the continuous-time synthetic trajectory of the acoustic beam flow generated by the present application;

[0016] FIG4 is a circuit diagram for implementing the method of the present application;

[0017] FIG5 is a timing diagram showing an embodiment of generating a driving unit output signal using the circuit of FIG4 :

[0018] FIG6 is a timing diagram showing another embodiment of generating a driving unit output signal using the circuit of FIG4;

[0019] FIG7 is a schematic diagram of a signal generator after the signal is tuned to a triangle wave;

[0020] FIG8 is a size comparison diagram of the bulk acoustic wave devices used in this application;

[0021] FIG9 is a schematic diagram of an application based on the method of the present application provided in an embodiment of the present application;

[0022] FIG10 is a schematic diagram of another application based on the method of the present application provided in an embodiment of the present application;

[0023] FIG11 is an analysis diagram of the result data of the experiment of this application;

[0024] FIG12 is a schematic diagram showing the dimensions of each high-frequency resonator used in the experiments of this application;

[0025] FIG13 is a schematic diagram of a particle separation device based on an acoustic beam according to an embodiment of the present application;

[0026] FIG14 is a schematic diagram of a first example of a particle sorting device based on an acoustic beam provided by the present application;

[0027] FIG15 is a schematic diagram of a second example of a particle sorting device based on an acoustic beam provided by the present application;

[0028] FIG16 is a schematic diagram of a third example of a particle sorting device based on an acoustic beam provided by the present application;

[0029] FIG17 is a schematic diagram of a fourth example of a particle sorting device based on an acoustic beam provided by the present application;

[0030] FIG18 is a schematic diagram of a fifth example of a particle sorting device based on an acoustic beam provided by the present application;

[0031] FIG19 is a schematic diagram of a sixth example of a particle sorting device based on an acoustic beam provided by the present application;

[0032] FIG20 is a schematic diagram of the relative positions of the designed ultra-ultrasonic device and the target flow channel inlet under different particle routes provided by the present application;

[0033] FIG21 is a simulation diagram of the force exerted by an acoustic beam on particles in a flow field in a microchannel according to an embodiment of the present application;

[0034] FIG22 is a partially enlarged top view of an acoustic beam flow separation of particles in an experiment of the present application;

[0035] FIG23 is a schematic diagram showing the relationship between the applied power and the corresponding acoustic beam jet velocity of the BAW resonator prepared in an embodiment of the present application;

[0036] FIG24 is a schematic diagram showing the relationship between the applied power, sample flow rate, and the corresponding acoustic beam jet height of the BAW resonator prepared in an embodiment of the present application;

[0037] FIG25 is a schematic diagram of a processing device based on a super ultrasonic device according to a ninth embodiment of the present application;

[0038] FIG26 is a partial enlarged schematic diagram of FIG25;

[0039] FIG27 is a schematic diagram of a replaceable probe of a super-ultrasonic device with different characteristics in the present application;

[0040] FIG28 is a diagram of an acoustic beam generated in the eleventh embodiment of the present application;

[0041] FIG29 is a diagram of different action areas at different intensities in the eleventh embodiment of the present application;

[0042] FIG30 is a schematic diagram of parameters corresponding to each figure in FIG29;

[0043] FIG31 is a diagram showing the regions of action at different ratios in the first stage of the driving cycle;

[0044] FIG32 is a graph showing the relationship between driving power and acoustic beam velocity or force at different distances;

[0045] FIG. 33 is a diagram showing an embodiment of the method acting on a single cell.

[0046] FIG34 is a schematic diagram of an output signal of a water hammer effect generated by a driving device of an ultra-ultrasonic device provided in an embodiment of the present application;

[0047] FIG35 is a schematic diagram of a drug delivery device according to a fifteenth embodiment of the present application;

[0048] FIG36 is a schematic diagram of the exploded components of the drug delivery device provided in the fifteenth embodiment of the present application;

[0049] FIG37 is a schematic diagram of a drug delivery device provided in another fourth embodiment of the present application;

[0050] FIG38 is a photograph of a drug delivery device according to the fifteenth embodiment of the present application;

[0051] FIG39 is a partial schematic diagram of a drug delivery device provided in an embodiment of the present application;

[0052] FIG40 is a schematic diagram of simulation of intermittent acoustic beam flow generated by several ultra-ultrasonic devices provided in an embodiment of the present application;

[0053] FIG41 is an experimental photograph showing that the effective area of ​​the acoustic beam of a super ultrasonic device provided by an embodiment of the present application increases with increasing distance;

[0054] FIG42 is a schematic diagram of a simulation of an array of three ultra-ultrasonic devices providing an embodiment of the present application generating intermittent acoustic beam flows;

[0055] FIG43 is a schematic diagram of a structure of three integrated ultra-ultrasound chips provided in an embodiment of the present application;

[0056] FIG44 is a diagram comparing the effects of a single and an array of three ultra-ultrasonic devices provided in an embodiment of the present application;

[0057] FIG45 is a simulation diagram of different effects of hollow needles of different lengths provided in an embodiment of the present application;

[0058] FIG46 is a schematic diagram of a simulation showing the different effects of hollow needles with different apertures on acoustic beam flow provided by an embodiment of the present application;

[0059] FIG47 is an experimental diagram of two hollow needles provided in an embodiment of the present application;

[0060] FIG48 is a graph showing the experimental results of subcutaneous administration of drugs to mice provided in the Examples of the present application;

[0061] FIG49 is a schematic diagram showing the principle of a method for continuously generating droplets provided in the sixteenth embodiment of the present application;

[0062] FIG50 is a schematic diagram showing the principle of a method for continuously generating droplets provided in the seventeenth embodiment of the present application;

[0063] FIG51 is a schematic diagram showing the principle of a method for continuously generating droplets provided in the eighteenth embodiment of the present application;

[0064] FIG52 is a diagram of droplets generated by the embodiment shown in FIG49 in the first droplet generation mode;

[0065] FIG53 is a diagram of droplets generated by the embodiment shown in FIG49 in a second droplet generation mode;

[0066] FIG54 is a diagram of droplets generated by the embodiment shown in FIG49 in a third droplet generation mode;

[0067] FIG55 is a diagram of droplet generation according to the embodiment shown in FIG51;

[0068] FIG56 is a schematic diagram showing the principle of forming a conical liquid column in Chinese patent application publication number CN110170343A;

[0069] FIG57 is a schematic diagram showing the principle of the process of generating droplets in FIG56;

[0070] FIG58 is a schematic diagram showing the principle of the process of breaking through the laminar flow interface to generate droplets in the present application;

[0071] FIG59 is a schematic diagram showing the principle of a device for continuously generating droplets provided in the twenty-third embodiment of the present application;

[0072] FIG60 is another schematic diagram of the twenty-third embodiment shown in FIG59;

[0073] FIG61 is a diagram showing droplet generation when the duty ratio of the driving signal is less than 50% in the twenty-third embodiment shown in FIG59;

[0074] FIG62 is a diagram showing droplet generation at different powers when the duty cycle of the driving signal is 100% in the twenty-third embodiment shown in FIG59;

[0075] FIG63 is a diagram showing the generation of droplets and solidified particles according to the twenty-third embodiment shown in FIG59;

[0076] FIG64 is a schematic diagram of a droplet ejection component provided in an embodiment of the present application;

[0077] Figure 65 is a schematic diagram of the principle of the printing device provided in an embodiment of the present application.

[0078] 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 the present invention. The relative positions and inclusion relationships between the blocks presented in the structural diagrams are merely schematic representations of the structural relationships between the blocks and do not limit the physical connection methods of the embodiments of the present invention. DETAILED DESCRIPTION

[0079] 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.

[0080] It should be understood that the solutions for generating micro-scale columnar high-speed acoustic beams provided in the embodiments of the present application include methods for generating micro-scale columnar high-speed acoustic beams and various applications thereof, including: methods for directional transport based on acoustic beams, methods for particle control based on acoustic beams, methods for particle sorting based on acoustic beams, methods for processing cells based on acoustic beams, methods for achieving micro-water hammer effects based on acoustic beams, methods and devices for continuous droplet generation based on acoustic beams, droplet ejection components, printing devices, and printing methods based on acoustic beams, etc. Since the principles of solving the problems of these technical solutions are partially identical or similar, some repetitions may not be repeated in the following description of the specific embodiments, but these specific embodiments should be considered to have been referenced to each other and can be combined with each other.

[0081] 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:

[0082] 1) High-frequency resonator: It can be a device based on the piezoelectric effect that generates mechanical vibration by applying voltage. In this application, a piezoelectric resonator that generates ultra-ultrasound of not less than 0.5 gigahertz (gigahertz, or GHz) when in operation is used. Preferably, it is a piezoelectric resonator that generates ultra-ultrasound of not less than 1 GHz and not more than 30 GHz when in operation. 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 assembled resonator (SMR), or a Lamb wave resonator (LWR). For the convenience of description, the piezoelectric resonator that can generate ultra-ultrasound of not less than 0.5 GHz will be referred to as an ultra-ultrasound device.

[0083] 2) The jet phenomenon is a phenomenon that occurs when sound waves from ultra-ultrasonic devices interact with the solid-liquid interface. The regional vibrations generated by the working interface of a high-frequency resonator can form traveling waves in the liquid, exerting a continuous thrust on the localized liquid within the liquid environment, causing at least a portion of that liquid to move linearly along the direction of sound wave propagation. This linear motion is called the jet phenomenon.

[0084] 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.

[0085] The jet flow phenomenon and the secondary flow phenomenon can be seen in the image and schematic diagram shown in a of Figure 1. A of Figure 1 shows a schematic diagram of capturing particles using vortex flow.

[0086] 3) Acoustic beam flow. Acoustic beam flow is a unique type of jet phenomenon. Its characteristic is that the fluid moves at high speed along the direction of sound wave transmission and the jet is in the shape of a thin cylinder within its stroke. The acoustic beam flow is basically in a laminar state with the surrounding liquid before it is obviously attenuated, and the degree of mixing with the surrounding liquid is low. As shown in Figure 1b, an image of the acoustic beam flow generated by the solution of the present application taken by a high-speed camera is shown. As can be seen from Figure 1b, the acoustic beam flow has a high degree of focus and is no longer a jet in the form of clusters like in Figure 1a, and the secondary flow phenomenon in Figure 1a is obviously not seen in Figure 1b.

[0087] 4) Restricted jet and free jet, refers to whether the jet is restricted by the external hardware wall after it is ejected, and is divided into restricted jet and free jet. Unless otherwise specified, the description of the jet in each embodiment of this application generally refers to a free jet.

[0088] 5) Reynolds number (Re): In fluid mechanics, the Reynolds number is a measure of the ratio of the inertial force to the viscous force of a fluid. The Reynolds number can be used to determine whether the flow of a fluid is laminar or turbulent, and can also be used to determine the resistance encountered by an object flowing in a fluid. When the Reynolds number is small, the fluid flow is stable and laminar; conversely, if the Reynolds number is large, the fluid flow is less stable, and small changes in flow velocity tend to develop and intensify, forming a chaotic, irregular turbulent flow field. In some cases, Re = ρvd / η, where v, ρ, and η are the flow velocity, density, and viscosity coefficient of the fluid, respectively, and d is a characteristic length, such as the diameter at the starting point of the jet, such as the diameter of the jet nozzle. In this application, d is used to represent the jet diameter.

[0089] 6) Signal duration within a driving cycle: In this application, electric energy is loaded in an intermittent manner, as shown in FIG5 . In the on-stage of the switching power supply (corresponding to the high level of the switching signal in FIG5 ), the signal duration within the driving cycle is also referred to as the first stage within the driving cycle, which corresponds to the output signal of the driving unit. During the signal duration, several signals will be output. For example, when the signal generator outputs a 1 GHz signal, assuming that the duration of the first stage is 1 microsecond, the driving unit will output 1000 signals during the first stage, and the power loaded during the first stage will be loaded onto the 1000 signals for output. The second stage is when there is no driving signal output within the driving cycle, which also corresponds to the off-stage of the switching power supply (corresponding to the low level of the switching signal in FIG5 ).

[0090] In a specific case, for example, the first stage is completed after only one execution, which is equivalent to, or regarded as, executing only one driving cycle in the present application, and therefore this case also falls within the protection scope of the present application.

[0091] 7) In some embodiments, the driving portion of the high-frequency resonator of the present application may be as shown in FIG. 4 , including a control unit and a driving unit, wherein the driving unit includes a signal generator and a power amplifier.

[0092] The signal generator is used to generate a high-frequency signal. The frequency of the original high-frequency signal generated by the signal generator is the same as or similar to the operating frequency of the load (such as an ultrasonic device).

[0093] The power amplifier is used to amplify the signal to be output so as to drive a load (such as an ultrasonic device).

[0094] The control unit can be a switching power supply, which has a controllable output switching signal, and the switching signal can be a periodic signal. The switch-on stage (such as the conduction stage of the switching power supply switch tube) corresponds to a high level, corresponding to the first stage in Figure 5, and the switch-off stage corresponds to a low level, corresponding to the second stage in Figure 5. The control unit can also control the operating voltage input to the power amplifier to achieve amplified output of different powers, and the output power is referred to as the first power in this application. In this application, the first power can be understood as a drive cycle (a drive cycle consists of a first stage and a second stage), and the average energy density input to the high-frequency resonator. Since the amount of energy is related to power and time, the amount of energy input to the high-frequency resonator in a drive cycle is related to the first power level, the duration of the first stage or its duty cycle.

[0095] The control unit can control the output of the drive unit in at least the following ways:

[0096] The first type: As shown in FIG5 , the original signal of the signal generator is modulated by the switching signal of the control unit, and the modulated output signal is amplified to form the output signal of the driving unit.

[0097] The second type: As shown in FIG6 , the original signal of the signal generator is power amplified, and the power-amplified signal is modulated under the control of the switch signal of the control unit. The modulated signal is the output signal of the driving unit.

[0098] The circuit of the driving part of the high-frequency resonator may also be in other forms, or the method of controlling the output signal may also be in other methods, as long as it can output the output signal of the driving unit of Figure 5 or Figure 6.

[0099] 8) Conversion rate of acoustic wave energy (or mechanical energy generated by a high-frequency resonator) into kinetic energy of the fluid: In this application, it refers to the conversion rate of the vibration energy (or acoustic energy) of the high-frequency resonator into the kinetic energy of the fluid along the direction of acoustic wave transmission.

[0100] 9) 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 (such as a saline solution) to force the sample (such as a liquid containing particles) into a smaller core flow (also called a hydrodynamic core, i.e., a laminar flow near the axis), so that each particle in the core flow travels along the same axis at approximately the same speed. After the sample enters the core flow, it can be detected by a laser detection point. In some embodiments, the height of the microchannel is designed so that when the particles in the flow channel are basically in a layer at the height, the sheath flow channel can be a two-dimensional sheath flow channel.

[0101] 10) Impact resistance: In this application, it is used to reflect the stability and resistance of the target object under the action of a set intensity of the acoustic beam. The value of resistance can be the number of times, duration, etc.

[0102] For example, when the acoustic beam is intermittent (i.e., pulsed, for example, the first stage accounts for 50%, 20%, etc.), and the target object is a cell, when the cell is impacted by the pulsed acoustic beam n times and the cell membrane is perforated, it can be called the cell membrane tolerance under the corresponding acoustic beam parameters (acoustic beam parameters include at least one of the following: power, drive cycle, first stage proportion, etc., and the distance and angle facing the target object) is n, which specifically reflects the cell's tolerance to maintaining the integrity of the cell membrane under the action of the acoustic beam parameters. For another example, when the acoustic beam is continuous (the first stage accounts for 100%, which is a special case), the tolerance value can also be a duration.

[0103] For example, in addition to the tolerance to maintaining structural integrity (integrity) as described above, since the target object may also be other particulate matter, etc., it may also reflect the tolerance to the stability of the target object in a fixed position or posture under the action of the above-mentioned acoustic beam flow parameters, the tolerance to the shape of the target object remaining stable under the action of the acoustic beam flow parameters, etc.

[0104] 11) Cellular response to stimulation: When cells are subjected to sustained mechanical stimulation, they respond to these stimuli through specific mechanisms. This process is also called mechanotransduction. For example, the following AEs are several possible cell responses:

[0105] A. Activation of Mechanosensitive Channels: A special class of proteins called mechanosensitive channels exist on the cell membrane. These channels can directly sense and respond to changes in mechanical forces. When the cell membrane is squeezed, stretched, or subjected to other forms of mechanical stimulation, these channels can open or close, allowing ions such as sodium (Na+), calcium (Ca2+), or chloride (Cl-) to enter and exit the cell, changing the cell membrane potential, triggering electrical signal transmission, and further affecting physiological activities within the cell.

[0106] B. Cytoskeleton Reorganization: The cytoskeleton (including microfilaments, microtubules, and intermediate filaments) is crucial for maintaining cell morphology and transmitting mechanical forces. Mechanical stimulation can promote cytoskeleton reorganization, such as promoting the polymerization and depolymerization of actin, and influencing cell behaviors such as adhesion, migration, and division.

[0107] C. Activation of signal transduction pathways: Mechanical stimulation can also activate multiple signal transduction pathways within cells, such as those regulated by the Rho family GTPases, affecting gene expression, cell proliferation, differentiation, and apoptosis. For example, when osteoblasts sense mechanical force, they promote bone formation and repair through these pathways.

[0108] D. Changes in secretory activity: Certain cells will change their secretory patterns after mechanical stimulation, releasing growth factors, cytokines and other bioactive molecules, which can affect the behavior of surrounding cells and the repair and remodeling of tissues.

[0109] E. Cell apoptosis or damage: If the mechanical stimulation is too strong or lasts too long, it may cause excessive cell stress response and eventually induce cell apoptosis or damage.

[0110] 12) Micro water hammer effect: The conventional water hammer effect is an important phenomenon in fluid mechanics. It describes the pressure fluctuation caused by sudden changes in flow velocity in a liquid flow system. For example, when a valve in a pipeline is suddenly closed or opened, a shock wave will be generated in the pipeline due to the inertia of the fluid. This shock wave is like a hammer hitting the pipeline, hence the name "water hammer effect".

[0111] In this application, the micro-water hammer effect refers to a directional (i.e., in the direction of the acoustic beam) shock wave generated by driving an intermittent (e.g., pulsed) acoustic beam flow generated by a super-ultrasonic device in a liquid. It is not difficult to understand that the acoustic beam flow will attenuate in the liquid. Therefore, the strength of the micro-water hammer effect at a certain position in the liquid is related to the distance from the super-ultrasonic device to the position. The micro-water hammer effect described in this application refers to the distance within which the micro-water hammer effect occurs. In addition, due to the high focus of the acoustic beam flow, the generated micro-water hammer effect also has a highly focused directionality (it is not difficult to understand that the directionality corresponds to the stage where the acoustic beam flow has not significantly attenuated), that is, the above-mentioned directional shock wave (i.e., in the direction of the acoustic beam flow).

[0112] 13) Positive and negative correlation between parameters: Taking two parameters as an example, positive correlation refers to that one parameter becomes larger as the other parameter becomes larger, and negative correlation refers to that one parameter becomes larger as the other parameter becomes smaller. The parameters mentioned in this application cannot be infinitely small or infinitely large. Therefore, unless otherwise specified, the parameter values ​​mentioned in this application all refer to being within a reasonable numerical range. For example, when describing that parameter A is positively correlated with parameter B, it means that within a certain range of values, parameter A is positively correlated with parameter B, and it can be foreseen that parameter B is no longer positively correlated with parameter A beyond this range (for example, after parameter A increases to a certain value, B is in a saturated state, and then parameter B no longer increases with the increase of parameter A), then this range of values ​​is a reasonable numerical range.

[0113] Below, the solution for generating micro-scale cylindrical high-speed acoustic beam flow provided by the embodiment of the present application is first introduced.

[0114] In a typical acoustofluidic scenario, the acoustic radiation generated by the working interface of an ultrasonic device creates a continuous thrust on a localized portion of the liquid surrounding it, pushing that portion of the liquid at high speed in the direction of the acoustic wave propagation. Simultaneously, this high-speed flow also drives the flow of surrounding liquid, creating an eddy effect (Eckart flow). Furthermore, due to the inherent heat generation of the acoustic device, thermal convection occurs at the interface between the device and the liquid. Therefore, the fluid (jet) moving in the direction of the acoustic wave propagation can be considered the direct fluid motion caused by the propagation of the acoustic wave in the water, while the eddy currents and thermal convection are secondary effects. From an energy transfer perspective, these secondary fluid effects (eddy currents and thermal convection) reduce the kinetic energy of the jet, hindering the formation of a single, high-speed acoustic beam. Furthermore, the fluid flow velocity is roughly proportional to the sound intensity (applied power), so higher power is often required to drive the fluid at high speed. In acoustofluidic scenarios, tiny ultra-sonic devices, such as bulk acoustic wave chips, are used, typically ranging in size from 0.01 x 0.01 mm² to 1 mm², or even smaller. Since microscale devices often have low power handling capabilities, currently in acoustofluidics scenarios, ultra-ultrasonic devices are mostly driven continuously at low power (milliwatt level, such as 0.1W, 0.2W, etc.). However, continuously driving ultra-ultrasonic devices at higher power will also lead to the accumulation of thermal effects and damage the devices.

[0115] First of all, it should be noted that when the present application solution forms an acoustic beam, it is in a basically laminar state with the surrounding liquid and has a low degree of mixing with the surrounding liquid. This means that there are no vortices and convection when the acoustic beam is formed, or the vortex and convection phenomena are extremely low, which also means that the energy loss of forming vortices or convection is reduced during energy conversion, and the acoustic beam has a higher conversion rate from sound wave energy to kinetic energy of the fluid, and the acoustic beam can reach the fluid faster. Among them, the continuous frame diagram of the acoustic beam generation process of the present application shown in Figure 2 is a multi-frame diagram of the acoustic beam generation process taken every 0.4ms by a high-speed camera when the input power of the high-frequency resonator is 1W. It can be seen that the present application can quickly generate an acoustic beam within 0.4ms after power is applied. Figure 3 is a continuous time synthetic trajectory diagram when the present application generates an acoustic beam, which shows a schematic diagram of trajectory synthesis after continuous 4ms high-speed shooting, and a schematic diagram of trajectory synthesis after continuous 40ms high-speed shooting. It is explained here that in the 40ms trajectory synthesis, the acoustic beam (mainly referring to the part before it acts on the bottom of the liquid environment) maintains a linear or columnar focus and is not as diffuse as a conventional jet, which indicates that the acoustic beam and the surrounding liquid have obvious laminar flow phenomenon; on the other hand, the partial displacement of the particles in the liquid environment corresponds to the trajectory formed by slow movement in the entire liquid environment (the acoustic beam is limited by the bottom of the liquid environment and acts obliquely on the bottom to drive the movement of the liquid environment, so that the particles in the liquid environment move along). The direction and length of the particle trajectory in the liquid environment can be observed (shorter, indicating slow movement), which are obviously different from the direction and length of the acoustic beam trajectory (longer, indicating fast speed). This means that the acoustic beam and the surrounding liquid (such as the liquid surrounding the acoustic beam) have obvious laminar flow phenomenon and do not obviously drive the liquid around the acoustic beam to move at high speed, and no high-speed vortex or high-speed convection is obviously formed, and no obvious displacement of suspended particles in the liquid layer around the acoustic beam occurs.

[0116] In order to form the desired acoustic beam flow, the following issues need to be considered:

[0117] 1) Focused sound waves are needed to increase the velocity of the acoustic fluid to achieve the flow rate of the acoustic beam.

[0118] The high-frequency resonators used in this application have dimensions ranging from 0.01 mm² to 1 mm² or smaller. This microscale allows for the desired acoustic wave focusing effect. The hypersonic devices used in some of the experiments described in this application are bulk acoustic wave devices, as shown in Figure 8, with dimensions of approximately 0.01-0.02 mm².

[0119] On the other hand, the device resonant frequency is also related to the device size. The above-mentioned micro-sized device can achieve the operating frequency of 0.5 GHz required by this application.

[0120] 2) The acoustic beam requires sufficient energy to drive, so higher power needs to be input into the ultra-ultrasonic device, but at the same time, it is also necessary to avoid the heat generated by high power acting on the micro-scale ultra-ultrasonic device and damaging the ultra-ultrasonic device.

[0121] Based on this, the present application adopts a first power as the input power, wherein the first power is increased by several times, dozens of times, or even nearly a hundred times compared to the above-mentioned low power. The first power is, for example, 0.4W, 0.8W, 4W, 10W, 60W, or even 100W or more of the input power. The magnitude of the first power is sufficient to drive the generation of an acoustic beam flow, wherein the intensity of the acoustic beam flow (such as speed, distance, strength, etc.) is related to the magnitude of the first power. At the same time, it is also necessary to put the high-frequency resonator in an intermittent working mode, that is, to shorten the time that the device is in a working state (or working stage) to reduce the heat generation of high input power, or to reduce or avoid the generation of secondary flows (eddy currents and convection).

[0122] Specifically, at least one drive cycle is executed in the intermittent operating mode, and each drive cycle includes a first phase and a second phase. In the first phase, the first power is used to drive the high-frequency resonator to generate ultrasonic waves of not less than 0.5 GHz, and in the second phase, the drive of the high-frequency resonator is stopped. The drive cycle can be in the microsecond (μs) to millisecond (ms) range, for example, the drive cycle can be between 1 microsecond and 100 milliseconds. The smaller the proportion of the first phase within a drive cycle, the shorter the time in the working state within the drive cycle, the shorter the heat generation time, and the lower the secondary flow effect. Accordingly, the longer the second phase, the longer the heat dissipation time within the drive cycle, and the more completely the generated secondary flow (referring to the weak secondary flow that may be generated in the first phase) dissipates. Therefore, when the drive cycle is a constant value, the smaller the proportion of the first phase, the higher the first power that can be applied. In this case, the temperature of the high-frequency resonator can be controlled to be within a third threshold, and the generation of secondary flow by the high-frequency resonator in the liquid environment can be suppressed. In some embodiments, the first phase may account for no more than 50% of a driving cycle, or last for no more than 10 milliseconds.

[0123] 3) Reduce or even avoid the generation of secondary fluid behavior (eddies and convection).

[0124] Secondary fluid requires more time to accumulate and produce, and when the high-frequency resonator is in intermittent working mode, the application shortens the time that the device is in working state (or working stage). The first stage time is not enough to produce secondary fluid or to produce obvious secondary fluid before entering the second stage time, thereby reducing the occurrence of secondary fluid. In other words, the first stage duration in the above-mentioned driving cycle is very short and then enters the second stage. The first stage duration has not yet led to the occurrence of secondary fluid, or the occurrence of secondary fluid is extremely insignificant. Among them, the shorter the duration of the first stage, the smaller the proportion of the first stage, the more difficult it is to produce secondary fluid or the less obvious it is. In some embodiments, when the ratio of the first stage to the second stage in the driving cycle is 1:1 (that is, the first stage accounts for 50% of the driving cycle), the first stage can be 0.5 microseconds to 10 milliseconds, especially when the first stage is between 0.5-100 microseconds, basically no secondary fluid is observed.

[0125] It should also be noted that the generation of secondary fluid requires time accumulation. Through observations with high-speed cameras, the generation of eddy currents requires the device to be continuously in an operating state (i.e., the first stage) for no less than milliseconds or tens of milliseconds (related to the driving power), while the generation of thermal convection usually requires the device to be continuously in an operating state (i.e., the first stage) for no less than 100 milliseconds (related to the driving power). Therefore, the above-mentioned intermittent working mode of the high-frequency resonator in this application, the selection of a suitable driving cycle and the duration of the first stage or the proportion within the driving cycle can effectively control the generation of secondary flow, especially the generation of thermal convection.

[0126] 4) It is necessary to improve the ability to convert mechanical energy (energy of sound vibration) into fluid kinetic energy, that is, to improve the energy absorption capacity of the fluid and improve the conversion efficiency.

[0127] When a resonator acts on a liquid, using high frequencies can shorten the distance sound waves travel in the liquid, increasing the liquid's ability to absorb energy in a short period of time, improving conversion efficiency, and shortening conversion time. The conversion efficiency mentioned here refers to the conversion rate of the core input energy (i.e., the vibration energy or sound energy of the high-frequency resonator) into the kinetic energy of the fluid along the direction of sound wave transmission.

[0128] The present application adopts a high-frequency resonator operating above 0.5 GHz, preferably a high-frequency resonator operating above 1 GHz, and more preferably a high-frequency resonator operating between 2 GHz and 2.5 GHz.

[0129] The specific ideas for realizing the acoustic beam flow in this application will be further introduced in detail below to better understand the solution provided by this application.

[0130] To form the desired high-speed acoustic beam, sufficient energy must first be applied to the localized liquid. This energy rapidly propels the liquid into a high-speed jet, thus forming the desired acoustic beam—the aforementioned microscale columnar high-speed acoustic beam. Therefore, the first issue to be addressed is increasing the energy applied to the localized liquid.

[0131] From a holistic perspective, the acoustic beam generation process involves converting electrical energy into an acoustic field (which can also be understood as a special high-frequency vibration mechanical energy) and then inputting the acoustic field into a fluid field. Therefore, increasing the initial energy input is a direct solution to increasing the energy output of the ultra-sonic device to the liquid. In other words, by increasing the input power of the ultra-sonic device, the energy applied to the local liquid by the ultra-sonic device can be increased to achieve the energy required to form the acoustic beam. However, since micro-scale devices of approximately 0.01 to 1 square millimeter often have low power tolerance, as previously mentioned, milliwatt-level input power is often used. Increasing the input power, especially by several times, dozens of times, or even nearly a hundred times, driving the ultra-sonic device in a conventional manner will inevitably lead to increased heating and even burning of the ultra-sonic device. However, the present application places the high-frequency resonator in an intermittent operating mode. Due to the limited duration of the first phase, the heat generated by the ultra-sonic device is limited, and the heat can be quickly dissipated in the second phase, thereby maintaining the ultra-sonic device within the allowable thermal range. On the other hand, since the solution of the present application achieves a high efficiency in converting the mechanical energy (or acoustic energy) of high-frequency vibrations into fluid kinetic energy, the heat generation is also extremely low, which in turn is beneficial to increasing the input power of the device.

[0132] In addition, as described above, compared to jets, eddies and thermal convection are secondary effects. Secondary fluid behavior (i.e., eddies and thermal convection) requires more time to accumulate and form compared to jets. However, the present application places the high-frequency resonator in an intermittent operating mode and limits the duration of the first stage (i.e., the device operating time within a drive cycle) to a time that is insufficient to form secondary fluids, effectively avoiding or reducing the generation of secondary fluids. On the other hand, due to the effective avoidance or reduction of subacoustic fluids, the conversion of fluid kinetic energy into the generation of acoustic beams is more concentrated, resulting in a higher conversion rate of mechanical energy to the kinetic energy of the fluid along the direction of sound wave transmission (i.e., the direction of the acoustic beam).

[0133] From a certain perspective, the heat generated by conventional low-frequency resonant devices (such as 20KHz to 100KHz ultrasonic devices) when acting on liquids can be regarded as energy loss in the process of the resonant device converting the input energy (electrical energy) into mechanical energy (ultrasound). This loss is presented in the form of heat and can also be called heat loss.

[0134] On the one hand, improving the efficiency and conversion rate of energy transferred from the resonant device to the water can reduce heat loss. As mentioned earlier, when using high-frequency devices to act on liquids, increasing the operating frequency means improving the efficiency and conversion rate of energy transferred to the water. Experimental testing has shown that the efficiency and conversion rate of energy transferred to water by ultra-sonic devices at operating frequencies above 0.5 GHz already meet the requirements, and heat loss (i.e., heat generation) can be maintained within the desired threshold. Further increasing the operating frequency (i.e., the output frequency of the ultra-sonic device) to above 1 GHz will further reduce heat loss, especially when the operating frequency is increased to above 2 GHz, where heat loss is further reduced.

[0135] From another perspective, the process by which the aforementioned ultra-ultrasonic device converts input energy (electrical energy) into mechanical energy (ultra-ultrasound) includes: a first process in which electrical energy is injected into the ultra-ultrasonic device; and a second process in which the ultra-ultrasonic device converts that energy into mechanical energy (ultra-ultrasound). The first process involves electron transfer to the device, while the second process involves the conversion of mechanical vibrations generated by the device into mechanical energy (ultra-ultrasound). Energy loss (heat loss) can be understood as the portion of input electrical energy that is not fully converted into mechanical energy (ignoring other energy losses). Shortening the duration of the first process is equivalent to shortening the power supply duration within a drive cycle, thereby reducing heat loss caused by continuous power supply (such as heat loss due to device internal resistance, etc.). Furthermore, shortening the duration of the first process also means a relative increase in the remaining time within a cycle, providing more time for the heat loss portion (i.e., generated heat) to dissipate from the ultra-ultrasonic device within a cycle, thereby helping the ultra-ultrasonic device remain within its heating threshold. Based on this, the signal at the input end of the special ultrasonic device is input in a manner modulated by the switching signal, as shown in Figure 5 or Figure 6, so that the signal at the input end of the special ultrasonic device (that is, the output signal of the driving unit) has a signal duration, and then the input signal is turned off for a period of time, and then the input signal can be continued for a period of time again, thus forming a periodic signal input.

[0136] Based on the above analysis, the power supplied by the switching power supply to the super-ultrasonic device is set to a first power. The magnitude of the first power matches the amount of energy required for the required acoustic beam flow. In addition, the first power is modulated by a periodic switching signal into an input driving unit to drive the super-ultrasonic device to operate. That is, the super-ultrasonic device is driven by the first power in an intermittent working mode. The intermittent working mode includes several driving cycles, each driving cycle includes a first stage and a second stage. In the first stage, the high-frequency resonator is driven to generate super-ultrasonic waves of not less than 0.5 GHz, so that the super-ultrasonic device generates super-ultrasonic waves above 0.5 GHz to act on the liquid environment, generating an acoustic beam flow in the liquid environment. In the second stage, the driving of the super-ultrasonic device is stopped.

[0137] Moreover, as mentioned above, the shortening of the first process time is conducive to the heat dissipation of the super ultrasonic device. Therefore, the pulse width of the high level of the switching signal can be made smaller than the first threshold value, that is, the duration of the first stage within the one driving cycle is made to have a duty cycle within the one driving cycle that is smaller than the first threshold value, or the duration is made to be less than the second threshold value. At this time, the temperature of the super ultrasonic device in the intermittent working mode can be made to be within the third threshold value.

[0138] Furthermore, increasing the intensity of the first power input to the ultra-ultrasonic device can increase the intensity of the acoustic beam. Furthermore, while increasing the intensity of the first power, simultaneously reducing the pulse width of the high-level switching signal (i.e., shortening the duration of the first phase), the intensity of the first power can be further increased, thereby further enhancing the intensity of the acoustic beam. Furthermore, since reducing the duty cycle or duration of the first phase within a drive cycle can further increase the intensity of the first power, this can also improve the response speed of the acoustic beam generation, enabling a more rapid response to the drive signal. Testing has shown that the pulse width of the high-level switching signal (i.e., the signal duration within a drive cycle shown in Figure 5, i.e., the duration of the first phase within a drive cycle) can be shortened to 0.1 to 1 microsecond, and when applied at a power of 60W, a high-speed acoustic beam is generated almost instantly, with an extremely short response delay to the drive signal, on the order of microseconds.

[0139] Furthermore, based on the characteristics of the special ultrasonic device itself, or through testing (the test can be performed with the special ultrasonic device in a liquid environment), the maximum efficiency of converting electrical energy into mechanical energy of the special ultrasonic device under different durations of the high level of the switching signal, or different duty cycle outputs, can be obtained. For example, when the high level duty cycle of the switching signal is m1% (corresponding to the switching power supply being in the on stage), by applying different powers (i.e., the amount of electrical energy injected), the amount converted into different mechanical energies is measured, or the amount of heat loss (heat generated by the special ultrasonic device) is measured to calculate the amount converted into mechanical energy. It can be predicted that, when the switching signal has a high duty cycle of m1%, as the power supplied to the hypersonic device by the switching power supply gradually increases, heat loss increases gradually at small increments (this portion represents normal device operation and heat dissipation). However, as the power gradually increases to a certain point, the incremental heat loss, or heat generation, will suddenly increase significantly. This point indicates that within a certain period (T) of the switching signal, the hypersonic device has not yet reached the time required to convert substantially all of the input energy into mechanical energy. The excess unconverted energy is lost as heat, resulting in a significant instantaneous increase in heat loss, which in turn results in a transient high heat generation. The input power corresponding to this point can be considered the input power threshold of the hypersonic device when the switching signal has a high duty cycle of m1%. Based on this approach, the input power thresholds for different switching signal high duty cycles of m1%, m2%, m3%, and so on can be obtained. Theoretically, assuming a constant total energy within this period (T), the smaller the switching signal's high duty cycle m1%, i.e., the shorter the switch's on phase, the higher the threshold power applied during the switching signal's high phase.

[0140] On the other hand, when the pulse frequency output by the switching power supply is relatively low, that is, the period T of the switching signal is long, the super ultrasonic device may convert almost all of the input energy into mechanical energy in less than T time. In this case, the power value output by the switching power supply can be increased as above, or the pulse frequency output by the switching power supply can be increased (that is, the period T of the switching signal can be shortened). Both methods can improve the energy output rate of the switching power supply, and accordingly increase the intensity of the sound beam flow of the super ultrasonic device acting on the liquid.

[0141] On the other hand, for a super-ultrasonic device, the closer its input pulse frequency (i.e., the signal frequency output by the driver) is to the device's operating frequency (i.e., its natural frequency), the greater the vibration amplitude and energy conversion efficiency of the device when it enters a resonant state. Therefore, the frequency of the signal generator's output signal can be designed based on the device's natural frequency.

[0142] On the other hand, increasing input energy also means that the ultra-sonic device drives an increase in the local liquid velocity. This increase in jet velocity leads to an increase in the Reynolds number. An increase in the Reynolds number itself is detrimental to maintaining laminar flow, or in other words, beam flow. However, in actual experiments and measurements, when sufficient energy is driven to generate a beam, the energy's focus makes the beam diameter orders of magnitude smaller than the increase in jet velocity. The Reynolds number remains sufficiently small to maintain the jet in a laminar state with the surrounding liquid, or beam flow. For example, preliminary calculations show that even when the ultra-sonic device input power reaches 60W, the switching signal period is 0.1-0.3 microseconds, and the high-level duty cycle is 50%, the beam velocity reaches 10m / s, and the beam diameter (including the observed width of the surrounding water of varying densities) remains at the 1mm level. The calculated Reynolds number is still small enough to exhibit a clear beam flow.

[0143] In addition, the acoustic beam flow should be controllable. The parameters of the acoustic beam flow that can be controlled include the following:

[0144] a1) The initial jet force, velocity, and jet stroke of the acoustic beam. Since the acoustic beam stroke is related to the velocity or the acoustic beam force, these acoustic beam parameter controls can be controlled using the same input parameters of the ultrasonic device. For ease of description, the initial jet force, velocity, or jet stroke of the acoustic beam will be represented by the first acoustic beam parameter.

[0145] a2) The diameter of the sound beam.

[0146] The input parameters of the ultra-ultrasonic device, or the parameters of the ultra-ultrasonic device itself, or the environmental parameters that may affect the parameters of the above-mentioned controlled acoustic beam flow include the following:

[0147] b1) Output parameters of the switching power supply: waveform parameters of the switching signal, such as the duration of the switching signal's high level within a drive cycle, the duty cycle of the high level, the number and location of high levels when the switching signal contains multiple high levels within a drive cycle; the frequency (or period) of the switching signal, and the applied power (or amplified power). These waveform parameters, frequency, and power can be fixed or variable within each drive cycle, and the variable values ​​can also vary in a regular pattern. For example, they can be divided into large drive cycles, each of which includes several small drive cycles, and the waveform parameters, frequency, or power of these small drive cycles are different.

[0148] For example, the waveforms of the signal generator, such as rectangular waves (square waves), sawtooth waves, spike pulses (or triangular waves), step waves, sine waves, and half-wave signals, are modulated into the output signals of the corresponding drive units into signals such as sawtooth waves, spike pulses (or triangular waves), step waves, sine waves, and half-wave signals. For example, FIG7 shows a modulated spike pulse (or triangular wave).

[0149] The parameter b1 is a controllable parameter, and the value of the first beam flow parameter a1 can be controlled by changing the parameter b1. For example, to enhance the first beam flow parameter, the applied power can be increased, or the applied power can be increased while shortening the duration of the first stage within the driving cycle (i.e., the high-level duration of the switching signal), or the frequency of the switching signal can be increased.

[0150] Testing has shown that increasing the applied power increases the beam diameter in parameter a2, but only slightly. This is reflected in the test data below. It's predictable that increasing the first beam parameter will also increase the beam diameter, but only slightly. The first beam parameter has an impact on the beam diameter, but the proportion of the impact is small. Furthermore, based on the analysis of the test data below, the observed beam diameter includes density variations around the beam, and the actual beam diameter remains very small.

[0151] b2) Parameters of the special ultrasonic device itself (for selection): device type, device shape, device size, device structure, device solid-liquid interface surface structure, device arrangement method when there are multiple special ultrasonic devices, etc. In some embodiments, the arrangement method of the device when there are multiple special ultrasonic devices here can be the arrangement method of multiple independent special ultrasonic devices, such as being arranged in rows, columns, or arrays on the inner wall of the flow channel or the inner wall of the container, such as the inner wall such as the side wall, bottom or top. In other embodiments, the arrangement method of the device when there are multiple special ultrasonic devices can refer to the arrangement of multiple special ultrasonic devices integrated on a substrate, such as having multiple special ultrasonic devices arranged as described above on a substrate, and the positive and negative poles of the multiple special ultrasonic devices are respectively collected at the positive and negative poles facing outward on the substrate. In addition, after the multiple special ultrasonic devices are integrated on the substrate, they exist as an independent device. In addition, when the embodiments of the present application mention multiple special ultrasonic devices, the arrangement of these special ultrasonic devices can be any of the above two types of arrangements.

[0152] The super-ultrasonic device can be a polygon, and in particular, a polygon with an odd number of sides. For example, in one embodiment, it can be a regular pentagon, or a pentagon with unequal sides. In some embodiments, the size of the super-ultrasonic device (here referring to the radial size, non-thickness size, that is, the device interface size) is about 0.01 to 1 square millimeter or less. The size of the super-ultrasonic device is negatively correlated with the achievable resonant frequency, so reducing the size can increase the resonant frequency. In other embodiments, the shape of the device, such as the number of polygonal variables, the angle between two adjacent sides, and the length of each side, can also be used to change the resonant frequency of the super-ultrasonic device.

[0153] In some embodiments, the direction of the acoustic beam can be perpendicular to the surface of the ultra-ultrasonic device. For example, when the ultra-ultrasonic device is a bulk acoustic wave (BAW) device, this is because the piezoelectric constant d33 of the piezoelectric layer (e.g., an AlN layer) of the ultra-ultrasonic device is oriented along the thickness direction. This means that the vibration direction of the piezoelectric layer of the ultra-ultrasonic device, and therefore the direction of acoustic wave transmission, is perpendicular to the ultra-ultrasonic device. In other embodiments, the direction of the acoustic beam can form an acute angle with the surface of the ultra-ultrasonic device. For example, when the ultra-ultrasonic device is a surface acoustic wave (SAW) device, the direction of the acoustic beam, and therefore the direction of acoustic wave transmission, can be approximately 30 to 50 degrees with respect to the surface of the ultra-ultrasonic device.

[0154] In some embodiments, the ultra-ultrasonic device is a bulk acoustic wave device operating in a thickness stretching vibration mode. The device is made by growing a thin film layer of piezoelectric material in a vertical direction, and excites vibration by coupling a vertical electric field with the d33 piezoelectric coefficient. In some embodiments, the ultra-ultrasonic device includes an acoustic wave reflecting layer, a bottom electrode layer, a piezoelectric layer, and a top electrode layer, arranged in order from bottom to top. The overlapping region of the bottom electrode layer, the piezoelectric layer, the top electrode layer, and the acoustic wave reflecting layer constitutes the ultra-ultrasonic generation region, and the thickness of the piezoelectric layer can range from approximately 1 nm to 2 μm. The top surface of the ultra-ultrasonic device can be configured on the wall of a cavity or other device within the cavity. The cavity is a liquid environment, and the ultra-ultrasonic device generates the aforementioned high-speed acoustic beam flow within this liquid environment.

[0155] The acoustic beam diameter, corresponding to the aforementioned parameter a2, is related to the intrinsic parameters of the ultra-ultrasonic device. For example, the smaller the size of the ultra-ultrasonic device (referring to the radial dimension or interface dimension), the smaller the acoustic beam diameter. Based on observations of the acoustic beam impacting target tissue (in a liquid environment, the target tissue is located between 200 and 300 microns from the opposite side of the acoustic beam), increasing the power has little effect on the target tissue impact range. The acoustic beam size generally matches the size of the ultra-ultrasonic device. For example, if a 0.01 square millimeter device is used, the target tissue impact range is also approximately 0.01 square millimeter. Therefore, the acoustic beam diameter is highly correlated with the size of the ultra-ultrasonic device.

[0156] b3) Environmental parameters that can affect the acoustic beam flow include: liquid surface thickness, liquid properties (such as density, viscosity, and liquid acoustic impedance), and the properties and thickness of the layer in contact with the ultra-sonic device in the case of multi-layer liquids. Since b3 is an environmental parameter that generally does not change during operation, this application briefly analyzes these parameters below.

[0157] In this application, experiments have shown that in a liquid environment dominated by aqueous solution, the acoustic beam will accelerate to its maximum speed between 100 microns and 400 microns, especially between 200 microns and 300 microns, from the interface of the ultra-ultrasonic device. Based on this, when considering the application of the maximum speed of the acoustic beam, the liquid surface thickness and the distance between the ultra-ultrasonic device interface and the target object when the acoustic beam acts on the target object can be designed accordingly. The target object may include liquids, solids, colloids, tissues, etc.

[0158] In addition, the properties of the liquid will be reflected in the resistance to momentum. Therefore, it is speculated that when the density, viscosity coefficient and acoustic impedance of the liquid increase, the position where the acoustic beam accelerates to the maximum speed will be shortened if the driving signal (including device input power, driving cycle, and the proportion of the first stage) remains unchanged.

[0159] Furthermore, when multiple layers of liquid are present, the first layer of liquid in contact with the ultra-sonic device will absorb acoustic energy, or, as described above, resist momentum. This can affect the point at which the acoustic beam in the distant second layer of liquid accelerates to its maximum velocity, or its maximum speed. This characteristic can be exploited by adding a first layer of liquid or adjusting its thickness to adjust the point at which the acoustic beam in the second layer of liquid accelerates to its maximum velocity, or its maximum speed. For example, the density, viscosity, or acoustic impedance of the first layer of liquid can be increased relative to that of the second layer of liquid to reduce the point at which the acoustic beam in the second layer of liquid accelerates to its maximum velocity, or its maximum speed.

[0160] The aforementioned environmental parameters that may affect the acoustic beam flow also, from another perspective, affect the first power required to generate a noticeable acoustic beam flow, such as the level of the first power, the duration of the first and / or second phases of the first power drive cycle, or the duty cycle. That is, depending on the environmental parameters of the acoustic beam flow, the aforementioned parameters related to the first power required to generate the acoustic beam flow will vary.

[0161] Among them, under various environmental parameters, the relevant parameters of the first power for generating the acoustic beam can be determined through an experimental process. For example, the desired acoustic beam intensity is first determined, such as the initial velocity of the acoustic beam (or the maximum velocity achievable), or the length of the acoustic beam (the farthest position the acoustic beam can reach corresponding to the maximum velocity), the acoustic beam pressure or pressure at a certain point within the acoustic beam travel, etc.; then, parameters such as the first power level, the size or duty cycle of the first stage and / or the second stage are adjusted until the desired acoustic beam is observed. Moreover, since the formation of the acoustic beam involves parameters such as the first power, the first stage, and / or the second stage, there may be multiple sets of parameters that can obtain an acoustic beam of the desired intensity, such as the first set of parameters (first power p01, first stage t11, second stage t12), the second set of parameters (first power p02, first stage t21, second stage t22), etc. Only the acoustic beam that obtains the desired intensity is discussed here. Under different sets of parameters, other relevant data of the acoustic beam flow obtained may be different, such as the diameter of the generated acoustic beam flow, the heat generated by the ultra-ultrasonic device, the degree of secondary flow phenomenon, etc., and can be further optimized from each set of parameters based on the desired degree of restriction on these other data.

[0162] In addition, this application also proposes some applications of generating acoustic beam flow in a liquid environment, for example, as follows:

[0163] 1) A method for directional high-speed transport of liquid based on acoustic beam flow, comprising: generating a high-speed acoustic beam flow based on the aforementioned method for generating an acoustic beam flow in a liquid environment, wherein the direction of the acoustic beam flow is the direction of directional transport of the liquid, and transporting the liquid in the form of an acoustic beam flow.

[0164] In some embodiments, it can be used as a power device for a local liquid to carry out high-speed directional transport of the local liquid. In other embodiments, when different liquids exist in a liquid environment, a local high-speed directional transport of one liquid can be carried out into another liquid. For example, the different liquids are two liquids in a laminar state, or two liquids that are immiscible in themselves, wherein a first layer of liquid is in contact with a super ultrasonic device, and an acoustic beam flow is generated in the first layer of liquid to transport the acoustic beam flow of the first layer of liquid into the second layer of liquid. In some embodiments, the speed or depth of the acoustic beam flow including the first layer of liquid injected into the second layer of liquid can be controlled by controlling the intensity of the acoustic beam flow, such as the maximum speed that the acoustic beam flow can reach, or the position of the maximum speed. The duration of the acoustic beam flow can be controlled to control the duration of the acoustic beam flow of the first layer of liquid injected into the second layer of liquid. In particular, when both the first layer of liquid and the second layer of liquid are continuously transmitted, the duration can be controlled to achieve intermittent injection of the acoustic beam flow generated in the first layer of liquid into the second layer of liquid. In some embodiments, a first layer of liquid can be injected into a second layer of liquid through an acoustic beam flow to react with the first layer of liquid in the second layer of liquid under the condition of excess of the second layer of liquid. The reaction can be a reaction between two liquids, or a reaction between particles in one liquid (such as particles in the first layer of liquid) and another liquid (such as the second layer of liquid), or a reaction between particles in two liquids, especially a reaction between one liquid (such as the first layer of liquid) or particles therein in an excess of another liquid (such as the second layer of liquid).

[0165] In addition, the amount of the delivered liquid can be controlled by controlling the number (or duration) of consecutive driving cycles including the first stage and the second stage.

[0166] 2) A method for directional high-speed transport of particles in a liquid based on an acoustic beam flow, comprising: generating a high-speed acoustic beam flow based on the aforementioned method for generating an acoustic beam flow in a liquid environment, allowing the transported particles to enter the acoustic beam flow for directional high-speed transport, the direction of the acoustic beam flow being the direction of directional transport of the liquid, and transporting the liquid including the particles in the form of an acoustic beam flow.

[0167] In some embodiments, experimental observations have shown that under the action of the acoustic beam, particles will actively enter the acoustic beam from the liquid environment. For example, one observed phenomenon is that particles will move along the solid-liquid interface of the ultra-ultrasonic device to the point where the solid-liquid interface is facing the acoustic beam, and then be transported out by the acoustic beam.

[0168] Based on this, a method for transporting particles in liquids based on acoustic beam flow can be: the direction of the acoustic beam flow generated by the ultra-ultrasonic device is oriented toward the solution transport direction, for example, consistent with the flow direction of the microchannel, so that the particles in the solution are moved into the acoustic beam flow (or captured by the acoustic beam flow), and under the constraint of the acoustic beam flow, they form a queue along the acoustic beam flow and are transported at high speed. This method can form a queue-like high-speed transport of large-flux particles. Furthermore, the queue-like transport of particles to the downstream facilitates further processing or manipulation of the particles downstream, such as at least one of the following: detection, capture, offset movement control, screening, etc. For example, FIG9 shows a schematic diagram of such an embodiment of capturing particles by acoustic beam flow to form a queue for high-speed transport.

[0169] In some embodiments, such as the scenario of two liquids described above, the particles may be located in the first layer of liquid, and the target liquid may be the second layer of liquid. The particles in the first layer of liquid are injected into the second layer of liquid by an acoustic beam flow, so that the particles react with the injected particles in the second layer of liquid under the condition of excess of the second layer of liquid. In particular, referring to a schematic diagram shown in FIG10 , the flow channel includes a first layer of liquid and a second layer of liquid in a laminar flow. The acoustic beam flow generated by the present application is used to capture the particles in the first layer of liquid and to inject the particles into the second layer of liquid at high speed under constraint of the acoustic beam flow, so that the particles react with the second layer of liquid under an excess environment. In particular, for the sake of simplicity of illustration, the figure does not show the effect of liquid flow on the acoustic beam flow.

[0170] In some embodiments, a particle may be delivered into another substance, such as into a vesicle such as a liposome, or into a cell or muscle tissue or a tissue similar to a cell or muscle, or into subcutaneous tissue.

[0171] In some embodiments, the particles can refer to microscopic particles that are located in a liquid environment, distinguishable from the liquid environment (i.e., insoluble), and movable within the liquid environment. In some embodiments, the particles can have diameters ranging from nanometers to micrometers, and can include cells, molecules, molecular polymers, DNA, and the like.

[0172] 3) In the above-mentioned method for directional high-speed transport of liquid or the method for directional transport of particles in liquid, one or more of the above-mentioned special ultrasonic devices can be set. These special ultrasonic devices can respectively realize their own functions, or they can work together to realize a function based on the design of arrangement position and orientation, such as realizing the turning process during the high-speed transport of liquid or particles, and transporting multiple liquids or multiple particles to the same target position at high speed to achieve high-speed collision.

[0173] 4) Based on the above application of directional high-speed delivery of liquids or particles, it can be further applied to the injection of liquids or particles into the subcutaneous tissue or the like.

[0174] As mentioned above, the diameter of the acoustic beam generated by the present application can be 0.1-1 mm or even smaller, with a diameter of 0.1 mm and the aforementioned 10-100 MPa level, which can meet the needs of needle-free injection.

[0175] In some embodiments, it is applied to needle-free injection, whereby liquid medicine (such as vaccines, injectable drugs, etc.) is injected into the subcutaneous tissue, or even into the subcutaneous muscle layer, by means of an acoustic beam flow. In some embodiments, it can be applied to beauty and skin care, whereby nutrient solution or some filling liquid is injected into the subcutaneous tissue by means of an acoustic beam flow. For example, one or more high-frequency acoustic wave resonators are activated to generate a bulk acoustic wave with a frequency of about 0.5 GHz in a liquid environment such as a solution, suspension or gel, so that the bioactive agent in the liquid environment enters or passes through the patient's skin. Preferably, the first power input to the high-frequency acoustic wave resonator to generate the bulk acoustic wave is about 0.1-500 W, preferably 2-50 W, and more preferably 5-10 W.

[0176] In some embodiments, in the implementation scheme of the injection device used for the above-mentioned injection, the working end of the injection device may have a working cavity with an open end, and a liquid environment may be formed in the working cavity. For example, the working cavity is connected to the drug liquid cavity through a channel or a catheter. The drug liquid cavity and the injection device are integrally arranged or detachably arranged. The working cavity has an interface of the special ultrasonic device, and the sound wave transmission direction of the special ultrasonic device is toward the open end of the working cavity.

[0177] In some embodiments, the distance between the ultra-sonic device interface and the open end of the working cavity can be between 200 and 300 microns, allowing the acoustic beam within the working cavity to exit the working cavity when accelerated to its maximum velocity. In other embodiments, the distance can be designed based on the pressure required for needle-free injection; for example, extending the distance to a distance greater than that required for maximum acceleration can achieve a reduction in pressure. In other embodiments, the pressure reduction can also be achieved by reducing the input power, or by shortening the first stage time while maintaining the same input power.

[0178] In some embodiments, the open end of the working cavity can contact a target object (e.g., skin) to seal the working cavity. In some embodiments, when the ultra-ultrasonic device is not activated and the open end of the working cavity is not in contact with the target object (e.g., skin), the size of the open end of the working cavity can also be designed to prevent the liquid in the working cavity from flowing out due to internal and external pressure differences or liquid surface tension.

[0179] It should be noted here that the size of the ultra-ultrasonic device is microscopic, such as about 0.01 square millimeters to 1 square millimeter, so the diameter of the open end of the working cavity can also be not large, a basic diameter of millimeters is sufficient to form and maintain the above-mentioned liquid surface tension.

[0180] In other embodiments, if there is a scenario in which multiple acoustic beams are generated simultaneously, the open end of the working cavity may have a mesh structure, and a number of special ultrasonic devices may be provided in the working cavity. The direction of the acoustic beam of each special ultrasonic device may be directly facing a mesh hole of the mesh. The mesh structure may use liquid tension to keep the liquid in the working cavity when the special ultrasonic device is not working. The mesh structure may also serve as isolation to maintain the required distance between the contact part of the special ultrasonic device in the working cavity and the target object to be injected.

[0181] 5) Based on the above application of directional high-speed transportation of liquids or particles, it can be further applied to cutting of target objects.

[0182] In some embodiments, a liquid (including a liquid containing particles) can be accelerated by an acoustic beam in a manner similar to a "water knife" to cut a target object, and in particular, the target object can be cut by using an acoustic beam accelerated to or close to the maximum speed. As previously mentioned, the maximum speed of the acoustic beam in a liquid environment can reach 10m / s, and the diameter of the acoustic beam is at the micron level. At this time, the pressure acting on the target object is extremely strong, and the target object can be cut based on this. For example, even when the maximum speed of the acoustic beam in a liquid environment is 1m / s at 200-300 microns of the device, the device size shown in Figure 8 is substantially the same as the device size (0.01-0.02 square millimeters). Under the same conditions, when the power is increased to drive the maximum speed of the acoustic beam to 10m / s, the pressure can reach 100Mpa. At the same time, since the diameter of the acoustic beam generated by this application can be 0.1-1 mm or even smaller, a diameter of 0.1 mm and a level of 10-100 MPa can far meet the pressure requirements for cutting tissues (such as muscles, internal organs, etc.) (usually the surgical water jet pressure is about 0.5-1 MPa).

[0183] In some embodiments, in the implementation of the cutting device used for the aforementioned cutting, the working end of the cutting device may have an open-ended working chamber, wherein a liquid environment may be formed within the working chamber. For example, the working chamber is connected to a liquid supply device via a channel or conduit, and the liquid supply device and the cutting device are integrally provided or detachably provided. The working chamber includes an interface for a super-ultrasonic device, and the sound wave transmission direction of the super-ultrasonic device is toward the open end of the working chamber. The distance between the super-ultrasonic device interface and the open end of the working chamber may be between 200 and 300 microns, so as to utilize the maximum speed to cut the target object.

[0184] In other embodiments, the application environment of the cutting device itself used for the above-mentioned cutting is in a liquid environment. In this case, the above-mentioned working chamber and liquid supply device can be simplified.

[0185] 6) Based on the above application of directional high-speed transport of liquids or particles, it can be further applied to the flushing, polishing, or stripping of attachments on the surface of the target object.

[0186] In some embodiments, when implementing these applications, the generated acoustic beam can be directed toward the target surface, wherein the acoustic beam and the target surface can be arranged at an angle. In other embodiments, the acoustic beam can be directed toward the target location at different angles during the scouring, polishing, or peeling process.

[0187] Below, we present some experimental data to verify the effects mentioned above (some of which have already been described previously). First, it should be noted that the beam width described below is based on optical observations. When a beam is generated, changes in density between the beam and its surroundings create different refractive indices, which can be observed. Furthermore, because the observed image includes areas of varying density, the observed width is wider than the actual beam width. As previously mentioned, the beam width is primarily related to the size of the ultrasonic device. The dimensions of the ultrasonic device used in this experiment are shown in Figure 8. Therefore, it is estimated that the beam width varies by approximately 0.1 mm.

[0188] After testing, in a water-based liquid environment, using a 2k-size (unit is square micrometer, the shape is a regular pentagon) ultra-ultrasonic device, the switching power supply outputs a 10ms / 20ms pulse (referring to a period of 20ms and a level pulse width of 10ms (i.e., the duration of the signal output by the control drive unit)) to the drive unit. Among them, when the drive unit is loaded with a power of 4W, the width of the sound beam (including the observed width of the surrounding water of different densities) is 0.32mm, and the sound beam travel can reach 7.2mm; when the drive unit is loaded with a power of 8W, the width of the sound beam (including the observed width of the surrounding water of different densities) is 0.46mm, and the sound beam travel can reach 8.2mm; when the drive unit is loaded with a power of 20W, the width of the sound beam (including the observed width of the surrounding water of different densities) is 1mm, and the sound beam travel can reach 13mm.

[0189] Using the same conditions, the beam velocity was measured at a distance of 1-2 mm from the point of contact with the ultrasonic device. When the driver power was 10 W, the beam velocity reached 0.41 m / s; when the driver power was 16 W, the beam velocity reached 0.7 m / s; and when the driver power was 20 W, the beam velocity reached 1 m / s. Based on the above analysis, the beam velocity is at its maximum between 200 and 300 microns from the point of contact with the ultrasonic device. Therefore, the measurements at 1-2 mm represent a decelerated beam. Calculations indicate that increasing the power could achieve a beam velocity of 10 m / s at this distance.

[0190] Furthermore, under the above conditions, when the driver unit load power is further increased to 30W, the ultra-ultrasonic device maintains a long-term stable operating state, and the intensity of the acoustic beam flow is further improved. Furthermore, when the pulse width of the switching power supply output waveform is shortened to the microsecond level, such as when the switching power supply outputs 40us / 80us pulses, the driver unit load power can be increased to 50W, and the ultra-ultrasonic device maintains a long-term stable operating state. It is also speculated that if the switching power supply outputs 10us / 20us pulses, the driver unit load power can be increased to 60W. If the pulse width ratio is reduced, for example, when the switching power supply outputs 10us / 30us pulses, the driver unit load power can be further increased. Furthermore, by further reducing the pulse width ratio and attempting to load the power to 100W, the ultra-ultrasonic device still maintains a long-term stable operating state.

[0191] It should also be noted that the solution provided by the present application can generate a high-speed cylindrical focused acoustic beam in a liquid environment, and can control the temperature generated by the thermal effect within a desired value, and reduce or avoid the occurrence of secondary flow. During application, it is possible to choose to focus more on temperature control or focus more on suppressing secondary flow, or the weight of both is basically the same, based on the application scenario, or / and the level of the first power applied to the high-frequency resonator in the application. In some embodiments, for example, when particles or fluids are transported at high speed through an acoustic beam in a microchannel, the first power used may be below 0.5W, and the heat generation itself is relatively easy to control within the desired threshold. In this way, more attention can be paid to suppressing secondary flow, and the duration or proportion of the first stage can be adjusted to minimize the occurrence of secondary flow. For example, the duration of the first stage can be shortened to reduce the possibility of secondary flow generation, or / and the duration of the second stage can be prolonged to increase the time for secondary flow dissipation, so that the liquid environment tends to be stable. Such adjustment is also conducive to suppressing the temperature generated by the device. In other embodiments, such as those used in the aforementioned subcutaneous injection or muscle tissue cutting, the first power used is relatively large, such as 20W to 100W, and is more focused on controlling the heat of the device at high power. In this case, the duration or proportion of the first stage can be adjusted with heat control as the priority to achieve temperature control within the desired threshold, such as reducing the duration of the first stage to reduce the heat generation time, or / and extending the duration of the second stage to increase the time for heat dissipation, so that the temperature of the device or the liquid environment in which the device is located is within the desired threshold. Such adjustments are also conducive to suppressing secondary flows. Here, only the adjustment of the duration of the first stage and / or the second stage is taken as an example. In actual applications, the first power can be adjusted together so that the first power can achieve the required intensity of the acoustic beam flow under the above-mentioned suppression of temperature and secondary flows.

[0192] This application also verified the following through experiments:

[0193] 1) Under the conditions that the first power of driving the high-frequency resonator is a constant value and the first-stage power supply time and the second-stage time are 1:1, the different first-stage durations (i.e., the device working time within a driving cycle) are as follows: wherein, the shorter the first-stage duration, the smaller the eddy current effect formed by the high-frequency resonator, and the more obvious the acoustic beam flow. It can be measured that when the first-stage duration is lower than a certain value, the acoustic beam flow cannot be formed. This is because the total energy is determined by power and time. If the time is too short, the energy required to generate the acoustic beam flow cannot be reached. Based on this, the lower limit of the first-stage duration for generating the acoustic beam flow when the first power is a constant value can be measured. It can also be measured that when the first-stage duration is higher than a certain value, obvious eddy currents will be formed. This is because the eddy current effect lags behind the acoustic beam flow. When the first-stage duration reaches or approaches the lag time that causes the eddy current effect, obvious eddy currents will be formed. Therefore, the upper limit of the first-stage duration for generating the acoustic beam flow when the power is a constant value can be measured. This upper limit avoids the formation of obvious eddy currents.

[0194] 2) When the first stage time and the second stage time are constant, the higher the first power, the faster the acoustic beam speed.

[0195] The high-frequency resonator has an upper limit on the power it receives. After exceeding the upper limit, the increase in the speed of the acoustic beam with the increase in the first power is no longer obvious, and exceeding the upper limit will result in a significant increase in the thermal effect. This is because the first-stage time and the second-stage time (the sum of the first-stage time and the second-stage time is the driving cycle) are constants. When the first power increases to exceed the upper limit of the energy that can be converted into the acoustic beam within the driving cycle, most of the excess energy is manifested in the form of thermal effects. Therefore, based on the temperature effect, the upper limit of the first power can be measured when the first-stage time and the second-stage time are constants. In addition, the lower limit of the first power that generates the acoustic beam when the first-stage time and the second-stage time are constants can also be measured as in 1) above.

[0196] 3) Under the conditions of a constant first power and a constant first-stage duration, and provided that a beam can be formed, the longer the drive cycle (i.e., the smaller the first-stage duty cycle, or the longer the second-stage duration), the smaller the eddy current effect. A drive cycle that is too short will cause eddy currents. This is because a longer drive cycle results in a longer interval between two adjacent first-stage times, while a shorter drive cycle results in a shorter interval between two first-stage times, which increases the likelihood of eddy currents.

[0197] 4) The vortex is located near the end of the acoustic beam. When the position of the acoustic beam is at its highest speed or near its vicinity, there is no need to pay too much attention to the vortex.

[0198] 5) The eddy current effect is later than the generation of the acoustic beam flow, and the thermal effect is later than the eddy current effect. Based on this, the length of the first stage can be controlled to suppress the thermal effect below the threshold, or to suppress the secondary eddy current effect.

[0199] 6) For high-frequency resonators of different sizes, at the same input power, the smaller the size, the higher the intensity of the acoustic beam and the faster the speed. This reflects that the smaller the device size, the stronger the focusing ability.

[0200] Among them, the result data of the experiment of this application can be seen in Figure 11, where the vertical axis is the average acoustic beam velocity at 600um from the surface of the high-frequency resonator device, and the unit is m / s; the power of the horizontal axis is the power input to the device (see Figure 4, that is, the input power of the input device after power amplification); the high-frequency resonators used are devices of 2k, 5k, 10k, and 20k sizes (unit is square microns), respectively. Among them, Figure 12 is a schematic diagram of the dimensions of the above-mentioned high-frequency resonators used in the experiment of this application. A pentagonal device is used, and the specific dimensions can be seen in the figure.

[0201] It should be noted that, unless otherwise specified, the above-mentioned particle examples are described using aqueous solutions (which may contain other particles). When the solution is other than an organic solution (e.g., oil) or a gel solution, the data mentioned above will vary depending on the properties of the liquid.

[0202] This application also combines experimental data with simulation analysis to further verify the conclusions obtained from the data of this application. Specifically, a COMSOL model of a 5K-sized high-frequency resonator is constructed, in which the flow field in the physical field model is 1mm wide and 2mm high, and the high-frequency resonator is located in the middle of the bottom of the flow field. By modifying the size of the volume force generated by the high-frequency resonator, a transient simulation is performed to obtain the maximum acoustic beam velocity (maximum acoustic beam velocity = 50um / time taken for the first beam to reach 50um from the device surface) and the average acoustic beam velocity (average acoustic beam velocity = 600um / time taken for the first beam to reach 600um from the device surface), and compared with the experimental results. The order of magnitude and growth trend of the maximum velocity and average velocity of the acoustic beam generated by the 5K high-frequency resonator in the simulation results are consistent with the experimental results, which also bidirectionally verifies the accuracy of the experiment and simulation.

[0203] The input power and volume force of the high-frequency resonator can be fitted into an approximately linear relationship, and the relationship between the input power and the maximum velocity and average velocity of the acoustic beam can be obtained as follows: on the one hand, as the power increases, the maximum velocity of the acoustic beam also gradually increases. This is because when the power applied to the device increases, the volume force generated above the device is greater, which can make the acoustic beam produce a higher initial velocity; on the other hand, the growth of the maximum velocity gradually slows down. This is due to the incompressibility of the liquid. The initial velocity of the acoustic beam does not increase indefinitely with the increase of the device power, but grows gradually and slowly and finally stabilizes at a certain value. The part that is not converted into kinetic energy will mostly appear in the form of heat. In particular, when the power increase exceeds a certain value, the heat generated in the first stage time cannot be completely dissipated within the complete cycle composed of the first stage time and the second stage time, and the high-frequency resonator will produce a significant thermal effect.

[0204] The following introduces the first type of applications provided by the embodiments of the present application. The first type of applications includes particle control and sorting schemes based on acoustic beam flow, such as control and sorting methods, control and sorting devices, etc.

[0205] Once the liquid environment is determined and the ultrasonic device is selected, the relationship between the acoustic beam intensity and the control parameters (the first power and / or the periodic signal composed of the first and second phases) can be calibrated. In one scenario, if the periodic signal is a constant (i.e., the first and second phases are constant), calibrating the acoustic beam intensity and the first power can reveal the relationship between the first power and the acoustic beam intensity (which corresponds to the distance the acoustic beam can propel the particles). This allows the appropriate first power to be controlled to propel the particles to the desired distance, or along the desired route.

[0206] Among them, the route along which the particles are pushed can be pre-calibrated (can be calibrated through simulation, experiment, or calculation), and this route can be used to design the relative position of the ultra-ultrasonic device and the target flow channel (the inlet of the diverter flow channel, or the junction section corresponding to the inlet of the diverter flow channel). Specifically, since the path of the particle is related to factors such as the liquid flow rate of the liquid environment (referring to the liquid flow rate in the microchannel, including the sheath flow rate and the sample flow rate), liquid properties (such as viscosity), acoustic beam intensity (related to the first power of the ultra-sonic device and / or the periodic signal formed by the first and second stages), and particle properties (including shape, size, and mass), when designing the relative position, the non-variable factors can be first determined (for example, after the sheath flow and sample flow and flow rate are selected, the liquid properties and liquid flow rate are the non-variable factors). Then, based on the variable factors (i.e., the factors used as control parameters in the specific control process), the different paths of the particle at different values ​​of the variable factors are calibrated (calibration can be performed through simulation, experiment, or calculation). Then, based on the paths, the relative position of the ultra-sonic device and the target channel is designed, and the path of the particle can be controlled based on the control parameters corresponding to the variable factors, so that the particle moves along the desired path.

[0207] For example, as shown in FIG20 , in order to avoid obstruction by the junction section of the downstream branch flow channel of the microchannel, the ultra-ultrasonic device in FIG20 can be set at a position slightly away from the junction section.

[0208] Furthermore, when the liquid environment is determined, the location of the hypersonic device also affects the power required to propel the particles. As shown in Figure 12, the closer the device is to the boundary, the faster the initial velocity of the particles toward the diversion channel is required to avoid obstruction by the boundary, thus increasing the power required. The farther the device is from the boundary, the less obstruction the boundary has on the diversion channel, and the lower the power required. In some embodiments, the power applied by the hypersonic resonator can be 100-2000 mW, the sheath flow rate can be 1-40 μL / min, and the device can be placed 100-3000 μm from the boundary.

[0209] The acoustic beam-based particle control and sorting solution provided in this application uses an optical solution to identify target particles among particles passing in a queue in a microfluidic channel. The ultra-sonic device described in this application then generates an acoustic beam of desired intensity in the fluid, pushing the target particles to change their direction of motion, such as toward a desired location within the microfluidic channel (e.g., a target laminar flow) or a target branch channel location in the microfluidic channel, thereby achieving control or sorting of the target particles. This is described in detail below with reference to the various figures and examples.

[0210] The first embodiment of the present application provides a particle control device based on an acoustic beam flow, wherein the particle control device is included in the schematic diagram of FIG22 , and the particle control device includes:

[0211] A microfluidic channel, the microfluidic channel comprising a first flow channel, wherein a fluid flowing downstream is contained in the first flow channel, the fluid contains particles, and the particles include first particles;

[0212] The first ultra-sonic device is arranged closely to the first flow channel, and is used to generate an acoustic beam flow of desired intensity when it is activated, deviate the moving direction of the first particles flowing through it by the acoustic beam flow, and make the particles flowing through it flow downstream when it is not activated.

[0213] In some embodiments, the trajectory of the first particle after the deviation aligns with the target flow channel position, so that the first particle enters the target flow channel after the deviation. The target flow channel is connected to the sidewall of the first flow channel or is located downstream of the first flow channel. In some embodiments, multiple flow channels may be connected to the sidewall or downstream of the first flow channel to enable the sorting of multiple types of particles. For details, see the embodiments regarding particle sorting described below.

[0214] In some embodiments, the fluid in the first flow channel forms a laminar flow, and the first particles move steadily downstream within the laminar flow. The acoustic beam deflects the movement of the first particles passing through it, changing their direction of motion, such as by leaving the current laminar flow and entering another laminar flow to move downstream. In some embodiments, the downstream has structures corresponding to different laminar flows, for example, different flow channels corresponding to different laminar flows (different branch channels corresponding to different laminar flows). For example, the downstream branch channel examples of Figures 16 or 19 can be applied in this manner.

[0215] In some embodiments, the flow rates of different laminar flows of the fluid in the first flow channel may be different. In other embodiments, the liquid properties (such as liquid composition, temperature, viscosity, etc.) of different laminar flows of the fluid in the first flow channel may be different. The moving direction of the first particles can be deviated by the acoustic beam flow to enter the target laminar flow.

[0216] In some embodiments, the liquid in the target laminar flow (ie, the laminar flow into which the first particles deviate) can react with the first particles, thereby driving the first particles to flow toward the target laminar flow.

[0217] The second embodiment of the present application provides a particle sorting device. FIG13 shows a schematic diagram of the particle sorting device. The particle sorting device includes at least a microfluidic channel and a first ultra-sonic device, wherein:

[0218] A microfluidic channel includes: a first channel, at least one second channel and one third channel connected to the downstream of the first channel. In some embodiments, the microfluidic channel is also referred to as a microfluidic chip. The second channel and the third channel constitute a diversion channel. In some embodiments, there may be more diversion channels connected to the downstream of the first channel, for example, a fourth channel or more connected to the downstream of the first channel, which can be used to sort different particles. The first channel contains a fluid flowing downstream, and the fluid contains particles, which include first particles and may also include other particles, such as second particles.

[0219] The first ultra-sonic device is arranged closely to the first flow channel, and is used to generate an acoustic beam flow of desired intensity when the first ultra-sonic device is activated, thereby deviating the moving direction of the first particles flowing through the first ultra-sonic device so that the particles flow toward the second flow channel, and to make the particles flowing through the first ultra-sonic device flow toward the third flow channel when the first ultra-sonic device is not activated.

[0220] In some embodiments, when the acoustic beam of desired intensity generated by the first ultra-sonic device is fixed, when the acoustic beam acts on different particles passing through it, the deviations in the movement directions of these different particles will vary, causing them to flow into different target separation channels, thereby achieving separation of different particles. This is because different particles have different masses, shapes, and / or volumes, resulting in at least one of their own inertia (inertia is related to mass), the force exerted by the fluid, and / or the fluid resistance experienced when changing direction under the force of the acoustic beam. Consequently, their deviated movement trajectories are also different. Accordingly, target diversion channels can be set corresponding to these trajectories to achieve separation of these different particles.

[0221] In some embodiments, the device further includes a driving unit for driving the first ultra-ultrasonic device to generate an acoustic beam, thereby driving the first ultra-ultrasonic device to generate the aforementioned acoustic beam. In some embodiments, the driving unit can drive the first ultra-ultrasonic device to generate acoustic beams of varying intensities, each acting on different target particles, causing these different particles to flow into different diversion channels, thereby sorting different particles into different diversion channels, for example, diverting a second particle flowing through the first particle to flow into a fourth channel.

[0222] In some embodiments, the particle sorting apparatus may further include a particle focusing unit configured to arrange the particles in the fluid in the first flow channel into a queue. The queued particles facilitate the activation of the acoustic beam of the first ultra-sonic device for each target particle (e.g., the first particle). Furthermore, this facilitates the individual passage of each particle through the detection unit described below.

[0223] In some embodiments, the particle sorting apparatus may further include a detection unit configured to detect the particles in the queue to identify the first particle in the queue. In some embodiments, the detection unit may identify different target particles in the queue, such as a second particle or more types of particles in the queue.

[0224] In some embodiments, a control device is further included for receiving a signal from a detection unit, performing analysis based on the signal, and identifying the first particle and / or other particles from the particles arranged in the queue, and accordingly controlling the driving device to drive the first ultra-sonic device to generate a sound beam flow of the desired intensity. In some embodiments, the control device is also used to identify and analyze the state of the particles, such as the particle flow rate, whether they are arranged in a queue, or whether the spacing between the particles reaches the desired spacing, based on the signal received from the detection unit, and adjust the particle focusing unit accordingly so that the particles in the sample flow are arranged in a queue with the desired flow rate and desired spacing, that is, a queue of the desired shape is obtained. In some embodiments, the control device can be an independent device, and in other embodiments, the control device can be integrated with the detection unit.

[0225] In some embodiments, such as the example of FIG. 14 , the microchannel's diverter can be a dual-diverter (where each downstream outlet is considered a diverter), or, as in the examples of FIG. 15 , FIG. 16 , or FIG. 19 , the microchannel's diverter can be a three-diverter or diverter structure with any number of diverters. In some embodiments, such as the examples of FIG. 15 or FIG. 19 , at least two of the inlets of these diverter channels are located on the path of the particles when the acoustic beams of different intensities from the same first ultra-sonic device act on the particles. In other embodiments, such as the example of FIG. 16 , multiple first ultra-sonic devices can be provided, each corresponding to the inlets of the multiple diverter channels at different locations. Accordingly, the positions of the multiple first ultra-sonic devices are also different. For example, in some embodiments, multiple first ultra-sonic devices can be arranged sequentially on the same side of the first channel, with the inlets of each diverter channel arranged sequentially on the other side of the first channel. Alternatively, multiple first ultra-sonic devices can be arranged on both sides of the first channel (as shown in FIG. 16 ).

[0226] In some embodiments, the diverter channel can be an independent channel located downstream of the first channel (as shown in FIG16 ), or an independent channel connected to the downstream sidewall of the first channel (as shown in FIG14 ). Multiple diverter channels can connect to the same location on the downstream sidewall of the first channel (as shown in FIG15 ), or multiple diverter channels can connect to different locations on the downstream sidewall of the first channel. The diverter channel can be a channel located downstream of the first channel that is separated by a partition along the flow direction of the channel (as shown in FIG19 ), and multiple partitions can be provided to separate multiple diverter channels.

[0227] In some embodiments, as shown in the examples of Figure 17 or Figure 18, the cross-sectional shape of at least a portion of the microchannel along the direction perpendicular to the fluid flow is a polygonal restriction with height restriction, length restriction, width restriction or a combination of dimensions (such as both height and width are narrowed). Through these shape restrictions, and in combination with a particle focusing unit, especially when combined with a sheath flow module, it is used to achieve single-column queue arrangement of particles in the sample flow.

[0228] In some embodiments, the microchannel material includes polydimethylsiloxane, optical glass, organic material, etc.

[0229] In some embodiments, the microparticle focusing unit includes a sheath flow module, which includes a sheath flow channel and a sample flow channel connected upstream of the first flow channel. The sheath flow channel is used to provide a flow field environment for the sample to be tested in the microchannel. The sheath flow arranges the microparticles in the sample flow flowing out of the sample flow channel in a uniform and single-file queue in the first flow channel. Parameters such as the flow rate of the input sheath flow can be controlled by a control device to control the valve opening or micropump power on the sheath flow input device or the sheath flow channel.

[0230] In some embodiments, when the height of the microchannel is relatively high, the height of the microchannel is designed so that the particles in the channel are arranged in at least two layers, as in the examples shown in Figures 14, 15 or 16, the sheath flow channel surrounds the sample flow channel, and sheath flow is applied uniformly in each direction around the sample flow, so that the particles in the sample flow flowing into the microchannel after the action of the sheath flow are arranged in queues.

[0231] In some embodiments, when the height of the microfluidic channel is relatively high, and the height of the microfluidic channel is designed so that the particles in the flow channel are arranged in at least two layers at the height, the inner contour of the sample inlet of the microfluidic channel can be narrowed, and the sheath flow channel can be used to make the particles in the sample flowing into the microfluidic channel after the sheath flow acts on it to be arranged in a queue. As shown in Figure 17, an embodiment is shown, in which the inner contour of the microfluidic channel inlet is horizontally narrowed (or the width or length is narrowed), and in terms of height, there is a sheath flow channel inlet above the microfluidic channel, so that the particles in the sample flow entering the microfluidic channel are arranged in a single row in the lower layer (the upper layer is sheath flow). As shown in Figure 18, another embodiment is shown, in which the inner contour of the microfluidic channel inlet is narrowed downward in height, and the sheath flow enters from both sides of the sample flow channel, so that both sides of the sample flow are sheath flow, thereby arranging the particles in the sample flow in a single row in the middle of the lower layer.

[0232] In some embodiments, the detection unit can be an optical or photoelectric detection unit. The target particles, i.e., the first particles, can be pre-modified with fluorescence. The detection unit can specifically be a device that can detect fluorescence, for example, it can detect parameters such as the brightness intensity, range, shape, size, and quantity of fluorescence. When a particle with fluorescence is detected, or a particle that meets the required fluorescence (such as brightness, range, and / or shape), or a particle that meets the requirements after detection and analysis (such as in combination with an analytical device such as a computer as a control device), it is considered that the first particle as the target particle has been detected. Based on the same principle, multiple target particles can be detected and analyzed.

[0233] In some embodiments, the optical or photoelectric detection unit may include a unit for providing excitation light to cause the sample or target particles in the microfluidic channel to emit fluorescence, and a collection unit for collecting the fluorescence and converting it into an electrical signal for transmission to a control device, which then analyzes the fluorescence parameters. In some embodiments, the optical or photoelectric detection unit detects an optical detection area of ​​2-20 μm within the first flow channel.

[0234] In some embodiments, the detection unit can be an electrical or electromagnetic based detection unit. In some embodiments, the target particles, i.e., the first particles, can be pre-magnetized or polarized (carrying positive or negative charge), and the magnetized or polarized particles are detected by the detection unit.

[0235] In some embodiments, the detection unit can be a detection unit based on image and analysis functions, such as an image acquisition device that reaches the required resolution and an analysis device (such as a computer as a control device), which identifies target particles by analyzing the acquired images through the analysis device.

[0236] In some embodiments, the position of the first ultra-sonic device can propel the first particle at high speed to a second position via an acoustic beam when activated, wherein, as in the examples shown in FIG. 14 or FIG. 15 , the second position is located within the second flow channel, or, as in the example shown in FIG. 16 , the second position is located upstream of the second flow channel inlet. When designing the positions of the first ultra-sonic device and the second flow channel inlet or more branch channel inlets, it is necessary to consider the particle trajectories when the acoustic beams of different intensities generated by the first ultra-sonic device act on different particles at the desired flow rate and different first powers. This allows different target particles to follow different paths and enter the corresponding branch channels by controlling the first power and using acoustic beams of different intensities. The design of the position of the first ultra-sonic device and the positions of each branch channel inlet can be achieved through simulation or experimentation.

[0237] In some embodiments, the branch channel entrance and the ultra-ultrasonic device are located on either side of the first flow channel. In some embodiments, as shown in the example of FIG15 , different sub-branch channel entrances are located within the branch channel at different distances from the ultra-ultrasonic device. These sub-branch channel entrances are positioned to match acoustic beams of varying intensities, allowing different target particles to enter through different routes. In some embodiments, as shown in the example of FIG16 , at least two ultra-ultrasonic devices can be positioned corresponding to the at least two branch channel entrances, respectively. The ultra-ultrasonic devices can be located on the same side or on both sides of the first flow channel.

[0238] In some embodiments, such as the example shown in FIG16 , the first super ultrasonic device is located on the first side inner wall 0-3000 μm in front of the junction of the straight flow section and the diverter flow section of the first flow channel, and a narrow channel is formed between the super ultrasonic device and the second side inner wall of the junction of the straight flow section and the diverter flow section of the first flow channel.

[0239] The first power output by the driving device satisfies the requirement that, when acting on the first particles in the direct flow section, the first particles' movement direction is altered and shifted, thereby redirecting the first particles' flow path to a desired path. The desired path allows the first particles to enter the target flow channel, thereby achieving separation of the first particles. The first power output ranges from approximately 0.1 to 500 W, preferably from 2 to 50 W, and more preferably from 5 to 15 W. The specific power range is selected based on the desired acoustic beam intensity. For example, in this embodiment, when the ultra-ultrasonic device operates at a frequency of 1 to 10 GHz, the power used is 100 to 2000 mW. The driving cycle consisting of the first and second stages is 1 to 1000 MHz, with a duty cycle of 0.1% to 100%. The generated acoustic beam can push fluorescent particles of 0.01 to 40 μm away from their original trajectory by 0 to 1000 μm, causing the fluorescent particles to move forward along a parabolic trajectory.

[0240] In some embodiments, the above-mentioned microparticles may refer to: microscopic particles that are located in a liquid environment and can be distinguished from the liquid environment (i.e., insoluble) and can be moved in the liquid environment can be regarded as the above-mentioned microparticles. In some embodiments, the diameter of the microparticles can range from nanometer scale to millimeter scale, and the microparticles can include: cells, molecules, molecular polymers, DNA nucleic acids, etc. In some embodiments, the microparticles can be fluorescently labeled microparticles, referred to herein as fluorescent microparticles, wherein the fluorescent microparticles include a microparticle core and a fluorescent layer or are doped with fluorescent substances, the microparticle core is silica, magnetic iron oxide, polystyrene, polylactic acid, polyacrylic acid, polyamides, polyaniline, gelatin, calcium carbonate, barium carbonate, cellulose, pectin, starch, albumin, chitosan, stained cells or bacteria, etc., and the fluorescent layer is a fluorescent dye, quantum dots, antibody protein or nucleic acid labeled with fluorescent molecules, etc.

[0241] A third embodiment of the present application provides a particle control method based on an acoustic beam flow, which uses any of the aforementioned particle control devices or separation devices based on an acoustic beam flow, or any of the aforementioned optional embodiments, to achieve particle control. The particle control method includes the following steps:

[0242] S01: allowing a fluid including particles to flow into a first flow channel of a microfluidic channel, wherein the particles include first particles;

[0243] S02: deactivating the first ultra-sonic device to allow the particles flowing through it to flow downstream; activating the first ultra-sonic device to generate an acoustic beam flow of desired intensity, thereby deviating the moving direction of the first particles flowing through it through the acoustic beam flow.

[0244] Among them, the contents related to particle focusing, particle detection, particle sorting, etc. can also be applied to this particle control method and will not be repeated here.

[0245] A fourth embodiment of the present application provides a particle sorting method based on an acoustic beam flow, wherein particles are sorted using any of the above-described particle sorting devices based on an acoustic beam flow or alternative embodiments thereof. The particle sorting method includes the following steps:

[0246] S10: allowing a fluid including particles to flow into a first flow channel of the microfluidic channel, wherein the particles include first particles;

[0247] S20: The first ultra-sonic device is not activated to allow the particles flowing through it to flow toward the third flow channel downstream; the first ultra-sonic device is activated to generate an acoustic beam flow of desired intensity, and the moving direction of the first particles flowing through it is deviated by the acoustic beam flow so that the particles flow toward the second flow channel downstream.

[0248] In some embodiments, between steps S10 and S20, the method further includes:

[0249] Arranging the particles in the fluid in the first flow channel into a queue by a particle focusing unit;

[0250] The particles in the queue are detected by a detection unit, and the first ultra-ultrasonic device is activated when a first particle included in the queue is identified, and the first ultra-ultrasonic device is deactivated when a non-first particle included in the queue is identified.

[0251] For example, when a sheath flow device is used as a particle focusing unit, a specific implementation method of arranging the particles in the fluid in the first flow channel in a queue through the particle focusing unit may be: injecting the sample to be tested into the sample flow channel inlet of the microchannel, so that the sample to be tested flows through the first flow channel and flows out to the downstream outlet, wherein the sample to be tested includes at least two different fluorescent particles; starting the sheath flow device to provide a flow field environment for the sample to be tested in the first flow channel, so that the fluorescent particles in the sample to be tested can pass through the first flow channel at a uniform speed and in a single file.

[0252] For example, when the detection unit is an optical detection unit, a specific implementation method of detecting the particles in the queue through the detection unit may be: providing excitation light through the optical detection unit to make the sample to be detected emit fluorescence, and then the optical detection unit collects the fluorescence of the sample to be detected and converts it into an electrical signal and sends it to the control device.

[0253] A specific implementation of step S20 may be as follows: a control device obtains analysis results based on the electrical signal, the analysis results including the size, quantity, fluorescence wavelength, and fluorescence intensity of the various fluorescent particles. When a first particle in the queue is identified, a control signal is sent to a drive device. The drive device controls the first ultra-sonic device to generate an acoustic beam flow of a desired intensity, thereby driving the particles into the corresponding second flow channel, thereby sorting the target fluorescent particles. When a particle other than the first particle in the queue is identified, the first ultra-sonic device is deactivated, causing the particles to flow downstream into the third flow channel.

[0254] In some embodiments, the diameter of the fluorescent particles is 0.01 to 40 μm, or 10 to 40 μm, or 0.1-15 μm, and the wavelength of stimulated emission is 400-1500 nm. In some embodiments, the width of the direct flow section of the first flow channel is 100 to 300 μm or 50 to 150 μm; the width of the diverter flow section is 100 to 300 μm or 50 to 150 μm, the width of the junction between the diverter flow section and the direct flow section is 10 to 100 μm, the flow channel height of the microchannel is 100 to 300 μm or 50 to 150 μm, and the flow rate of the sample to be tested is 0.1 to 100 uL / min. The power of the driving unit for driving the first ultra-sonic device is 50 to 2000 mW.

[0255] The present application is further introduced below with reference to the particle separation method based on acoustic beam provided in the fifth to seventh embodiments of the present application. In the fifth to seventh embodiments, the ultra-sonic device adopts an area of ​​30000 μm 2的A regular pentagonal bulk acoustic wave resonator, wherein a first power for driving the bulk acoustic wave resonator is 50 to 2000 mW, a signal period is 30 to 50000 μs, and a duty cycle is 0.1% to 5%.

[0256] Among them, the particle sorting method based on acoustic beam flow provided in the fifth embodiment of the present application verifies the particle sorting effect. In this embodiment, the fluorescent particles are solid polystyrene microspheres with a diameter of 15 μm doped with fluorescein isothiocyanate (FITC) dye. The schematic diagram of the selected microfluidic chip (i.e., the microchannel part) is shown in Figure 21, wherein the direct flow channel is 100-300 μm wide and 100 μm high, the diversion flow channel is 50-200 μm wide and 70 μm high, and the width of the junction between the two is 30 μm. The bulk acoustic wave resonator is located on the first side inner wall 0-300 μm in front of the junction of the direct flow channel section and the diversion flow channel section of the microchannel. The sheath flow device has a flow rate of 1-40 μL / min, and applies hydraulic pressure uniformly around the sample flow in each direction.

[0257] Based on the relationship between the BAW resonator applied power and the corresponding acoustic beam jet velocity shown in FIG23, and the relationship between the BAW resonator applied power, sample flow rate, and the corresponding acoustic beam jet height shown in FIG24, the specific parameters within the effective range can be determined. As shown in FIG22, a specific example, the BAW resonator applied power is 1200 mW, the flow rate is 10 μL / min, the straight channel width is 240 μm, the height is 110 μm, the diverter channel section width is 70 μm, and the junction section width is 30 μm (left side of FIG22). The BAW resonator is located on the first side inner wall 700 μm before the junction section. The fluorescent particles (flowing from right to left in FIG22) pass from the lower layer through the BAW resonator and are pushed to the uppermost layer by the acoustic beam generated by the resonator. They then flow a distance and enter the diverter channel section.

[0258] Among them, the trajectory of the particles from deviation to the target position (such as the target branch channel) is related to the liquid flow rate in the first flow channel (including sample flow and sheath flow), the physical properties of the particles (such as shape, size, and mass), the physical properties of the fluid (such as the liquid's own density and viscosity), and the properties of the acoustic beam flow (such as direction, intensity, and duration). After determining the target particles, the fluid used, the target branch channel position, the ultra-sonic device and its position, the relationship diagram of Figure 24 can be obtained through experiments or simulations, which can be used for control in particle sorting.

[0259] In the method of the sixth embodiment of this application, different types of sheath flow devices, microfluidic chips, and bulk acoustic wave resonators are used in combination to verify the particle sorting method based on acoustic beam flow. The sheath flow device used in the fifth embodiment uniformly applies hydraulic pressure in all directions to enable fluorescent particles to pass through the microchannel at a uniform speed and in a single file. This sixth embodiment uses unidirectional or bidirectional sheath flow supplemented by bidirectional or unidirectional restrictive channels in conjunction with a bulk acoustic wave resonator to complete the sorting of fluorescent particles. A microfluidic chip with a unidirectional sheath flow in the height direction and a bidirectional restrictive channel in the length and width direction is shown in Figure 17, and a microfluidic chip with a bidirectional sheath flow in the length and width direction and a restrictive channel in the height direction is shown in Figure 18. Both designs enable fluorescent particles to pass through the optical detection area and above the bulk acoustic wave resonator at a uniform speed and in a single file. The unidirectional sheath flow velocity in the height direction is 5-40 μL / min, the end of the bidirectional restrictive microchannel in the length and width direction is 10-30 μm, the bidirectional sheath flow velocity in the length and width direction is 1-20 μL / min, and the height of the restrictive microchannel in the height direction is 10-30 μm. The subsequent microchannel design and BAW resonator power design and coordination may refer to the fifth embodiment.

[0260] The present application will be further introduced below in combination with the particle sorting method based on acoustic beam flow provided in the seventh embodiment of the present application.

[0261] In the seventh embodiment of this application, a scheme for simultaneously sorting more than two fluorescent particles is used to verify the particle sorting method based on acoustic beam flow. While the fifth embodiment described above uses a single branch flow channel to sort two different fluorescent particles, this seventh embodiment improves on the fifth embodiment by using multiple branch flow channels to simultaneously sort multiple particles.

[0262] Figure 15 shows the separation of three types of fluorescent particles using two branch flow channels of a single BAW resonator. According to the relationship between the power applied by the BAW resonator, the sample flow rate, and the corresponding acoustic beam jet height, increasing the power applied by the BAW resonator can increase the acoustic beam jet height. That is, the particles passing through the acoustic beam flow enter different branch flow channels according to the different powers applied by the BAW resonator. The number of branch flow channels can be 1-3, and their total width (including all junction sections) is 100-300μm. The power applied by the BAW resonator is 100-2000mW, and the sheath flow rate is 1-40μL / min.

[0263] A device for further improving the number of particle sorting is shown in Figure 16. It includes two bulk acoustic wave resonators and two, four, or six branch flow channels, achieving the sorting of three, five, or seven types of fluorescent particles. The two bulk acoustic wave resonators are placed relative to each other on the first side inner wall and its opposite side inner wall located 0-3000μm before the junction section. The microchannel height is 50-400μm, the width of the first flow channel before the junction section is 100-400μm, and the width after the junction section is 30-200μm. The branch flow channel is 30-200μm wide. The sheath flow device has a flow rate of 1-40μL / min. The first power applied to the two bulk acoustic wave resonators is controlled and adjusted according to the target fluorescent particles to complete the particle sorting.

[0264] Next, the second type of application provided by the embodiments of the present application is introduced. The second type of application includes solutions for processing cells based on acoustic beam flow, such as methods and devices for processing cells.

[0265] The solution for treating cells based on acoustic beam provided in the present application can control the super ultrasonic device to generate a highly concentrated acoustic beam in the liquid, thereby treating the target cells through the acoustic beam to change the state of the target cells. The acoustic beam described in the present application has a small effective area (or a small diameter or cross-section), high pressure, and fast response (that is, it can be generated and disappeared instantly, or the pulsed acoustic beam has a high frequency, which can be in the microsecond level). Among them, the pulsed acoustic beam is generated by periodically driving the super ultrasonic device to act on the target cells, so as to act on the target cells through pulsed impact simulation of slapping (or knocking, hammering), poking, stabbing, etc. The target cells are directly affected by the acoustic beam and change their state, or change their state in response to the stimulation of the impact. The solution based on highly concentrated acoustic beam in the present application can act on the target cells in a high-frequency impact manner, and the super ultrasonic device has a fast response speed in generating the acoustic beam. Below, a detailed example is given.

[0266] An eighth embodiment of the present application provides a method for treating cells based on an acoustic beam flow, comprising:

[0267] The ultra-ultrasonic device and the target cells are relatively fixed in position, and at least the ultra-ultrasonic device is placed in a liquid environment, and the target cells are within the range of the acoustic beam of the ultra-ultrasonic device;

[0268] The ultra-ultrasonic device is driven to generate an acoustic beam in the liquid environment, and the acoustic beam acts on a target position of the target cell to change a state of the target cell.

[0269] In some embodiments, the ultra-sonic device may be periodically driven to generate a pulsed acoustic beam in the liquid environment, and the acoustic beam acts on a first position on the surface of the target cell, causing the first position on the surface of the target cell to be impacted by the pulsed acoustic beam, thereby causing at least one of the following changes: deformation of the target cell surface, generation of pores on the target cell surface, generation of pores at the first position, cutting at the first position, or entering a corresponding state in response to stimulation;

[0270] Among them, the target cell enters a corresponding state in response to stimulation, including at least one of the following: activating the cell's mechanical gate channel, reorganizing the cytoskeleton, activating the signal transduction pathway, and changing the secretory activity.

[0271] In some embodiments, the target cell is much larger than the cross-sectional area of ​​the acoustic beam. In this case, the first position is located somewhere on the surface of the target cell. In this case, the impact of the pulsed acoustic beam on the target cell can be simulated as a poke or stab. In other embodiments, the ratio of the target cell surface area to the cross-sectional area of ​​the acoustic beam is less than a certain ratio (e.g., 50%). For example, the target cell surface is completely covered by the cross-sectional area of ​​the acoustic beam. In this case, the impact of the pulsed acoustic beam on the target cell can be simulated as a complete slap (or knock, hammer).

[0272] In some embodiments, when the cross-sectional area of ​​the acoustic beam is small, or relatively small relative to the target cell surface area, a stronger acoustic beam is more likely to directly impact the target cell surface, creating pores or cutting. In some embodiments, when the cross-sectional area of ​​the acoustic beam is large, or relatively large relative to the target cell surface area, or when the impact of the relatively weak acoustic beam is relatively weak, the cell is more likely to enter a state corresponding to the stimulus, thereby activating the cell's mechanical gating channel. Of course, both situations may exist simultaneously.

[0273] In some embodiments, the target cell may be a single cell as described above. In other embodiments, the cross-sectional area of ​​the generated acoustic beam may be controlled to cover two or more single cells, in which case the target cells are the two or more cells.

[0274] In some embodiments, the target cell may be measured based on the impacts to measure the number of impacts required to induce a certain state change.

[0275] For each of the changes in the target cells listed above, further experiments can be conducted to test which changes are more prominent when different acoustic beam flow parameters are applied, as well as the changing trends of different acoustic beam flows and the changes. The parameters for applying different acoustic beam flows herein may include at least one of the following: the driving power of the ultra-ultrasonic device, the driving cycle, the duration or duty cycle of the first and second phases of the driving cycle, the duration of the action, the distance and / or angle between the ultra-ultrasonic device and the target location, etc.

[0276] In some embodiments, a substance in the liquid environment can be allowed to enter the interior of the target cell through the pore or the mechanical gate channel, or a substance in the liquid environment can be allowed to enter the interior of the target cell through the pore or the mechanical gate channel via the transmission of the acoustic beam. In some embodiments, when a substance in the liquid environment is allowed to enter the interior of the target cell via the transmission of the acoustic beam, the substance is accelerated by the acoustic beam and introduced into the interior of the target cell. In some embodiments, when the substance is accelerated by the acoustic beam and introduced into the contents of the target cell, it can, for example, enter directly by perforating the cell membrane.

[0277] In some embodiments, the substances in the liquid environment can include ions (e.g., Na+, Ca2+, Cl-), genetic material (e.g., DNA or RNA), pharmaceutical agents, particles (e.g., vesicles or particulate drugs), etc., to achieve effects on the physiological activities of target cells after introduction into target cells, transfection of target cells, drug injection, etc. In some embodiments, after the impact of the acoustic beam ends, the pores or mechanical gates of the cells will automatically close.

[0278] In some embodiments, the first position on the surface of the target cell includes a portion of the surface of the target cell perpendicular to the acoustic beam, that is, a position directly opposite the acoustic beam, to achieve a better acoustic beam impact. In some embodiments, in addition to achieving the vertical position (i.e., the front) rapid impact, it can also include a side rapid impact, and continuous impact can achieve dynamic squeezing of the cell, continuous mechanical stimulation, etc.

[0279] In some embodiments, the ultra-ultrasonic device can be periodically driven to generate a pulsed acoustic beam flow in the liquid environment, and the acoustic beam flow acts on a second position on the surface of the target cell, where the second position is located at the binding position between the target cell and the binding object, so that the second position is impacted by the pulsed acoustic beam flow and separated from the binding object.

[0280] In some embodiments, the method further includes collecting the target cell that has detached from the binding object. For example, a mouth pipette can be placed near the target cell. Preferably, the mouth pipette is located in the direction of movement of the target cell after detachment, such as on the other side of the second position of the target cell.

[0281] In some embodiments, the binding target can be a carrier, such as a glass slide, and the detachment of adherent cells (i.e., target cells) on the glass slide can be achieved, for example, by acoustic beam streaming. In other embodiments, the binding target can also be another cell bound to the target cell, for example, the other cell is located on a carrier, and the target cell is separated from the other cell by acoustic beam streaming.

[0282] In some embodiments, when separating a target cell from another cell, a specific principle may be that the cells are bound to each other through multiple protein contact interfaces (i.e., multivalent interaction binding). Through the high-speed pulsed acoustic beam flow of the present application, it is possible to quickly cut the second protein after cutting the first protein and before the first protein recovers, and so on to cut each bound protein, thereby achieving efficient cell peeling.

[0283] In some embodiments, the target cells are located on a binding object, and the portion of the binding object containing the target cells is in the liquid environment. In this case, for example, a carrier containing the target cells is placed in a vessel in the liquid environment, and the ultra-sonic device is inserted into the liquid environment to act on the target cells on the carrier.

[0284] In some embodiments, the target cells are located on the binding object, the portion of the binding object with the target cells is not in the liquid environment, and the portion of the binding object with the target cells is in a position where the acoustic beam can rush out of the liquid environment and reach. For example, the carrier with the target cells is placed upside down (with the target cells facing downward) above a vessel in the liquid environment and is not immersed in the liquid environment. The ultra-ultrasonic device extends into the liquid environment to generate an acoustic beam that is upward and breaks through the surface of the liquid environment to act on the target cells on the carrier. For example, in another case, the ultra-ultrasonic device is equipped with a liquid supply device. When the ultra-ultrasonic device is working, the liquid supply device provides a liquid environment (such as the ultra-ultrasonic device is located in an open microcavity, and the microcavity is connected to the liquid supply device), generating an acoustic beam that can break through the surface of the liquid environment and act on the target cells on the carrier.

[0285] In some embodiments, the device implementing the aforementioned ultra-sonic device-based cell treatment method can be a robotic arm, as described below. In some embodiments, it can also be handheld, such as the one described above, configured with a liquid supply environment, where the ultra-sonic device is located within an open microcavity, which is connected to a liquid supply device to provide a liquid environment during operation. The microcavity can be located at the end of a handheld device, which can contain a drive circuit, etc. In some embodiments, it can also be implemented in a microfluidic system, for example, located at the bottom of a flow channel or microcavity, through which a liquid containing target cells can flow.

[0286] The ninth embodiment of the present application provides a processing device based on a super ultrasonic device, as shown in FIG. 25 and FIG. 26 , and the processing device may include:

[0287] a stage on which a target object in a liquid environment can be placed, the target object including a target cell;

[0288] A robotic arm, wherein a probe is mounted on a movable end of the robotic arm, and an ultra-ultrasonic device is mounted on the end of the probe, and the probe can be moved or stopped at a position above the stage by the robotic arm;

[0289] The ultra-ultrasonic device is used to generate an acoustic beam in the liquid environment to act on the target object.

[0290] In some embodiments, the probe tip is equipped with one or more ultra-sonic devices. In some embodiments, when multiple ultra-sonic devices are provided, they can be arranged in an array, with the working surfaces of at least two ultra-sonic devices coplanar or arranged at an acute angle. In some embodiments, the multiple ultra-sonic devices can have the same or different parameters to generate acoustic beams of the same or different intensities and diameters under the same driving parameters.

[0291] In some embodiments, the ultra-sonic device assembled on the probe end can be located on both sides of the probe end, so that the probe can be rotated 180 degrees along its axis and then clamped and fixed at the rotating part, thereby realizing quick selection of the ultra-sonic device for work.

[0292] In some embodiments, when the probe has multiple ultra-ultrasonic devices, each ultra-ultrasonic device can be driven separately, and the ultra-ultrasonic device to be used can be moved to a desired position and posture by moving the robotic arm to act on the target object.

[0293] In some embodiments, the stage is made of a transparent material; an image capture device is disposed below the stage, comprising at least one lens that is adjustable to face the stage. Thus, the image capture device below can capture images (since video is composed of frames of images, images here include video) of the process and results of the acoustic beam acting on the target object, for analysis, or to control the operating status of the ultra-sonic device and the position of the robotic arm's movable end based on the obtained image data or analyzed data.

[0294] In some embodiments, the image acquisition device may be a microscope having multiple lenses, wherein the multiple lenses are mounted on a rotating component to achieve switching of the working lenses so that the working lenses face upward.

[0295] In some embodiments, the image capture device may be positioned beside or above the stage (e.g., diagonally above), and the lens of the image capture device may be adjusted to face the target object on the stage for image capture. In some embodiments, the image capture device may include multiple lenses positioned at different locations (e.g., below, beside, or diagonally above the stage).

[0296] In some embodiments, the robotic arm includes a three-axis robotic arm disposed beside the stage, the movable end of the three-axis robotic arm is equipped with a rotating portion, and the rotating portion is equipped with the probe. In some embodiments, the rotating portion can rotate along a horizontal axis. In some embodiments, the rotating portion has a clamping portion to facilitate the replacement of the probe. In some embodiments, as shown in FIG27 , the probe end portion can be composed of two detachable parts, one part for being assembled to the rotating portion, and the other part having a probe end portion, which is equipped with the special ultrasonic device, so that the probe can be replaced as needed, or the part with the probe end portion can be replaced. Among them, the size of the special ultrasonic device in the right figure in FIG27 is smaller than that in the left figure. Under the same conditions, the diameter of the sound beam flow that can be generated by the special ultrasonic device in the right figure is much smaller than the diameter of the sound beam flow generated by the special ultrasonic device in the left figure, that is, it is more focused and the unit area that can be processed is smaller.

[0297] In some embodiments, the loading platform can move horizontally; wherein, the loading platform can be mounted on a horizontal guide rail, so that it can be driven by a motor to move along the guide rail to adjust the target object on the loading platform to a desired position, and can be equipped with an electrical control box, which may have a control unit for controlling the movement of the loading platform.

[0298] In some embodiments, the probe can be moved and rotated using the three-axis robotic arm and the rotating portion. In some embodiments, the three-axis robotic arm comprises an x-, y-, and z-axis robotic arm, enabling translation of the probe. The rotating portion can be the aforementioned horizontal axis rotation. This combination enables probe movement and rotation, thereby adjusting the ultra-ultrasonic device at the probe end to a desired position. This desired position allows the ultra-ultrasonic device to contact or be immersed in the aforementioned liquid environment. A robotic arm controller 21 can also be provided to control the robotic arm's posture.

[0299] In some embodiments, the ultra-ultrasonic device is driven with a first power cycle to generate the acoustic beam flow. For details, see the previous description of the acoustic beam flow, drive cycle, and drive device, which will not be repeated here. It should also be noted that in subsequent experiments, under conditions where the ultra-ultrasonic device temperature is allowed, the drive cycle also used a first phase accounting for 100% (which can be understood as continuous drive without forming a pulsed drive mode).

[0300] In some embodiments, the liquid environment, for example, is liquid contained in a vessel placed on a stage, with the target object located within the vessel. The vessel may also be made of a transparent material to facilitate image acquisition by an image acquisition device below the stage. In other embodiments, the liquid environment refers to liquid present on the surface of the target object. This liquid may be liquid carried on the surface of the target object itself, or liquid continuously sprayed or drained to the target location of the target object during operation of the ultra-ultrasonic device.

[0301] In some embodiments, the target object is fixed relative to the probe, for example, the target object may be attached to the surface of a device (such as a glass slide, etc.) or on the surface of other tissues (such as organic tissue), and the device or organic tissue may be fixedly placed in the aforementioned vessel.

[0302] The tenth embodiment of the present application provides a method for treating cells based on a super-ultrasonic device, using any of the above-described treatment devices based on a super-ultrasonic device or its optional embodiments, the method comprising the following steps:

[0303] S1: placing a target object in a liquid environment on a stage, wherein the target object includes a target cell.

[0304] S2: Controlling the robotic arm to adjust the posture of the ultra-ultrasonic device mounted on the end of the probe, such that the ultra-ultrasonic device faces the target object at a certain angle, and at least a portion of the ultra-ultrasonic device is located in the liquid environment.

[0305] S3: enabling the ultra-ultrasonic device to generate an acoustic beam in the liquid environment to act on the target object.

[0306] In some embodiments, the method is used for at least one of the following:

[0307] a. The target object is continuously or intermittently impacted by a sound beam with set parameters to measure a certain attribute parameter of the target object.

[0308] b. The target position or target object is detached from the surface of another object to which the acoustic beam is applied by acting on the target position or target object. In some embodiments, the other object can be a glass slide as described above, or can be an organic tissue.

[0309] c. The sound beam acts on the target object, so that a hole is generated in the target object at the position where the sound beam acts.

[0310] d. The sound beam acts on the target object, causing the particles carried by the sound beam in the liquid environment to enter the interior of the target object.

[0311] e. Applying mechanical stimulation to the target object by applying an acoustic beam to the target object for analysis, where the mechanical stimulation includes at least one of the following: poking the target object, bombarding the target object, shoveling the target object, and cutting the target object.

[0312] In some embodiments, when used for measuring a property parameter of a target object as described in a above, the property includes the impact resistance of the target object under an acoustic beam flow with set parameters, the method includes:

[0313] S1a: Place an object containing a target object, such as a glass slide with adherent cells (the cells are the target objects), in a vessel containing liquid.

[0314] S2a: Adjust the position of the robotic arm and the stage so that the ultra-ultrasonic device at one end of the probe is inserted into the vessel and immersed in the liquid, and faces the target object. The distance from the target object is set, and the sound beam flow with the set parameters is controlled to continuously or intermittently impact the target object.

[0315] S3a: Continuously capture images through the image acquisition device under the stage, and analyze the time or number of intervals required for the target object to change its state based on the image. The time or number of intervals is used as a property parameter for measuring the impact tolerance of the target object under the acoustic beam flow of the set parameters.

[0316] The state change includes at least one of the following: a change in the integrity of the target object, a change in the position or posture of the target object, or a change in the shape of the target object.

[0317] In some embodiments, when used for detaching the target object from the surface of another object to which it is attached as described in b above, the method includes:

[0318] S1b: Place an object containing a target object, such as a glass slide with adherent cells (the cells are the target objects), in a vessel containing liquid.

[0319] S2b: Adjust the position of the robotic arm and stage so that the ultra-ultrasonic device at one end of the probe is inserted into the vessel and immersed in the liquid, facing the target object at a set distance from the target object. Control the generation of a sound beam with set parameters, and continuously or intermittently impact the target location to act on the target object. The target location can be a location where the target object is separated from the surface of another object.

[0320] S3b: Continuously capture images using an image acquisition device below the stage, and analyze the images to determine whether the target object has detached from another object (e.g., a glass slide). Based on the image analysis, at least one parameter in S2b can be automatically or manually adjusted to adjust the impact process or the impact area.

[0321] In other embodiments, different target objects have different binding forces (or adhesion forces) with another object. The other object can be the aforementioned glass slide or an organic tissue (such as a cultured cell wall). By controlling at least one parameter in step S2b to different values, it is possible to selectively separate a desired target object from multiple target objects. For example, if a glass slide has target objects with different binding forces, by controlling one or more parameters in step S2b so that the force (or flow rate) of the acoustic beam when it reaches the target object is a certain value, the target object with a binding force less than or equal to that value is separated from the glass slide.

[0322] In some embodiments, different target objects can be modified with different numbers / types of antibodies, so that the antibodies have different binding forces with another object. This can be achieved by modifying a substance with antibodies, so that the liquid includes different substances modified with different numbers / types of antibodies to form different target objects, and then allowing each substance modified with antibodies to bind to the surface of the target object (i.e., the above-mentioned other object, such as a glass slide) to form a wall-adherent substance, wherein the substance is bound to the surface of the target object through the modified antibodies. The different numbers / types of antibodies modified on the substance will result in different binding forces between the substance and the target object (i.e., different target objects have different binding forces with another object).

[0323] In some embodiments, when applied to the above-mentioned step b to detach the target object from the surface of another object to which it is applied, a suction port is further provided facing the target object or target position, and the suction port is connected to a negative pressure device, and the peeled target object is collected through the suction port. The suction port can be in the extension direction after the sound beam acts on the target object or target position. In some embodiments, the suction port is located near the position of the captured substance of the second super ultrasonic device described later, and is provided toward the position. In some embodiments, the suction port is movable, for example, it is the suction port of a hose, and the hose can be moved to the corresponding position by hand.

[0324] In some embodiments, a filter is further provided at the suction port, wherein the mesh size of the filter matches the size of the target object. In some embodiments, the filter is replaceable and can be replaced with a filter of a desired mesh size.

[0325] In some embodiments, the invention further comprises a channel communicating with the suction port, wherein at least one of the following is provided in the channel:

[0326] 1) A queue device, configured to arrange the target objects flowing through the channel into a queue. The queue device includes a sheath flow structure or another ultrasonic device with a tip (e.g., a blade-shaped or shuttle-shaped tip). For example, the sheath flow structure can be a sheath flow introduced into the channel from the side, a three-dimensional structure such as a sheath flow structure surrounding the channel, or a two-dimensional structure such as a sheath flow structure located on both sides or one side of the channel. A pointed ultrasonic device, with its tip located downstream, captures the target objects at its edge and releases them through the tip.

[0327] 2) Detection device, used to detect the target object flowing through. This can be a laser detection device, an image detection device, a fluorescence detection device, an electrical detection device, a magnetic detection device (for example, when the substance is bound to magnetic beads), etc.

[0328] 3) An image acquisition device, used to acquire images of the target object passing through. This can be used to analyze the target object using images and can be combined with AI technologies, such as neural network technology, to analyze the images.

[0329] In some embodiments, a second ultra-ultrasonic device is further included to capture the peeled target object; the working surface of the second ultra-ultrasonic device is also located in the liquid environment, forming a vortex effect to capture the target object that is free after peeling in the liquid environment.

[0330] In some embodiments, other operations can be performed on the captured target object. For example, when the target object is a cell, other microfluidic instruments can be used to achieve at least one of the following: cell transfection, cell selection, cell measurement, interaction between cells and other substances, cell assembly, cell fusion, and cell analysis (gene analysis, protein analysis, cytogenomics analysis).

[0331] In other embodiments, the binding force between the target object and another object may be measured and calibrated based on the principles of the above steps S1b-S3b.

[0332] In some embodiments, when used in step d above to allow particles carried by an acoustic beam in a liquid environment to enter a target object, the method includes:

[0333] S1d: Place an object containing a target object, such as a glass slide with adherent cells (the cells are the target objects), in a vessel containing liquid.

[0334] S2d: Adjust the position of the robotic arm and the stage so that the ultra-ultrasonic device at one end of the probe is inserted into the vessel and immersed in the liquid, and faces the target object. The distance from the target object is set, and the acoustic beam flow with the set parameters is controlled to impact the target object continuously or intermittently.

[0335] The particles are guided into the path of the acoustic beam in the liquid environment, for example, through a microchannel or a catheter, and the particles are injected into the path of the acoustic beam, or injected near the ultra-ultrasonic device, so as to be captured by the acoustic beam.

[0336] Based on the acoustic beam flow, the particles carried by the acoustic beam flow are impacted into the interior of the target object.

[0337] S3d: Continuously capture images using an image acquisition device below the stage, and analyze the images to determine whether the particle has entered the target object. Based on the image analysis, at least one parameter in S2d can be automatically or manually adjusted to adjust the impact process.

[0338] In order to better understand the present application, the present application also provides an eleventh embodiment, which uses the generated acoustic beam to peel off adherent cells, wherein reference may be made to Figures 28-32. Figure 28 shows the relative position of the ultra-ultrasonic device and the target object, the generated acoustic beam and the target position. The embodiment of Figure 28 uses the acoustic beam to peel off adherent cells from a glass slide (adherent cells are the target object), so the acoustic beam in Figure 28 is at a certain angle to the glass slide with adherent cells attached (for example, the glass slide with the target object in Figure 28 is placed horizontally and the direction of the acoustic beam is inclined). In order to compare the pulsed acoustic beam with the continuous acoustic beam (i.e., the first stage accounts for 100%, i.e., the device is normally open), the continuous acoustic beam is first used to act on the adherent cells to obtain the range of action, and then the pulsed acoustic beam is used. The comparison shows that reducing the proportion of the first stage can further have a highly concentrated range of action.

[0339] Figure 29 shows the different sizes of the acoustic beam flow's action area on the glass slide when the ultra-ultrasonic device is driven at different first powers in the normally open state (i.e., the first stage of the drive cycle accounts for 100%). The cross diagrams in each figure in Figure 29 indicate the widest and longest points of the action area. Figure 30 is a list of parameters corresponding to each figure in Figure 29. It can be seen that the smaller the first power, the smaller the acoustic beam flow's action area, that is, the more focused it is. From the normally open acoustic beam flow in Figure 30, it can be inferred that the trend relationship (here refers to positive correlation or negative correlation) between the various parameters of the pulsed acoustic beam flow is similar.

[0340] Figure 31 shows the area affected by the first phase of the drive cycle at different proportions. The first power is 2W, with the first phase accounting for (100µs / 1000µs)% in the left figure and 100% (i.e., normally on) in the right figure. It can be seen that the range of the acoustic beam generated by the pulsed ultra-ultrasonic device in the left figure (the circled area in Figure 31) is significantly reduced. Due to the relative tilt of the ultra-ultrasonic device and the stage (refer to the positional relationship shown in Figure 28), the circled area in Figure 31 (the image captured by the image acquisition device) is offset from the position of the ultra-ultrasonic device. The area of ​​the ultra-ultrasonic device in Figure 31 is 2k square microns. Furthermore, experiments have shown that reducing the first phase proportion and increasing the first power still produces a high-intensity acoustic beam with a smaller range.

[0341] Figure 32 shows the relationship between drive power and acoustic beam velocity or force at different distances between the ultrasonic device and the target object. The distances of 400 μm and 1000 μm in Figure 32 represent the distances between the ultrasonic device and the target object. As can be seen, the force or velocity of the acoustic beam reaching the target object decreases as the distance increases.

[0342] FIG33 shows an image of an experimental result of using the present invention's solution to act on a single cell. The image is specifically a frame of an image from a video taken with a bottom-mounted microscope. The experimental environment is as follows: 2 mL of PBS buffer and 10 microliters of PI (propidium iodide) reagent were added to a 3.5 cm diameter culture dish. The cells used were MCF-7 human breast cancer cells (seeded at a density of 10 to the power of 4 and cultured in a dedicated cell culture incubator for 48 hours). Before the experiment, the cells were stained with calcein (cell activity detection reagent) in the dark for 30 minutes to make the cells appear green (proving survival). During the experiment, the culture dish was placed on the stage of a processing device based on a super-ultrasonic device provided in an embodiment of the present invention (such as a device shown in FIG25 ), and the super-ultrasonic device of the processing device was adjusted vertically downward to face the target cell. The super-ultrasonic device was adjusted to 500 microns away from the target cell; the driving parameters of the super-ultrasonic device were: power 1W, signal period 200ms, and high level proportion (i.e., first stage proportion) 25%. Among them, the processing device based on the special ultrasonic device provided in the embodiment of the present application can realize automatic control after inputting parameters. Specifically, it automatically focuses on the target object based on the microscope, and automatically controls the movement of the manipulator and / or the stage to adjust the posture and position of the special ultrasonic device to be facing and 500 microns away.

[0343] Once the ultra-ultrasonic device is in place, the drive parameters described above drive the ultra-ultrasonic device to generate an acoustic beam, and a video is captured by the image acquisition device below the stage for observation. In the image obtained in Figure 33 (i.e., the image of the experimental result), the green represents a small piece of tissue on the slide (or indicated by A in the figure), indicating that it remains active after the experimental treatment. The red point (or the position indicated by B in the figure) is a single cell on the green tissue. This single cell is the target cell of the acoustic beam, and it turns red due to the introduction of drugs during the experiment. The captured video shows that approximately 2 seconds after the ultra-ultrasonic device generates the acoustic beam, the single cell at the target location turns red, indicating that the drug contained in the liquid in the vessel has been introduced into the single cell.

[0344] Possible ways in which drugs can be introduced into the single cell are as follows:

[0345] First, it is speculated that since the drug is introduced into the single cell after 2 seconds of observation (the color of the single cell changes after 2 seconds), it is speculated that the intensity of the acoustic beam controlled in this experiment does not directly pierce the cell membrane with a single pulse. This intensity causes the single cell to be impacted by a high frequency, and the effect of this high-frequency impact is closer to a pulse-like slapping (or beating), which stimulates the cell accordingly and opens its mechanical channels (at least one mechanical channel), and the drug in the liquid environment passes through the mechanical channels to allow the drug in the liquid to enter the cell (exchange between inside and outside the cell).

[0346] Secondly, it is possible that in addition to opening the mechanical channel, the impact of the acoustic beam may also be used to provide power for the drug in the liquid to be injected into the cell through the mechanical channel.

[0347] Another possibility is that after the cell membrane is loosened by high-frequency impact, the drug can be directly injected into the cell through the loosened cell membrane via the acoustic beam. For example, a granular drug in a liquid environment is accelerated by the acoustic beam and then injected into the cell. The granular drug can be located near the surface of the ultra-ultrasonic device or directed to the surface of the ultra-ultrasonic device via a pipeline. When the ultra-ultrasonic device is operating, the granular drug flows to the root of the acoustic beam, is carried by the acoustic beam, and is accelerated and injected into the cell.

[0348] These experimental results demonstrate that the cell treatment method based on the ultra-sonic device, as provided in the examples of this application, can achieve single-cell targeting accuracy (which can be understood as the diameter or cross-section of the acoustic beam). The intensity (pressure) of the action on a single cell is related to the distance between the ultra-sonic device and the target cell, the intensity of the generated acoustic beam, the mode of action (intermittent or continuous) of the beam, and the duration of the action.

[0349] Next, the third type of application provided in the embodiments of the present application is introduced. The third type of application includes a solution for realizing a micro water hammer effect based on an acoustic beam flow, such as a method and device for realizing a micro water hammer effect, and a liquid feeding device based on the micro water hammer effect.

[0350] The embodiment of this application provides a solution for achieving a micro-water hammer effect based on acoustic beam flow. This solution can control a hypersonic device to intermittently generate a highly concentrated acoustic beam flow in a liquid, thereby creating a water hammer effect. Compared to a continuous acoustic beam flow (i.e., one without water hammer), this water hammer-based acoustic beam flow has a stronger force. This water hammer-based acoustic beam flow can be used for drug delivery, cleaning, and microparticle manipulation.

[0351] Drug administration, for example: injecting liquid or substance in liquid into the target object through the acoustic beam flow of the water hammer effect, such as injecting into the subcutaneous epidermis of an organism, or injecting into a cell. The application scenario of the present application can be subcutaneous drug administration, which can be realized by a device such as a syringe, such as subcutaneous drug administration on the skin of the arm or buttocks, etc. The medicine here includes therapeutic drugs that can be in liquid form or dissolved in liquid, nutrients, etc., such as subcutaneous injection, or subcutaneous supply of nutrients, such as subcutaneous supply of nutrients on the face, neck, etc., nutrients such as hyaluronic acid, collagen, hyaluronic acid gel and other beauty or skin-friendly substances or water, etc. Since the acoustic beam flow has high focusing properties, another application scenario of the present application is fixed-point dyeing of the skin, such as use for making patterns on the skin (such as skin tattoos, skin branding).

[0352] Cleaning: For example, the sound beam flow through the water hammer effect acts on the surface or skin of the material to clean the surface or skin.

[0353] For example, manipulation of particles can be performed by continuously applying an acoustic beam based on the water hammer effect to a particle (such as a cell) to test its mechanical properties, such as impact resistance (force magnitude), tolerance (impact durability, etc.), and affinity (such as cell adhesion to an attached object). Another example is changing the particle's spatial position (such as the detachment of a cell from its attached object), morphology, or structure (such as perforation of the particle's surface membrane).

[0354] As a further example, when the microparticles are cells, the manipulation of the cells can also include, for example, stimulating the cells with an acoustic beam based on the water hammer effect, so that the cells respond to the stimulation and activate mechanosensitive channels, reorganize the cytoskeleton, activate signal transduction pathways, or change secretory activity.

[0355] Below, the solution for realizing the micro water hammer effect based on the acoustic beam flow provided in the present application is described in detail with reference to the accompanying drawings and embodiments.

[0356] The twelfth embodiment of the present application provides a method for realizing a micro water hammer effect based on an acoustic beam flow, including a liquid environment and a hypersonic device;

[0357] When the ultra-ultrasonic device is in operation, it generates ultra-ultrasonic waves of 0.5-30 GHz to act on the liquid environment, so as to generate directional fluid motion at the solid-liquid interface along the direction of propagation of the sound wave in the liquid, and the directional fluid motion includes a focused columnar acoustic beam flow. Thus, the ultra-ultrasonic device is driven to operate in at least one driving cycle with a first power, and each driving cycle includes a first stage and a second stage. In the first stage, the ultra-ultrasonic device is driven to generate ultra-ultrasonic waves of 0.5-30 GHz, and in the second stage, the driving of the ultra-ultrasonic device is stopped. The magnitude of the first power enables the ultra-ultrasonic device to generate the acoustic beam flow in the first stage.

[0358] Furthermore, the duty cycle of the second phase in at least one driving cycle is adjusted to intermittently generate the acoustic beam flow, and the duration of the intermittent generation is greater than a threshold value, and the intermittently generated acoustic beam flow below the threshold value produces a micro water hammer effect.

[0359] In some embodiments, the duty cycle of the second phase of at least one driving cycle is adjusted to intermittently generate the acoustic beam flow. This can be achieved by adjusting the duty cycle of the second phase of each driving cycle. Referring to the example shown in FIG. 34 a, this example is described as follows:

[0360] Assuming that under the driving signal with the duty cycle output shown in FIG5 , based on the characteristics of the fluid (fluidity, viscosity, and continuity), the generated acoustic beam flow is a continuous acoustic beam flow (a continuous acoustic beam flow means that there is no or no obvious water hammer effect). Referring to FIG34 a, the duty cycle of the second stage is increased, and when the duty cycle of the second stage is increased to a certain extent while still ensuring that the acoustic beam flow can be generated, an intermittent acoustic beam flow can be formed to generate a micro-water hammer effect. In this case, the duration of each cycle output by the driving device remains unchanged, and what changes is the distribution ratio between the first stage and the second stage. Among them, the shorter the first stage, the less energy the ultra-sonic device obtains in one cycle, and the lower the energy of each micro-water hammer. It should be noted that the first stage cannot be shorter than the duration of the acoustic beam flow (too low energy makes it difficult to generate an acoustic beam flow).

[0361] In some embodiments, adjusting the duty cycle of the second phase of at least one driving cycle to intermittently generate the acoustic beam flow can be accomplished by adjusting the duty cycle of the second phase of at least one driving cycle in at least two consecutive driving cycles. The examples shown in FIG. 34 b and c are described below.

[0362] In the example shown in b of FIG34 , the driving signal outputted relative to FIG5 is modulated into a low-level signal every 2nth cycle, thereby realizing the generation of intermittent acoustic beam flow to generate a micro water hammer effect.

[0363] In the example shown in c in FIG34 , the driving signal outputted relative to FIG5 is modulated into a low-level signal every 3nth cycle, thereby realizing the generation of intermittent acoustic beam flow to generate a micro water hammer effect.

[0364] Among them, compared with b in Figure 34, the frequency of micro water hammer is lower, and the acoustic beam flow of each micro water hammer lasts longer, so the energy of each micro water hammer is higher.

[0365] In some other embodiments, micro water hammer may be generated with a variable time interval (or variable frequency). For example, the second and fifth cycles of the driving signal outputted in FIG5 are modulated into low-level signals.

[0366] In some embodiments, in addition to adjusting the micro-water hammer effect in the manner provided above, the micro-water hammer effect can also be controlled by at least one of the following methods: controlling the strength of the micro-water hammer effect by the first power strength; controlling the interval degree of the micro-water hammer effect by the duty cycle of the second stage.

[0367] In some embodiments, the liquid environment is located in a cavity, a hollow needle extending outward is provided on a wall of the cavity, and the acoustic beam generated by the ultra-ultrasonic device is directed toward the hollow needle.

[0368] The hollow needle can be used to influence the range and / or directionality of the micro-water hammer effect. For example, in the example shown in Figure 39 , the middle hollow needle is directly facing the ultra-ultrasonic device. For details on the effect of the hollow needle on the micro-water hammer effect, please refer to Figures 45 and 46 below.

[0369] In some embodiments, the hypersonic devices and corresponding hollow needles are arranged in an array to produce a micro-water hammer effect. This allows for application of an acoustic beam with a micro-water hammer effect to targets over large areas. The hypersonic devices can be discrete or, as shown in Figure 43 , integrated onto a single substrate using multiple hypersonic chips. For details, see the description of the embodiment shown in Figure 43 below.

[0370] In some embodiments, the method further includes: the target object on which the acoustic beam flow of the generated micro water hammer effect acts includes at least one of the following: a first particle, epidermis or surface, and tissue within the range of the micro water hammer effect.

[0371] In some embodiments, the liquid environment further includes second particles, and the acoustic beam flow generated by the micro water hammer effect carries the second particles.

[0372] The thirteenth embodiment of the present application provides a device for realizing micro water hammer effect based on acoustic beam flow, comprising the liquid environment and ultra-ultrasonic device described in the twelfth embodiment. The ultra-ultrasonic device can intermittently generate acoustic beam flow based on any method described in the twelfth embodiment to produce micro water hammer effect.

[0373] In some embodiments, the liquid environment is located in a cavity, the wall of the cavity is provided with a hollow needle extending outward, and the sound beam generated by the ultra-ultrasonic device is directly facing the hollow needle; the hollow needle is used to extend the effective distance of the micro-water hammer effect and / or maintain the directionality of the micro-water hammer effect.

[0374] The fourteenth embodiment of the present application provides a liquid feeding device based on the micro-water hammer effect, comprising: a cavity having an open end; a liquid injection hole on the wall of the cavity for injecting liquid into the cavity; a super-ultrasonic device is arranged in the cavity, and after the liquid is injected into the cavity, the super-ultrasonic device is placed in a liquid environment, and based on any of the methods for realizing the micro-water hammer effect based on the acoustic beam flow described in the twelfth embodiment, an acoustic beam flow with a micro-water hammer effect is generated toward the open end of the cavity, so that the liquid is injected into the skin that closes the open end through the acoustic beam flow with the micro-water hammer effect.

[0375] In some embodiments, the position of the ultra-ultrasonic device relative to the opening end of the cavity is adjustable.

[0376] Based on the principles of any of the methods or devices in the twelfth, thirteenth, and fourteenth embodiments, the present application further provides a specific implementation example, namely, a drug delivery device based on the micro-water hammer effect provided in the fifteenth embodiment, which is hereinafter referred to as an injection device. As shown in the schematic diagrams of FIG35 or FIG36 and the actual photograph of FIG38 , the injection device based on the micro-water hammer effect of this embodiment may include:

[0377] A cavity 1 having an open end; a liquid injection hole 4 is provided on the wall of the cavity 1 for injecting liquid into the cavity 1; a special ultrasonic device 2 is provided in the cavity 1, and after the liquid is injected into the cavity 1, the special ultrasonic device 2 is placed in a liquid environment, and the special ultrasonic device 2 is used to generate an intermittent acoustic beam flow with a micro water hammer effect in the liquid environment toward the open end of the cavity 1, so as to inject the liquid into the skin that closes the open end through the acoustic beam flow with the micro water hammer effect.

[0378] In some embodiments, the cavity 1 can have any shape, such as a cylinder, a hemisphere, a spherical segment, or a bell. In some embodiments, the open end of the cavity 1 can be in contact with a target object (e.g., skin), thereby sealing the open end of the cavity 1. In some embodiments, when the ultra-ultrasonic device 2 is not activated and the open end of the cavity 1 is not in contact with the target object (e.g., skin), the size of the open end of the cavity 1 can also be designed to prevent the liquid in the cavity 1 from flowing out due to the internal and external pressure difference or the surface tension of the liquid.

[0379] In some embodiments, the ultra-ultrasonic device 2 can be mounted on the inner wall of the cavity 1, or on a support portion protruding inward from the inner wall, or on a bracket 3 that can be mounted on the cavity 1, and the ultra-ultrasonic device 2 faces the open end of the cavity 1.

[0380] The injection hole 4 on the cavity 1 is used to connect to an external liquid supply device. In some embodiments, as shown in FIG38 , the liquid supply device can be a syringe that can be inserted into the injection hole 4 to inject liquid into the cavity 1. Alternatively, a bottle container such as a medicine bottle can be inserted into the injection hole 4. For example, the insertion can be performed directly through the tubular opening of the medicine bottle, or a conduit (such as a hose or a rigid tube) can be used to connect the medicine bottle and the injection hole 4. In other embodiments, the liquid supply device can also be an external liquid supply device connected via a conduit, and the liquid supply device has a micropump to pump the liquid into the cavity 1.

[0381] In some embodiments, the wall of the cavity 1, distal from the open end, has a through hole; a bracket 3 partially extending into the cavity 1 is mounted in the through hole. The ultra-ultrasonic device 2 is mounted on the end of the bracket 3 located within the cavity 1. In some embodiments, the through hole for mounting the bracket 3 may also be located on the side wall of the cavity 1. In some embodiments, as shown in FIG37 , the injection hole 4 may also be located on the bracket 3.

[0382] In some embodiments, the bracket 3 is connected to the through-hole thread 31, and the end of the bracket 3 away from the ultra-ultrasonic device 2 is located outside the cavity 1. The connection through the thread 31 allows the relative position of the bracket 3 and the cavity 1 to be adjusted, so that the position of the ultra-ultrasonic device 2 in the cavity 1 can be adjusted. In some embodiments, the through-hole is located opposite the opening end (i.e., the axial direction of the through-hole is opposite the opening end). By screwing the bracket 3 in or out of the through-hole, the distance between the ultra-ultrasonic device 2 and the opening end can be adjusted. In some embodiments, the range of the distance between the ultra-ultrasonic device 2 and the opening end can be adjusted from 0 to 2 cm. In other embodiments, when the through-hole is not located opposite the opening end (e.g., the axial direction of the through-hole is inclined to the plane of the opening end), by screwing the bracket 3 in or out of the through-hole, the distance between the ultra-ultrasonic device 2 and the opening end is adjusted, and the position of the horizontal component of the ultrasonic device at the opening end is also adjusted.

[0383] In some embodiments, the support 3 is tubular, with wires connected to the ultra-ultrasonic device 2 routed within the tube. In some embodiments, the portion of the support 3 located outside the cavity 1 can serve as a handheld portion for operating the device of this embodiment. Therefore, the portion of the support 3 located outside the cavity 1 can be shaped to be easily held. When the support 3 is tubular, the ultra-ultrasonic device 2 and the tubular support 3 together form an ultra-ultrasonic probe.

[0384] In some embodiments, the drive device and power supply device for driving the ultra-ultrasonic device 2 can be independently provided relative to the aforementioned structure (i.e., the portion including the cavity 1 and the support 3), and the electrical connection between the drive device and the ultra-ultrasonic device 2 is achieved through the aforementioned wires. A push-type switch, a touch switch, a drive power adjustment control, or a display screen can be provided on the handheld portion, or these can be provided on the external drive device and power supply device, wherein the drive device and power supply device can be assembled into a housing.

[0385] In some embodiments, the drive device (including the control unit) and power supply for the ultra-ultrasonic device 2 can be integrated into the aforementioned structure of the bracket 3 serving as the handheld portion, located outside the cavity 1, thereby making the device a handheld device. The corresponding handheld portion can be provided with a mechanical (e.g., push-type) switch, a touch-sensitive switch, a drive power adjustment control (e.g., a knob), or a display screen. These switches or controls can be used to control the start and stop of the injection device, the mode of driving the ultra-ultrasonic device 2 (e.g., intermittent operation, continuous operation), and the power of the ultra-ultrasonic device 2. In some embodiments, the power supply includes a transformer and corresponding circuits (e.g., filtering, modulation module, protection circuit, etc.), and is connected to an external AC power source. In other embodiments, the power supply includes a rechargeable battery and corresponding circuits (e.g., DC / AC, adjustment module, charging circuit, protection circuit, etc.).

[0386] In some embodiments, the ultra-ultrasonic device 2 includes: at least two ultra-ultrasonic chips located on the same substrate and arranged in an array, and the at least two ultra-ultrasonic chips share electrodes on the substrate. This type of integration can reduce wires, reduce energy losses caused by line resistance, etc. Figure 43 shows such an example, in which three ultra-ultrasonic chips are provided on a substrate (the ultra-ultrasonic chip here refers to the sound wave reflection layer and piezoelectric layer located on the substrate). The upper electrodes of the piezoelectric layers of the three ultra-ultrasonic chips are connected to the same endpoint on the substrate, and the lower electrodes are also arranged to the same endpoint. These two endpoints are used for external drive circuits. Figure a in Figure 43 is a photo taken under a microscope, and Figure b is a photo of the actual object. The three claws in the figure are electrodes, and the rectangular frames are endpoints (gold fingers).

[0387] In some other embodiments, the ultra-ultrasonic device 2 includes: relatively independent ultra-ultrasonic devices 2 can be arranged to form an array, for example, different ultra-ultrasonic devices 2 composed of different ultra-ultrasonic chips located on different substrates.

[0388] In some embodiments, when multiple hypersonic chips are provided, the parameters of these chips may be the same to achieve the same function or effect under the same drive. In other embodiments, the parameters of these chips may be different to achieve different functions or effects simultaneously under the same drive.

[0389] In some embodiments, when multiple hypersonic chips are present, the chips are arranged in a configuration (e.g., position and orientation) such that the acoustic beams generated by the micro-water hammer effect can be parallel or divergent, thereby increasing the effective area. For example, the chips can be arranged in an array on the same plane or on the same convex surface. In some embodiments, the chips can be arranged in a configuration (e.g., position and orientation) such that the acoustic beams generated by the micro-water hammer effect can converge, thereby increasing the effect on a specific point. For example, the chips can be arranged in an array on the same concave surface.

[0390] The overall shape of the array of multiple ultra-ultrasonic chips or the array of multiple ultra-ultrasonic devices 2 can be rectangular, annular, linear, or other shapes. For example, the example of the array of multiple ultra-ultrasonic chips shown in FIG42 includes three ultra-ultrasonic chips.

[0391] In some embodiments, as shown in FIG37 , the wall of the cavity 1 further comprises an air hole 7. The air hole 7 is provided to facilitate the exhaust of liquid during the injection process into the cavity 1, or the replenishment of air during the injection of liquid in the cavity 1 into the subcutaneous tissue. In some embodiments, the air hole 7 is a micro-pore, and the aperture of the micro-pore is set to achieve the characteristics of being air-permeable but liquid-tight, that is, the air permeability is guaranteed, and the possibility of the liquid in the cavity being spilled to the outside from the air hole 7 during the use of the device can be reduced. In other embodiments, when the aperture of the air hole 7 is not limited, the position of the air hole 7 can also be used to solve the problems of exhausting, replenishing air and avoiding spillage by applying an elastic film with micropores. The elastic film can be applied to the outer wall or inner wall of the cavity 1 corresponding to the air hole 7. In some embodiments, when it is expected that the part of the device of the present application that contacts the skin can overflow the liquid when the contact is not close, the aperture of the above-mentioned air hole 7 can be slightly larger, for example, when the device of the present application is used as a beauty and skin care device. In other embodiments, when it is expected that the device of the present application and the skin contact part will not overflow the liquid as much as possible when the contact is not close, the size of the aperture of the above-mentioned pore 7 is a size, and the aperture size is large enough to balance the liquid in the cavity with other external air pressure, or the above-mentioned elastic mold with micropores is used to achieve micro-balance of the air pressure inside and outside the cavity 1, so that even in the case of loose contact, the possibility of liquid leakage is reduced when the ultra-ultrasound chip is not started.

[0392] In some embodiments, the ultra-ultrasonic device 2 is further configured to generate one or any combination of the following in the liquid environment: eddy currents, cavitation effects, thermal effects, jets, etc. The different effects produced by a ultra-ultrasonic device 2 can be achieved by adjusting the drive power, such as adjusting the cycle of the drive signal, the proportion of the drive level within a cycle, the power level, the continuous drive duration, etc. In some embodiments, when multiple ultra-ultrasonic chips are present, as described above, when these chips have different parameters, different effects can be achieved under the same power drive. When the ultra-ultrasonic device 2 generates eddy currents, the eddy currents act on the skin, thereby enhancing the cleansing effect on the skin surface. When the ultra-ultrasonic device 2 generates cavitation bubbles, they enhance cleansing of the skin surface. Cavitation removes surface oil, debris, dust, and other substances, unclogging pores and cleansing the face. Furthermore, cavitation softens the stratum corneum and accelerates keratin metabolism, restoring skin elasticity and tightening the skin. Cavitation also opens intercellular spaces, increasing skin permeability, allowing cosmetic substances like collagen and hyaluronic acid to penetrate the epidermis and reach the dermis, achieving transdermal delivery without causing skin trauma. During operation, some of the ultrasonic energy generated by the ultra-ultrasonic device 2 is converted into heat, which accelerates blood circulation, enhances metabolism, improves local tissue nutrition, and enhances enzyme activity. Furthermore, because the power applied to the ultra-ultrasonic device 2 is low, for example, no more than 10W, the thermal effects of the ultra-ultrasound do not damage the skin. Furthermore, when the ultra-ultrasonic device 2 generates a jet, the force of the jet is less than that of the acoustic beam, enabling the jet to cleanse the skin.

[0393] In some embodiments, as shown in FIG39 , the open end of the cavity 1 is provided with a cover 8 that seals the open end. The cover 8 has an outwardly extending hollow needle 81 located directly opposite the ultra-sonic device 2. The acoustic beam, which generates a micro-water hammer effect, generated by the ultra-sonic device 2 is directed toward the cavity of the hollow needle 81. In other embodiments, the hollow needle 81 may also be located in a portion of the cover 8 that is not directly opposite the ultra-sonic device 2. The hollow needle 81 can penetrate the skin to varying depths depending on the length of the hollow needle 81, making it easier to inject the acoustic beam into the subcutaneous space where the hollow needle 81 reaches. In some embodiments, the cover 8 is integrally formed with the cavity 1, for example, by being pressed together. This integral arrangement allows for better control of the distance between the ultra-sonic device 2 and the hollow needle 81 during assembly. In other embodiments, the cover 8 and cavity 1 are configured as separate bodies that can be assembled, facilitating the replacement of the cover 8 with different hollow needles 81. The hollow needles 81 can be microneedles manufactured using high-precision 3D printing or micro-nanofabrication techniques. In some embodiments, the hollow needles 81 can be arranged in an array. In some embodiments, the structure of the hollow needles 81 can maintain the liquid within the cavity 1 by utilizing liquid tension when the ultra-ultrasonic device 2 is not operating.

[0394] In some embodiments, hollow needles of various shapes can be used. For example, a hollow needle as shown in Figure 39 may have a cylindrical inner diameter, i.e., the inner diameter is uniform along its entire length. In other embodiments, a hollow needle as shown in Figures 45 or 46 may have a conical inner diameter. The shape of the hollow needle, such as its cylindrical or columnar inner diameter, its length, and the distance between the hollow needle and the ultra-ultrasonic device, can all have varying effects on the acoustic beam flow.

[0395] In some embodiments, when the inner diameter of the hollow needle is conical, the inner diameter of the hollow needle 81 can be gradually reduced in the direction away from the cavity 1. Based on this structure, the acoustic beam can be further focused, ejected from the tip of the hollow needle 81 and injected subcutaneously. Among them, on the one hand, the structure of the hollow needle 81 reduces the direct transmission of the acoustic beam energy to the external laminar fluid, which can enhance the local pressure of the acoustic beam with a micro-water hammer effect, increase the effective distance of the micro-water hammer effect, limit the generation of vortexes in the acoustic beam, and reduce power dissipation. But on the other hand, the inner wall of the hollow needle 81 itself will also generate resistance to the acoustic beam, which will lead to the loss of some energy. Therefore, a comprehensive analysis is required.

[0396] Among them, different apertures at the tip of the hollow needle 81, different lengths of the hollow needle 81, and different distances between the ultra-ultrasonic device 2 and the facing hollow needle 81 have different effects on the effect of the sound beam being emitted from the needle tip. The above specific parameters can be designed based on the desired effect of the subcutaneous injection, such as the injection depth and the diffusion of the injected liquid.

[0397] For example, when the inner diameter of the hollow needle 81 is conical, for different apertures at the tip of the hollow needle 81: when the aperture is small, the acoustic beam attenuates faster due to the smaller aperture at the outlet and the rapid shrinkage of the aperture (one possibility is that the inner wall of the hollow needle 81 loses energy in resisting the acoustic beam), the pressure at the outlet is significantly smaller, and the effective distance is shortened, but the angle of the effective range (the spray angle ejected from the outlet) is larger (when the energy is not enough to maintain a high directivity, it is more divergent), which can reach 45 degrees. As the aperture increases, the pressure at the outlet increases, the effective distance increases, and the angle of the effective range gradually becomes smaller and the directionality is better. Figure 45 shows the outlet aperture of the hollow needle 81.

[0398] For example, when the inner diameter of the hollow needle 81 is conical, for different lengths of the hollow needle 81: when the aperture of the tip of the hollow needle 81 is the same, the longer the length of the hollow needle 81, the more obvious the acceleration effect on the sound beam. The better the directionality of the sound beam after passing through the hollow needle 81, the smaller the diffusion angle. The selection of the length of the hollow needle 81 depends on the transdermal depth and the transdermal effect to be achieved. In some embodiments, the length of the hollow needle 81 can be 50 to 2000 μm. Figure 46 shows the acceleration effect of the hollow needle 81 with a needle length of 200 μm and 300 μm on the sound beam. It can be seen that the sound beam with a needle length of 300 μm has a longer range than the sound beam with a needle length of 200 μm in basically the same length of time. When it is a sound beam with a micro-water hammer effect, the micro-water hammer effect is farther.

[0399] For example, when the inner diameter of the hollow needle 81 is conical, for different distances from the hollow needle 81 to the ultra-ultrasonic device: the farther the hollow needle 81 is from the ultra-ultrasonic device, the less energy the sound beam entering the hollow needle 81, and the larger the final injection angle ejected from the outlet of the hollow needle 81 (when the energy is not enough to maintain a high directivity, the divergence is more reflected).

[0400] In some embodiments, when the ultra-ultrasonic device 2 operates in the frequency range of 0.1 to 10 GHz, the drive power is 0.1 to 100 W, and the total pulse period is 10 to 2000 ms, the range, area of ​​action, and intensity of the acoustic beam generated have the following relationship: within 100 μm from the device surface, the area of ​​action of the acoustic beam is similar to the shape and area of ​​the device itself, and the maximum pressure point also occurs within this distance. When the distance exceeds 100 μm, the shape of the acoustic beam gradually becomes circular, the area of ​​action increases, and the intensity decreases. Based on this, the distance between the ultra-ultrasonic device 2 and the facing hollow needle 81 can be designed. In some embodiments, the distance between the ultra-ultrasonic device 2 and the facing hollow needle 81 is 0 to 2000 μm.

[0401] In some embodiments, the open end of the cavity 1 has a cover body that closes the open end, and the cover body has a mesh surface. The direction of the sound beam flow of each special ultrasonic device 2 in the cavity 1 can be directly facing a mesh hole of the mesh surface. The mesh surface structure can use liquid tension to keep the liquid in the working cavity when the special ultrasonic device 2 is not working. The mesh structure can also serve as isolation to keep the special ultrasonic device 2 in the cavity 1 at a required distance from the contact part of the injected target object.

[0402] In some embodiments, the device provided by the embodiments of the present application is fastened to the skin by means of straps or rubber bands. For example, as shown in FIG35 , the bottom of the cavity may have an outer edge extending outward, and the outer edge may have a hole 5 to fit a magic tape 6. In other embodiments, the device of the present application may be pressed against the skin by directly applying pressure by hand. In some embodiments, the position where the open end of the cavity 1 of the device of the present application contacts the skin may be designed to be smooth so that it can fit tightly when pressed against the skin. In some embodiments, the position where the open end of the cavity 1 contacts the skin may also be fitted with or wrapped with an elastic material with good biocompatibility, such as soft silicone, rubber, etc., to further ensure sealing and reduce the possibility of side leakage of liquid inside the cavity 1.

[0403] In some embodiments, the device provided in the embodiments of the present application may also be equipped with a laser positioning device for alignment, which can emit laser to indicate the area where the ultra-ultrasonic device 2 is currently aligned.

[0404] In some embodiments, when the ultra-ultrasonic device 2 is pulse-driven, the different ratios of the first and second phases in each drive cycle can achieve different pulse effects. The ratio of the first and second phases and the drive cycle length can be adjusted accordingly to achieve a more obvious micro-water hammer effect. Among them, the pressure generated by a conventional pulsed water jet is much greater than the pressure generated by a continuous water jet. By utilizing the fatigue effect of the material of the target object, the periodic transient impact stress wave can cause the target object material to reach the fatigue limit faster than the stagnation pressure of the continuous water jet. This principle of water jet also applies to acoustic beam flow. Compared with continuous acoustic beam flow, the micro-water hammer effect generated by intermittent acoustic beam flow has high energy utilization efficiency and can generate high water pressure in a pulsed manner at a lower liquid flow rate. As described above, the parameters of the intermittent acoustic beam flow can be flexibly adjusted, including pulse frequency (corresponding to the drive cycle), duty cycle (corresponding to the ratio of the first and second phases in the drive cycle), distance from the material surface, etc. In addition, the micro-water hammer effect combined with the focusing of the acoustic beam flow can reduce the transmission of compressive stress on the surface of the target object, enhance the transmission of shear stress along the surface, and reduce the impact on areas not directly impacted.

[0405] In some embodiments, any of the aforementioned injection devices (i.e., drug delivery devices) of this application may also be combined with low-frequency ultrasound. For example, a low-frequency ultrasound device may be provided on the introduction portion, thereby enabling the simultaneous or non-simultaneous operation of the low-frequency ultrasound and the ultra-ultrasonic device 2. The low-frequency ultrasound, with its low energy but wide range, is used to treat large areas, while the ultra-ultrasonic device, with its high energy, is used to treat specific areas. The low-frequency cavitation effect combined with the high-frequency fixed-point cavitation effect can improve the transdermal speed.

[0406] In some embodiments, any of the injection devices (i.e., drug delivery devices) described above in the present application can also be used in conjunction with a chemical permeation enhancer. For example, a chemical permeation enhancer can be injected into the liquid reservoir, or applied to the skin to interact with the stratum corneum lipids to change their arrangement structure, thereby enhancing the drug's penetration ability by weakening the barrier function of the stratum corneum without causing significant damage to the cells.

[0407] In some embodiments, any of the above-described injection devices (i.e., drug delivery devices) of the present application can also be combined with radio frequency, microcurrent, and / or LED lights, for example, radio frequency devices, microcurrent needles, and / or LED lights are provided in the above-mentioned introduction portion. These three can be used as auxiliary devices, and their main functions are wrinkle removal and improvement of skin condition. For example, by utilizing the penetrability of radio frequency and / or microcurrent, they penetrate the epidermis and act on the dermis, heat the dermal tissue through the LED thermal effect, and stimulate fibroblasts to synthesize collagen and elastin. Integrate wrinkle removal and improvement of skin condition with transdermal function.

[0408] In some embodiments, any of the above-described injection devices (i.e., drug delivery devices) of the present application can also be combined with electroporation. For example, an electroporation electrode is provided in the above-mentioned introduction part, and electric pulses are used to stimulate the skin or subcutaneous tissue to open the keratin phospholipid bilayer or the gap between skin cells, thereby forming an input channel for the active ingredient and realizing transdermal delivery of the cosmetic substance.

[0409] The present application is further described below with reference to specific embodiments. In this embodiment, we first investigate the characteristics of a hypersonic device generating an intermittent acoustic beam in a liquid to produce a micro-water hammer effect (also known as the characteristics of the acoustic beam at the solid-liquid interface). We then explore the characteristics of the acoustic beam combined with a microneedle structure, and finally explore an example of its application in an injection device.

[0410] Characteristics of ultrasonic beams with micro-water hammer effects generated by ultra-ultrasonic devices in liquids: Intermittent acoustic beams of pentagonal, circular, and annular ultra-ultrasonic devices were simulated, and some experiments were conducted. The conclusions are as follows:

[0411] 1) For ultra-ultrasonic devices with frequencies ranging from 0.1 to 10 GHz, powers ranging from 0.1 to 100 W, and total pulse periods ranging from 1 to 2000 ms, the range, area, and intensity of the acoustic beam generated exhibit the following relationship: within 100 μm of the surface of the ultra-ultrasonic device, the area of ​​the acoustic beam is similar to the shape and area of ​​the device itself, and the maximum pressure also occurs within this distance. Beyond 100 μm, the shape of the acoustic beam gradually becomes circular, the area of ​​the acoustic beam increases, and the intensity decreases. See Figure 40 for a simulation of pulsed acoustic beams generated by several ultra-ultrasonic devices, and Figure 41 for experimental photographs showing the increase in the area of ​​the acoustic beam with increasing distance.

[0412] 2) When the shape and area of ​​the ultra-ultrasonic device remain unchanged, the effective area and intensity of the acoustic beam flow increase with the increase of driving power.

[0413] 3) When calculating the pressure generated by the acoustic beam at the solid-liquid interface by means of liquid dynamic pressure, the dynamic pressure of the liquid can be: Formula for calculation. Where: p 动 is the dynamic pressure of the liquid, ρ is the liquid density, and v is the liquid velocity at a certain point.

[0414] Dynamic pressure refers to the pressure generated by a fluid due to its velocity, representing its kinetic energy. Dynamic pressure varies with fluid velocity: if the velocity increases, the dynamic pressure increases; if the velocity decreases, the dynamic pressure decreases.

[0415] The energy conversion at the solid-liquid interface is as follows: the acoustic pressure field generated by the ultra-ultrasonic device accelerates the fluid to eject, forming an acoustic beam. The acoustic beam is accelerated by the acoustic pressure field and reaches its maximum speed at a certain point. At this time, the kinetic energy reaches its maximum. Then, due to the existence of liquid resistance, it will decelerate to a certain extent. When it hits the solid wall at the solid-liquid interface, the speed drops to 0. At this time, all kinetic energy is converted into pressure potential energy when it hits the wall. By calculating the kinetic energy at the maximum speed, the pressure potential energy when it hits the wall can be obtained, and the pressure and force at this time can be calculated. The calculation of pressure and force according to the maximum speed is shown in the following table:

[0416] 4) It was verified that the intermittent acoustic beam flow has a water hammer effect and its energy utilization efficiency is higher than that of the continuous acoustic beam flow.

[0417] The short-pulse, high-speed, discontinuous acoustic beam flow formed by the present application can achieve rapid, multiple, high-pressure continuous impacts, that is, the formation of a water hammer effect. From another perspective, the present application is equivalent to a miniature water hammer generator. Among them, the initial pressure of the water hammer effect is much higher than the steady-state pressure, so the pulsed output can achieve the effect of significantly increasing the pressure and improving the transdermal efficiency. The following is an introduction to the principle that the initial pressure of the water hammer effect is much higher than the steady-state pressure (such as a continuous acoustic beam flow):

[0418] The water hammer pressure in the initial stage can be derived based on the Bernoulli equation, where the Bernoulli equation is: p = ρ·c·v, where p is the pressure of the fluid at a certain point and ρ is the density of the fluid (water), which is about 1000 kg / m 3 , c is the wave velocity of the fluid (water), which is about 1400m / s in the pipe, and v is the velocity of the fluid (water). Since water hammer pressure is composed of discontinuous sound beam flow, the water hammer pressure formula is derived from the Bernoulli equation: △P=ρ·c·△v, where △v is the change in water velocity (which can be understood as the change in velocity between two sampling points). For example, if △v is 0.5m / s at a certain position in the experiment, the water hammer pressure at that position in the experiment is △P=1000Kg / m 3 ·1400m / s·0.5m / s=700kPa.

[0419] During the stagnant phase, i.e., the steady-state pressure phase (e.g., continuous acoustic beam flow), the pressure can be calculated based on the kinetic energy theorem, where the kinetic energy theorem formula is: Where P is the impulse (pressure) of the fluid (water), ρ is the density of the fluid (water), and v is the velocity of the fluid (water). If v is also 0.5 m / s at this location, P can be calculated to be 125 Pa at this location, which is much lower than the initial water hammer pressure.

[0420] In further experiments, the initial pressures at different distances from the interface of the ultra-ultrasonic device were calculated. When the ultra-ultrasonic device was driven by 16W, the initial pressure within a distance of 1mm was at the MPa level, and the initial pressure gradually increased with the shortening of the distance, and was much greater than the pressure in the stagnation stage.

[0421] From the above, it can be seen that the high-pulse (i.e., intermittently generated) acoustic beam flow has a water hammer effect, and its energy utilization efficiency is higher than that of the continuously driven acoustic beam flow, and the pressure generated is much higher than the pressure generated by the continuous acoustic beam flow.

[0422] 5) Based on the distance between the ultrasonic device and the skin and the power, the treated skin area can be from 0.1mm^2 to 10mm^2.

[0423] 6) Advantages of forming an array of multiple devices: it can increase power utilization while increasing the active area.

[0424] Figure 42 shows a simulation of an array of three super-ultrasonic devices generating a pulsed acoustic beam (corresponding to a water hammer effect). Figure 44 shows a diagram of the interface treatment of a single super-ultrasonic device and the three super-ultrasonic devices shown in Figure 42. Specifically, at the same power, the interface treatment area of ​​a single super-ultrasonic device and multiple super-ultrasonic devices is characterized. By photographing the shape of red fluorescent particles (5μm) adhered to the interface being blown away after the super-ultrasonic device is turned on, the size of the treatment area of ​​the device at different heights from the interface is characterized. The results show that at the same driving power, the treatment area of ​​multiple super-ultrasonic devices is significantly improved compared to a single device. The figure shows three super-ultrasonic devices, and the treatment area is expanded by about 3 times, increasing the effective area. Among them, the three super-ultrasonic devices are driven by a single driving module (i.e., one with three). That is, at the same driving power of the same driving module, the treatment area is expanded by about 3 times, thereby improving power utilization.

[0425] 7) A microneedle structure with a tapered hollow needle with an increasing inner diameter in the direction opposite the ultrasonic device can enhance the local pressure of the acoustic beam, increase the beam's range or diffusion angle, limit eddy current generation, and reduce power dissipation. Simulations of this tapered hollow needle have demonstrated that varying the tip diameter and length of the hollow needle have varying effects on the acoustic beam's emission from the needle tip. This is shown in Figures 45 and 46.

[0426] 8) By using a microneedle structure with a cylindrical hollow needle with an increasing inner diameter facing the ultra-sonic device, the effect of the acoustic beam can be adjusted. See Figure 47 , where Panel (a) shows an actual acoustic beam shot and a schematic diagram of the injection angle using a 200μm-long microneedle, and Panel (b) shows an actual acoustic beam shot and a schematic diagram of the injection angle using a 400μm-long microneedle. The outlet diameter of both microneedles is 60μm. The ultra-sonic device is located at the top of the figure, generating the acoustic beam downward. The microneedle was placed directly below the ultra-sonic device for the experiment.

[0427] The following table shows the experimental data of the acoustic beam flow corresponding to Figure 47a under a 200μm long microneedle:

[0428] The following table shows the experimental data of the acoustic beam flow corresponding to Figure 47b under a 400μm long microneedle:

[0429] From the above usage data, we can preliminarily draw the following conclusions when using hollow needles with cylindrical inner diameters:

[0430] a. When the acoustic beam passes through the microneedles, the jet speed is slower, but the jet area is wider. This is mainly due to energy loss caused by part of the acoustic beam not entering the microneedles, and energy loss caused by the inner wall of the microneedles.

[0431] b. The injection speed and injection angle can be changed by controlling the length of the microneedle and the distance between the microneedle and the ultrasonic device, as shown in Figure 47. The farther the microneedle is from the ultrasonic device, the less acoustic beam enters the microneedle, and the slower the injection speed after passing through the microneedle. However, the injection angle is larger, making it more suitable for diffuse drug delivery over a large area.

[0432] c. Comparing a and b in Figure 47 or the experimental results data above, for the 400μm microneedle and the 200μm microneedle, under the same distance from the microneedle to the ultra-ultrasonic device, the injection angle of the acoustic beam after being ejected from the microneedle does not change much, but the injection speed is slower when using the 400μm microneedle than when using the 200μm microneedle.

[0433] Hollow needles with different structures (lengths and shapes) and different distances from the ultra-ultrasonic device will have different effects on the sound beam ejected from the hollow needle. Therefore, the corresponding hollow needle structure or distance from the ultra-ultrasonic device can be designed based on this to achieve the speed and injection angle of the liquid (such as medicine) ejected from the hollow needle, thereby realizing different forms of drug delivery.

[0434] Another experiment of the present application is as follows: a super ultrasonic device was used to perform transdermal treatment on the back of shaved mice. The solution used was a 2 mmol rhodamine dye solution. The experimental group turned on the super ultrasonic device with a power of 8W for 10 minutes, and the control group was only infiltrated with the solution to test the transdermal effect of the device on small molecules. After the treatment, the treated sites of both groups were sectioned and frozen and fixed, and stained with DAPI (DAPI is an organic fluorescent dye that can penetrate the cell membrane and bind to double-stranded DNA in the cell nucleus to play a labeling role). As can be seen from the experimental result diagram shown in Figure 48, both sections of the experimental group had a certain degree of transdermal phenomenon, especially the first section. The rhodamine dye solution had penetrated the epidermis to the dermis and subcutaneous tissue layer. However, the control group only had fluorescence where the epidermis was infiltrated with rhodamine reagent, and almost no fluorescent substance was seen in the deeper layers. Therefore, it was proved that rhodamine itself was difficult to penetrate the mouse epidermis, and the addition of super ultrasonic device treatment could improve its permeability.

[0435] In another set of experiments in this application, ultra-sonic devices were used to perform transdermal treatment on the backs of shaved mice, mainly to explore the differences in transdermal transdermal properties of different molecular weights, as follows:

[0436] Transdermal Experiment A: Solution used: 1% FITC-dextran solution, molecular weight: 3-6k; Ultrasonic probe operating power: 4W; Pulse output cycle: 50ms / 200ms, 15 minutes. Experimental Conclusion: Low-molecular-weight substances can significantly transdermally penetrate the skin under the influence of acoustic fluidics. Different transdermal depths and effects can be achieved by controlling power, distance, and duration.

[0437] Transdermal Test B: Solution used: 1% FITC-dextran solution, molecular weight: 40k; Ultrasonic probe operating power: 8W; Pulse output cycle: 50ms / 200ms, 15 minutes. Conclusion: Medium-molecular-weight substances can penetrate smoothly, but may cause skin damage. Appropriate control of device power, skin distance, and exposure time is required.

[0438] Transdermal Experiment C: Solution used: 0.8% FITC-dextran solution, molecular weight: 250k; Ultrasonic probe operating power: 8W; Pulse output cycle: 50ms / 200ms, 15 minutes. Conclusion: High-molecular-weight substances show no significant transdermal penetration with short-term treatments. Transdermal delivery of high-molecular-weight substances requires integration with other methods (such as microneedles).

[0439] Based on the above experiments, it can be used to design the actual use of special ultrasonic devices for injection, based on the molecular weight of the injected liquid, the injection (transdermal) depth, etc., to predict the driving power, distance from the skin, action time, whether to use microneedles, etc. of the special ultrasonic device to be used.

[0440] The dosing regimen provided in this application can be achieved in a non-invasive manner, that is, transdermal delivery of substances can be achieved without causing trauma to the skin. When an arrayed super-ultrasonic device design is adopted, large-area rapid treatment of the skin can also be achieved. Among them, the precision, high-speed acoustic jet or acoustic beam flow and super-ultrasonic device cavitation have good directionality and regionality, and the transdermal treatment range can be accurately controlled; the treatment process is uniform and controllable, and there will be no problems such as accumulation and agglomeration of cosmetic substances. When a handheld design is adopted, it is easy to use and does not require use in a specific place. And it has a high degree of integration and can be integrated with cosmetic products based on other principles (such as radio frequency, microcurrent, LED lights, ultrasound, etc.), and a variety of modes are convenient for users to choose and use.

[0441] The present application also provides a method for administering a drug, using the above-mentioned drug delivery device or any of its optional embodiments to achieve subcutaneous injection. Specific methods for achieving the injection, such as controlling the driving process of the acoustic beam flow, can be found in the relevant description of the above-mentioned injection device and will not be repeated here.

[0442] The fourth category of applications of this application is introduced below, which includes a solution for continuous droplet generation based on acoustic beam flow, including a method and device for continuous droplet generation.

[0443] In the prior art, Chinese patent application publication number CN110170343A discloses a system and method for producing water-in-oil micro-droplets. This patent application utilizes the volume force exerted by high-frequency acoustic waves generated by a thin film bulk acoustic resonator on a sample liquid, pushing the liquid toward the oil layer, forming a liquid column at the interface. When the liquid column falls back, the viscosity of the oil relative to the liquid column and the oil-water interfacial tension pinch off the liquid column to form a water-in-oil droplet. The volume force utilized in this patent application, namely, the continuous thrust exerted on the localized liquid by the jet phenomenon, is used to generate the liquid column. Because the jet itself has a relatively large range of action, the liquid column formed at the oil-water interface takes a conical shape, as shown in FIG56 . The bottom of the liquid column has a large contact area with the sample liquid below the oil layer, resulting in a strong bonding force, making it difficult for the liquid column to directly separate from the sample liquid. Therefore, it is necessary to stop driving the thin film bulk acoustic resonator. The viscosity of the oil relative to the liquid column and the oil-water interfacial tension pinch off the liquid column at a certain point in the conical liquid column to form a water-in-oil droplet. FIG57 shows a schematic diagram of droplet formation.

[0444] The present application provides an improved solution. The solution for continuous droplet generation provided by the present application is not limited to the generation of droplets when the super-ultrasonic device stops working. The droplet generation method is more flexible, and the size of the generated droplets is easier to control. The solution for continuous droplet generation provided by the present application has the following main principles: at least two immiscible phases of fluid are introduced into the flow channel, and a super-ultrasonic device is used to periodically generate an acoustic beam flow toward the laminar interface in one phase of the fluid, wherein the periodically generated acoustic beam flow of the phase fluid breaks through the laminar interface and enters the other phase fluid to form continuous droplets. Alternatively, a super-ultrasonic device is used to periodically generate an acoustic beam flow along the laminar interface of the two phases of fluid, and the periodically generated acoustic beam flow induces part of the liquid in one phase of the fluid to enter the other phase of the fluid to form continuous droplets. The present application is described in detail below in conjunction with the various figures and embodiments.

[0445] A sixteenth embodiment of the present application provides a method for continuously generating droplets, comprising:

[0446] introducing at least two immiscible fluids into the first flow channel, wherein the at least two-phase fluids include a first liquid and a second liquid in laminar flow, and a laminar interface is formed between the first liquid and the second liquid;

[0447] The ultra-ultrasonic device is driven with a first power cycle, so that the ultra-ultrasonic device periodically generates an acoustic beam flow toward the laminar interface in at least the second liquid, the acoustic beam flow breaks through the laminar interface and enters the first liquid, and forms droplets in the first liquid, wherein the droplets are composed of the second liquid.

[0448] FIG49 illustrates an embodiment of the sixteenth embodiment, specifically an embodiment in which a two-phase fluid is introduced into the first flow channel. In some embodiments, FIG49 may be a side view, i.e., the two-phase fluid is layered vertically within the first flow channel, and the ultra-sonic device is located at the bottom of the first flow channel (e.g., on a substrate forming the flow channel bottom). In other embodiments, FIG49 may be a top view, i.e., the two-phase fluid is layered horizontally within the first flow channel, and the ultra-sonic device is located at the sidewall of the first flow channel (e.g., on a substrate forming the flow channel sidewall).

[0449] Among them, referring to the acoustic beam shown in Figure 2, the acoustic beam is in the shape of a thin column as a whole. It is explained here that the acoustic beam shown in Figure 2 is generated in a static liquid. In the embodiment shown in Figure 49, due to the existence of two fluid flow rates, the acoustic beam will have some deviation. However, since it is necessary to control the intensity of the acoustic beam generated in the second liquid so that its own speed in the acoustic beam before entering the first liquid can reach a speed that breaks through the constraints of the laminar interface, the acoustic beam's own speed before entering the first liquid is much higher than the flow rate of the two-phase flow, and the deviation of the acoustic beam before entering the first liquid can be ignored. After the acoustic beam enters the first liquid, the factors that generate droplets are related to the intensity of the acoustic beam (or the residual energy of the acoustic beam after entering the first liquid), the laminar interface shear force formed by the difference in the flow rates of the two-phase flow, and the physical properties of the first liquid.

[0450] In order to facilitate understanding of the scheme of the present application, reference can be made to FIG57 showing a schematic diagram of the principle of generating droplets according to the existing scheme and FIG58 showing a schematic diagram of the principle of generating droplets according to the present application based on the acoustic beam breaking through the laminar interface (for the convenience of comparative analysis, FIG58 does not consider the flow of the first liquid and the second liquid). It can be seen from the comparison that due to the strong focusing of the acoustic beam, the overall shape is thin columnar, and the acoustic beam of the second liquid breaks through the laminar interface and enters the first liquid. The intersection surface of the acoustic beam and the laminar interface is very small (basically the cross-sectional size of the acoustic beam). Compared with the conical liquid column in FIG57, on the one hand, it reduces the difficulty of the acoustic beam detaching from the second liquid; on the other hand, since the detachment position is basically at the laminar interface, it is easier to quantify and control the process. On the other hand, the amount of acoustic beam flow injected into the first liquid, that is, it is easier to control the droplet size, and it is easier to generate larger droplets than in Figure 57; on the other hand, the disturbed area of ​​the laminar interface is smaller than that in Figure 57, so the laminar interface is easier to recover to execute the next droplet generation process, which is conducive to the stability of the size of each droplet generated, and since the next droplet generation can be executed quickly, the droplet flux generated is larger than that in Figure 57; on the other hand, when taking laminar flow into consideration, compared with the conical liquid column at the laminar interface in the method of generating droplets in Figure 57, the intersection area of ​​the liquid column driven by the acoustic beam flow in Figure 58 and the laminar interface is very small, and it can be easier to realize the shear force of the laminar interface to separate the acoustic beam flow from the second liquid to form droplets.

[0451] In some embodiments, the thickness of the second liquid is less than a threshold value, which allows the acoustic beam generated in the second liquid to still maintain a flow velocity (or energy) capable of breaking through the laminar interface when reaching the laminar interface.

[0452] The seventeenth embodiment of the present application also provides a method for continuously generating droplets. Compared with the sixteenth embodiment, the at least two-phase fluid includes a first liquid, a second liquid, and a third liquid in laminar flow. Specifically, the method includes:

[0453] introducing at least two immiscible fluids into the first flow channel, the at least two-phase fluids comprising a first liquid, a second liquid, and a third liquid in laminar flow, wherein a first laminar interface is formed between the first liquid and the second liquid, and a second laminar interface is formed between the second liquid and the third liquid;

[0454] The ultra-ultrasonic device is driven with a first power cycle, causing the ultra-ultrasonic device to periodically generate an acoustic beam flow toward the second laminar flow interface in at least the third liquid. The acoustic beam flow breaks through the second laminar flow interface and the first laminar flow interface and enters the first liquid, forming a first droplet in the first liquid. The first droplet includes an adjacent second droplet and a third droplet, and the second droplet and the third droplet are respectively composed of the second liquid and the third liquid. In other embodiments, the first droplet formed in the first liquid includes a second droplet, which is encapsulated by a third droplet, and the second droplet and the third droplet are respectively composed of the second liquid and the third liquid. This situation is more common than the situation where the first droplet includes an adjacent second droplet and a third droplet. For example, the first liquid, the second liquid, and the third liquid can be inorganic reagents such as water, mineral oil, silicone oil, fluorinated oil, various biological agents, etc. For example, in one embodiment, the first liquid is a DNA solution, the second liquid is mineral oil, and the third liquid is water.

[0455] FIG50 illustrates an embodiment of the seventeenth embodiment described above, specifically an embodiment in which a three-phase fluid is introduced into the first flow channel. In some embodiments, FIG50 may be a side view, i.e., the three-phase fluid is sequentially layered vertically within the first flow channel, with the ultra-sonic device located at the bottom of the first flow channel (e.g., on a substrate forming the flow channel bottom). In other embodiments, FIG50 may be a top view, i.e., the two-phase fluid is sequentially layered horizontally within the first flow channel, with the ultra-sonic device located at the sidewall of the first flow channel (e.g., on a substrate forming the flow channel sidewall).

[0456] Regarding the embodiment shown in FIG50 , in some embodiments, a first droplet can be formed in the first liquid as described above. In other embodiments, the intensity of the acoustic beam can be controlled so that the acoustic beam generated in the third liquid toward the second laminar flow interface only breaks through the second laminar flow interface, generating a droplet in the second laminar flow. The droplet is composed of the third liquid. In other words, the intensity of the acoustic beam can be controlled to generate different droplets in the first liquid or in the second liquid.

[0457] In some embodiments, the combined thickness of the third liquid and the second liquid is less than a threshold value. This threshold value allows the acoustic beam generated in the third liquid to maintain a velocity sufficient to break through the laminar interface between the first and second liquids even after breaking through the second liquid and reaching the laminar interface. Similarly, multiple phases of fluid can be introduced into the first flow channel, resulting in a droplet comprising multiple layers. The liquids within the multi-layer droplet, from the innermost to the outermost layers, correspond sequentially to the respective phases of liquid extending in the direction directly opposite the ultra-sonic device.

[0458] The eighteenth embodiment of the present application provides another method for continuously generating droplets, including:

[0459] introducing at least two immiscible fluids into the first flow channel, wherein the at least two-phase fluids include a first liquid and a second liquid in laminar flow, and a laminar interface is formed between the first liquid and the second liquid;

[0460] The ultra-ultrasonic device is driven with a first power cycle, so that the ultra-ultrasonic device generates an acoustic beam flow along the laminar interface periodically at the laminar interface, and the acoustic beam flow induces a portion of the second liquid to enter the first liquid and form droplets in the first liquid, wherein the droplets are composed of the second liquid.

[0461] FIG51 illustrates an embodiment of the eighteenth embodiment described above, specifically an embodiment in which a two-phase fluid is introduced into the first flow channel. In some embodiments, FIG51 may be a side view, i.e., the two-phase fluid is layered vertically within the first flow channel, with the ultra-sonic device located on the sidewall of the first flow channel (e.g., on a substrate forming the flow channel sidewall). In other embodiments, FIG51 may be a top view, i.e., the two-phase fluid is layered horizontally along the direction of extension within the first flow channel, with the ultra-sonic device located at the bottom of the first flow channel (e.g., on a substrate forming the flow channel bottom). FIG55 illustrates a schematic diagram of droplet generation in this manner, a top view, showing the two-phase fluid layered horizontally along the direction of extension within the first flow channel. In the example of FIG55 , the ultra-sonic device is a bulk acoustic wave device located at the interface of the two-phase flow. The first power driving the ultra-sonic device is 0.5 W, the driving period is 2 ms, the first phase (i.e., pulse width) is 1 ms, the first liquid is mineral oil with a flow rate of 3 ul / min, and the second liquid is water with a flow rate of 1 ul / min.

[0462] 51 , in some embodiments, the viscosity of the first liquid is higher than the viscosity of the second liquid. In other embodiments, the viscosity of the first liquid may also be lower than the viscosity of the second liquid.

[0463] In some embodiments, such as the embodiment shown in FIG. 49 or FIG. 50 , the acoustic beam of the ultra-ultrasonic device may be perpendicular to the laminar interface. In other embodiments, the acoustic beam may also form an acute angle or an obtuse angle with the laminar interface in space.

[0464] In some embodiments, as shown in FIG51 , the acoustic beam of the ultra-sonic device is located on the laminar interface. In other embodiments, the acoustic beam can also be spatially parallel to the laminar interface, with a spacing less than a threshold value. This threshold value enables the induction of the second liquid into the first liquid to form droplets as described in the embodiment of FIG51 . In some embodiments, the acoustic beam in the embodiment shown in FIG51 can be perpendicular to the direction of liquid flow, or at an acute or obtuse angle.

[0465] In some embodiments, the ultra-sonic device is driven at a first power cycle to generate an acoustic beam. The magnitude of the first power can be found in the aforementioned description of the acoustic beam and drive cycle and will not be further described. Furthermore, the magnitude of the first power should be such that the generated acoustic beam can break through the aforementioned laminar flow interface to form droplets in the target liquid (e.g., the first liquid).

[0466] As previously described, the factors that influence the formation of droplets after the acoustic beam enters the first liquid (e.g., droplet size, droplet spacing, droplet velocity, and flux) are related to the intensity of the acoustic beam (or the residual energy of the acoustic beam after entering the first liquid), the laminar interface shear force formed by the velocity difference between the two phases, and the physical properties of the first liquid. Specifically, in some embodiments, the acoustic beam forms droplets in the first liquid by at least one of the following methods a1-a2 when breaking through the laminar interface and entering the first liquid. If the acoustic beam does not break through the laminar interface, droplets may be formed by the following method a3:

[0467] a1. When the super-ultrasonic device is driven with a first power cycle, the droplets are formed based on the driving energy of the first stage of the driving cycle. In this way, the first power can make the acoustic beam flow break through the laminar flow interface and enter the first liquid. Please refer to the principle diagram shown in Figure 58. The acoustic beam flow entering the first liquid can form droplets. The a1 method can be understood as using the force of the acoustic beam flow generated by the super-ultrasonic device as the main force to generate droplets. Figure 52 shows a diagram of droplet generation on the rising edge (i.e., the first stage). Figure 52 is a top view. In the example of Figure 52, the driving power is 0.5W.

[0468] a2. The value of the velocity difference in the two-phase flow of the first liquid and the second liquid makes the first laminar interface shear force exceed a threshold value so that the acoustic beam flow forms the droplets. Among them, under this method, relative to the aforementioned a1 method, the velocity difference in the two-phase flow is larger, and the laminar interface shear force formed is larger, thereby shearing the acoustic beam flow and forming droplets. The a2 method can be understood as the two-phase shear force formed by the inertial fluid is the dominant factor in generating droplets. As shown in Figure 53, a diagram of the generation of droplets dominated by the laminar interface shear force is shown. In the example of Figure 53, the second liquid is water with a flow rate of 1ul / min, and the second liquid is mineral oil with a flow rate of 8ul / min.

[0469] a3. In addition, when the acoustic beam does not break through the laminar interface, droplets can also be generated based on a method similar to the principle of Figure 57. For example, the first power is relatively weak. In the first stage of the driving cycle, the generated acoustic beam does not break through the laminar interface. The tension of the laminar interface and the thrust of the acoustic beam form a conical laminar interface that bulges toward the first liquid (due to the focusing of the acoustic beam, the diameter of the conical bottom surface formed by the acoustic beam is much smaller than the diameter of the conical bottom surface formed by the jet). In the second stage of the driving cycle, the bulge falls back to form the droplets (the principle is similar to that shown in Figure 57 and will not be repeated). The method a3 can be understood as the viscosity of the first liquid and the interface force of the laminar interface being the dominant force in generating droplets. As shown in Figure 54, the acoustic beam does not break through the laminar interface and generates droplets in the second stage. In the example of Figure 54, the driving power is 0.25W.

[0470] In some embodiments, the size of the droplets formed when the acoustic beam breaks through the laminar flow interface is controlled by at least one of the following parameters b1-b4:

[0471] b1. The first power of the ultra-sonic device is positively correlated with the droplet size. Referring to Figure 58 , this is explained by the fact that a higher first power propels the second liquid to form a longer acoustic beam, meaning a greater amount of acoustic beam enters the first liquid, resulting in larger droplets.

[0472] b2. The duration of the first phase of the drive cycle is positively correlated with the droplet size. Referring to Figures 58 and 5 , this can be explained by the fact that the longer the first phase, the more acoustic beam is pushed into the first liquid, and thus the larger the droplets formed.

[0473] b3. The shear force generated by the velocity difference in the two-phase flow of the first and second liquids. The magnitude of the velocity difference is negatively correlated with the droplet size. The velocity difference and shear force are positively correlated; the greater the velocity difference, the greater the shear force. The greater the shear force, the easier it is to cut off the acoustic beam at the laminar flow interface. Therefore, the velocity difference and droplet size are negatively correlated.

[0474] b4. Physical properties of the first liquid, including viscosity and temperature. The viscosity is positively correlated with the droplet size. Temperature affects viscosity, so temperature is negatively correlated with droplet size.

[0475] b5. For the case of b2, another phenomenon occurred in the experiment. When the signal duty cycle length of the first stage in the driving cycle for driving the acoustic beam flow increases by more than a threshold value, for example, 90%-100%, the droplet size will be reduced. One possible reason for this is that the second stage (i.e., the non-driving stage) is too short, and the laminar interface formed by the first liquid and the second liquid cannot be restored in time, resulting in a decrease in the interfacial force, and thus the particle size of the generated droplets will be reduced.

[0476] In some embodiments, the size of the droplets formed when the acoustic beam fails to break through the laminar interface is related to the interfacial force at the laminar interface formed by the first and second liquids, and the magnitude of this interfacial force is positively correlated with the droplet size. Referring to FIG. 57 , this can be explained by the fact that greater interfacial forces make it easier to truncate the liquid column near the bottom of the cone, resulting in larger droplets.

[0477] In some embodiments, the first liquid and the second liquid can be water, various biological reagents such as DNA solutions, solutions containing cells, inorganic solutions such as calcium chloride, oils, or a random combination of two immiscible liquids. For example, in one embodiment, the first liquid can be an oil phase and the second liquid can be an aqueous phase. The viscosity of the first liquid can be higher or lower than that of the second liquid.

[0478] In some embodiments, the second liquid can be water or another liquid immiscible with the first liquid. In other embodiments, the second liquid can be a liquid containing other substances, such as particles, so that the generated droplets contain the particles. When the droplets contain particles, the particles can be screened, analyzed, or chemically reacted with the droplets downstream.

[0479] In some embodiments, the above-mentioned microparticles may refer to: microscopic particles that are located in a liquid environment and can be distinguished from the liquid environment (i.e., insoluble) and can be moved in the liquid environment can be regarded as the above-mentioned microparticles. In some embodiments, the diameter of the microparticles can range from nanometer scale to millimeter scale, and the microparticles can include: cells, molecules, molecular polymers, DNA nucleic acids, etc. In some embodiments, the microparticles can be fluorescently labeled microparticles, referred to herein as fluorescent microparticles, wherein the fluorescent microparticles include a microparticle core and a fluorescent layer or are doped with fluorescent substances, the microparticle core is silica, magnetic iron oxide, polystyrene, polylactic acid, polyacrylic acid, polyamides, polyaniline, gelatin, calcium carbonate, barium carbonate, cellulose, pectin, starch, albumin, chitosan, stained cells or bacteria, etc., and the fluorescent layer is a fluorescent dye, quantum dots, antibody protein or nucleic acid labeled with fluorescent molecules, etc.

[0480] In some embodiments, the above-mentioned flow channels, such as the first flow channel and the sample flow channel, can be closed flow channels with a top cover, such as a micro flow channel, or can be open flow channels without a top cover.

[0481] The nineteenth embodiment of the present application provides a device for continuous droplet generation, which can be seen in the schematic diagram shown in Figure 49 or Figure 50, including: a first flow channel; at least two sample flow channels located upstream of the first flow channel, for passing at least two-phase immiscible fluids, wherein the at least two-phase fluids include a first liquid and a second liquid, which are laminar flows in the first flow channel, and a horizontal laminar interface is formed between the first liquid and the second liquid; a super-ultrasonic device is provided at the bottom of the first flow channel, and the super-ultrasonic device is driven with a first power cycle, so that the super-ultrasonic device periodically generates an acoustic beam flow toward the laminar interface in at least the second liquid, and the acoustic beam flow breaks through the laminar interface and enters the first liquid, and forms droplets in the first liquid, and the droplets are composed of the second liquid.

[0482] The twentieth embodiment of the present application provides a device for continuous droplet generation, which can be seen in the schematic diagram shown in Figure 51, including: a first flow channel; at least two sample flow channels located upstream of the first flow channel, for passing at least two-phase immiscible fluids, wherein the at least two-phase fluids include a first liquid and a second liquid, which are in a left-right laminar flow in the first flow channel, and a vertical laminar interface is formed between the first liquid and the second liquid; a special ultrasonic device is provided at the bottom of the first flow channel, and the special ultrasonic device is directly opposite to the laminar interface position, and the special ultrasonic device is driven with a first power cycle, so that the special ultrasonic device generates an acoustic beam flow along the laminar interface during the laminar interface period, and the acoustic beam flow induces a portion of the second liquid to enter the first liquid and form droplets in the first liquid, and the droplets are composed of the second liquid.

[0483] The fourth category of applications also includes another solution for continuous droplet generation based on acoustic beam flow, including a method and apparatus for continuous droplet generation, which will be introduced below.

[0484] Another solution for continuous droplet generation provided in this embodiment of the present application adopts two flow channels, and the flow channel walls are connected by through holes. The fluid in one flow channel is driven by a super ultrasonic device to be injected into the other flow channel through the through hole, and droplets are generated in the fluid in the other flow channel. The cost of the droplet generation method is not only lower than that of the conventional extrusion generation method, but also the size and frequency of the generated droplets can be controlled based on the control of the super ultrasonic device. The control method is more flexible and convenient, and the response of the acoustic beam is faster. The droplet generation method of the present application can be applied to the generation of droplets, the generation of particles after the generated droplets are solidified, etc. The present application is described in detail below in conjunction with the various figures and embodiments.

[0485] The twenty-first embodiment of the present application provides a device for continuously generating droplets, comprising:

[0486] a first flow channel and a second flow channel, wherein the first flow channel and the second flow channel include a first position closely disposed with each other, and the first position includes a through hole connecting the first flow channel and the second flow channel; the first flow channel and the second flow channel are used to respectively pass a first liquid and a second liquid;

[0487] A super-ultrasonic device can act on the first liquid in the first flow channel. When the super-ultrasonic device is driven with a first power cycle, an acoustic beam flow toward the through hole is generated in the first liquid. The acoustic beam flow enters the second liquid through the through hole and forms droplets composed of the first liquid in the second liquid.

[0488] In some embodiments, the size of the through hole can be set so that when the ultra-sonic device is not turned on, the liquid in the two flow channels will basically not enter the other flow channel through the through hole.

[0489] In some embodiments, the first and second flow channels can be arranged vertically, for example, with the first flow channel positioned at the bottom and the ultra-sonic device positioned at the bottom of the first flow channel, facing the through-hole. In other embodiments, the first and second flow channels can be arranged horizontally, with the ultra-sonic device positioned on the sidewall of the first flow channel, facing the through-hole. In other embodiments, the channels can be arranged spatially at an angle, etc.

[0490] In some embodiments, the first flow channel and / or the second flow channel can be straight channels or curved channels. The first flow channel and the second flow channel can be arranged closely together to form two parallel flow channels, or they can be spatially staggered, with only the intersection being closely arranged.

[0491] In some embodiments, the first flow channel and the second flow channel have a first position where they are closely arranged, and the first position has a through hole.

[0492] In some embodiments, the first flow channel and the second flow channel have multiple first locations arranged closely together, each having a through hole. Accordingly, multiple ultra-ultrasonic devices are provided, facing each through hole. The shapes and / or resonant frequencies of these multiple ultra-ultrasonic devices may be the same or different. The driving methods for driving these multiple ultra-ultrasonic devices may be the same or different. Examples of the driving methods include drive power, drive signal frequency, and drive signal duty cycle. These multiple ultra-ultrasonic devices can be driven individually as needed to generate desired droplets.

[0493] In some embodiments, there may be a first flow channel and multiple second flow channels, each of which is connected through a through hole at each first position arranged closely to the first flow channel, and accordingly, there are multiple super ultrasonic devices facing each through hole. In this way, droplets can be generated in multiple second flow channels in parallel. In some embodiments, the following parameters of the liquid in each second flow channel may be the same or different, including: liquid type or composition, liquid flow rate, liquid temperature, etc. The shape and / or resonant frequency of these multiple super ultrasonic devices may be the same or different. The driving methods for driving these multiple super ultrasonic devices may be the same or different. In some embodiments, each second flow channel may be connected to its own droplet collection device downstream.

[0494] In some embodiments, there may be multiple first flow channels and one second flow channel, each first flow channel being connected via a through hole located at a first position adjacent to the second flow channel. Accordingly, multiple ultra-sonic devices may be positioned facing each through hole. This allows droplets to be generated in each of the second flow channels. In some embodiments, the following parameters of the liquid within each first flow channel may be the same or different, including: liquid type or composition, liquid flow rate, liquid temperature, etc. The shapes and / or resonant frequencies of the multiple ultra-sonic devices may be the same or different. The driving methods for the multiple ultra-sonic devices may be the same or different.

[0495] In some embodiments, the size of the generated droplets is positively correlated with the power driving the hypersonic device. This can be explained by the fact that a higher driving power results in a stronger acoustic beam, which in turn increases the amount of first liquid that enters the second flow channel through the through-hole, resulting in larger droplets.

[0496] In some embodiments, the size of the generated droplets is positively correlated with the duty cycle of the drive signal driving the ultra-ultrasonic device. This can be explained by the fact that a larger duty cycle of the drive signal leads to a stronger acoustic beam flow, which in turn increases the amount of first liquid that enters the second flow channel through the through hole, resulting in larger droplet sizes.

[0497] In some embodiments, the size of the generated droplets is negatively correlated with the flow rate of the second liquid. This can be explained by the fact that the faster the second liquid flows, the greater and more rapid the shear force on the fluid at the through-hole, making it easier to quickly cut off the acoustic beam flow, resulting in smaller droplets.

[0498] In some embodiments, the size of the generated droplets is positively correlated with the size of the through-hole. This can be explained by the fact that the larger the through-hole size, the more first liquid can be driven into the second flow channel, and thus the larger the size of the generated droplets.

[0499] In some embodiments, the size of the generated droplets is related to the physical properties of the second liquid, including viscosity and temperature. The viscosity is positively correlated with the droplet size. Temperature affects viscosity, so temperature is negatively correlated with droplet size.

[0500] In some embodiments, the frequency of forming the droplets is positively correlated with the frequency of a driving signal driving the hypersonic device.

[0501] In some embodiments, it also includes: solidifying the generated droplets to form microspheres. In some embodiments, the droplets may be collected downstream of the second flow channel before solidification. In other embodiments, a solidification unit may be directly set downstream of the second flow channel to achieve droplet solidification in the flow channel, and then the solidified droplets (i.e., microspheres) are collected downstream. The present application can generate droplets and microspheres with highly uniform sizes. Compared with the existing method of achieving microspheres by stirring, emulsifying and screening, it saves time, saves raw materials, does not require screening, and has highly uniform sizes, so the cost of generating microspheres is lower.

[0502] In some embodiments, the curing unit provided in the flow channel downstream of the second flow channel may be a temperature control device in close contact with the flow channel downstream of the second flow channel, so as to achieve thermal curing or temperature-induced curing of the droplets in the flow channel. In some embodiments, the curing unit provided in the flow channel downstream of the second flow channel may be an ultraviolet light or other light source directed toward the flow channel downstream of the second flow channel, so as to achieve photocuring of the droplets. In some embodiments, the curing unit provided in the flow channel downstream of the second flow channel may be a branch channel connected to the flow channel downstream of the second flow channel, and the branch channel may inject a cross-linking agent, a solution of a certain pH value, or multivalent cations into the downstream of the second flow channel, so as to achieve cross-linking curing of the droplets, curing of the droplets triggered by changes in pH value, ionic cross-linking curing, etc.

[0503] In some embodiments, the first liquid and the second liquid can be water, various biological reagents, such as DNA solutions, solutions containing cells, inorganic solutions, such as calcium chloride, or oils, such as mineral oil, silicone oil, fluorinated oil, etc. The first liquid and the second liquid can be a random combination of two immiscible liquids. The viscosity of the first liquid can be higher or lower than the viscosity of the second liquid.

[0504] In some embodiments, the first liquid may further include at least one substance different from the first liquid. Thus, after the first liquid containing this substance is injected into the second liquid in the second flow channel via an acoustic beam, the resulting droplets of the first liquid include this substance, thereby simultaneously encapsulating the substance within the droplets as they are generated. In some embodiments, the substance may be a particle, allowing downstream screening, analysis, chemical reactions, and other methods to be performed on the particles within the droplets.

[0505] In some embodiments, the above-mentioned microparticles may refer to: microscopic particles that are located in a liquid environment and can be distinguished from the liquid environment (i.e., insoluble) and can be moved in the liquid environment can be regarded as the above-mentioned microparticles. In some embodiments, the diameter of the microparticles can range from nanometer scale to millimeter scale, and the microparticles can include: cells, molecules, molecular polymers, DNA nucleic acids, etc. In some embodiments, the microparticles can be fluorescently labeled microparticles, referred to herein as fluorescent microparticles, wherein the fluorescent microparticles include a microparticle core and a fluorescent layer or are doped with fluorescent substances, the microparticle core is silica, magnetic iron oxide, polystyrene, polylactic acid, polyacrylic acid, polyamides, polyaniline, gelatin, calcium carbonate, barium carbonate, cellulose, pectin, starch, albumin, chitosan, stained cells or bacteria, etc., and the fluorescent layer is a fluorescent dye, quantum dots, antibody protein or nucleic acid labeled with fluorescent molecules, etc.

[0506] In some embodiments, the super ultrasonic device may be perpendicular to the first position, and the direction of the generated sound beam is facing the through hole. In other embodiments, the super ultrasonic device may also form an acute angle or an obtuse angle with the first position in space, and the direction of the sound beam is toward the through hole.

[0507] In some embodiments, the ultra-sonic device is driven at a first power cycle to generate an acoustic beam in the first liquid. The magnitude of the first power can be found in the aforementioned description of the acoustic beam and drive cycle and will not be further described. Furthermore, the magnitude of the first power should be such that the generated acoustic beam can penetrate the through-hole and enter the second liquid to form droplets.

[0508] In some embodiments, the system further includes a detection device for detecting the droplets in the second flow channel, wherein the detection result of the detection device is used to adjust the power level, frequency, and / or duty cycle of the driving signal of the first power. This can further improve the uniformity of the generated droplets or the particles generated after solidification.

[0509] The twenty-second embodiment of the present application provides a method for continuously generating droplets, using any of the above-mentioned devices for continuously generating droplets, the method comprising:

[0510] introducing a first liquid and a second liquid into the first flow channel and the second flow channel respectively;

[0511] The ultra-sonic device is driven with a first power cycle to generate an acoustic beam flow in the first liquid toward the through hole. The acoustic beam flow enters the second liquid through the through hole, forming droplets composed of the first liquid in the second liquid.

[0512] In some embodiments, the method further includes at least one of the following: adjusting the power of the ultra-ultrasonic device to adjust the size of the droplets; adjusting the duty cycle of the driving signal for driving the ultra-ultrasonic device to adjust the size of the droplets; adjusting the flow rate of the second liquid to adjust the size of the droplets; and adjusting the frequency of the driving signal for driving the ultra-ultrasonic device to adjust the frequency of forming the droplets.

[0513] In some embodiments, the method further comprises solidifying the generated droplets to form microspheres.

[0514] In some embodiments, the method further includes: detecting the droplets in the second flow channel, and adjusting the power level, frequency, and / or duty cycle of the driving signal of the first power according to the detection result.

[0515] The twenty-third embodiment of the present application provides a device for continuous droplet generation, which can be seen in the schematic diagrams shown in Figures 59 and 60. Figure 59 shows a three-dimensional schematic diagram, a top view, and an enlarged cross-sectional view of the device. The device includes: a substrate, a lower layer flow channel located on the substrate as a first flow channel, and an upper layer flow channel as a second flow channel. A thin film is provided between the medium forming the lower layer flow channel and the medium forming the upper layer flow channel. The thin film has a through hole at the intersection of the upper layer flow channel and the lower layer flow channel. The lower layer flow channel and the upper layer flow channel respectively have an inlet and an outlet. The upper layer flow channel is connected to the first liquid phase, and the lower layer flow channel is connected to the second liquid phase. A super ultrasonic device is provided at the position opposite the through hole of the substrate. When the device is in operation, it generates an acoustic beam flow in the second liquid phase of the lower layer flow channel. The acoustic beam flow enters the upper layer flow channel through the through hole and is cut by the first liquid phase in the first liquid phase to form droplets.

[0516] Experiments conducted with Example 23 demonstrated that this application can generate uniformly sized microdroplets at high throughput. Furthermore, by varying the flow rates of the first and second liquid phases, droplets of varying sizes and frequencies can be generated. Furthermore, the droplet generation process can be flexibly controlled based on the drive power and drive signal frequency of the ultra-sonic device. This is described below.

[0517] Experiment 1: Controlling droplet generation size and frequency when the ultra-ultrasonic device's drive signal duty cycle is below 50% (i.e., the duty cycle is below 50% during the first phase of the drive cycle, hence the term "intermittent ultra-ultrasonic device operation"). Figure 61 shows that the droplet generation frequency matches the drive signal frequency (or period), and droplet size remains uniform at the same frequency. Further experiments verified that droplet size can be controlled by varying the drive signal duty cycle and drive power, and both are positively correlated with droplet size.

[0518] Experiment 2: When the ultra-ultrasonic device drive signal duty cycle is 100% (i.e., the duty cycle is 100% during the first phase of the drive cycle, hence the ultra-ultrasonic device operating in continuous mode), droplet size and frequency can be controlled by varying the power. Figure 62 shows that under these conditions, higher power results in larger droplet size and lower droplet generation frequency. At the same power, droplet size remains uniform.

[0519] In addition, Figure 63 shows that by utilizing the above-mentioned droplet generation method, the generated droplets are used as templates. After the droplet template is solidified, microspheres with highly uniform sizes can be formed. In addition, in the same hundred-micron-level flow channel, microspheres in the range of 1-150 μm can be synthesized, which has high versatility. At the same time, the wide flow channel can greatly reduce the risk of flow channel blockage.

[0520] The fifth category of applications of the present application is introduced below. This category of applications includes a droplet ejection component, a printing device and a printing method based on acoustic beam flow, which are introduced below.

[0521] In the patent application with Chinese patent number 202211398776.4, a method, device and manufacturing method of acoustic droplet ejection with a refill structure are specifically provided. When a bulk acoustic wave driver drives the droplet ejection process, the refill structure realizes timely replenishment of liquid during the droplet ejection process. In the process of manufacturing a printing device based on an acoustic droplet ejection device, the ejection device is assembled on a translation stage (such as a reciprocating translation stage, a three-axis translation stage, a robotic arm, etc.), and the refill structure is connected to the corresponding fluid pump through a pipeline. During the use of droplet ejection-based printing, it is often necessary to move the nozzle to another position before continuing the ejection printing, and the bulk acoustic wave driver needs to be temporarily shut down during the movement. When the bulk acoustic wave driver is turned off, if the fluid pump is in the open state, the continuously supplied liquid may flow out of the nozzle. When the fluid pump is also controlled to be closed, this leads to the following problem: the fluid pump has a "capacitive effect", that is, the response time of opening and closing is long, which will reduce the overall printing speed. This is particularly obvious when the ejection printing position is changed at a high frequency, which is not suitable for high-throughput and fast printing. In addition, the fluid pump will cause huge instantaneous changes in the pressure and flow rate of the liquid supply when it is started or shut down, which will affect the stability of droplet generation and the uniformity of size.

[0522] The present application provides an improved technical solution that can solve the problem of liquid flowing out of the nozzle when the bulk acoustic wave driver is temporarily turned off and the fluid pump is not turned off, and the solution of the present application can maintain the stability of droplet generation and the uniformity of size when the ultra-ultrasonic device driving signal remains unchanged, and is more suitable for high-throughput, high-speed droplet injection and printing. On the other hand, the present application can also control the size of the generated droplets based on different controls on the ultra-ultrasonic device driving signal, that is, it can change the resolution of droplet injection printing, and based on the ability to control the frequency of ejected droplets, droplet injection printing is made more flexible. The droplet injection solution provided in the embodiment of the present application can be applied to inkjet printing, bioprinting, 3D printing, and then applied to technical fields such as micro-mechanical manufacturing, material forming, such as conformal printing of electronic devices, microstructure printing, etc. The solution of the present application is described in detail below in conjunction with the various figures and embodiments.

[0523] The twenty-fourth embodiment of the present application provides a droplet ejection component, as shown in FIG64 , comprising a liquid chamber and a super-ultrasonic device. The liquid chamber comprises an inlet port and an outlet port, and the wall of the liquid chamber has a through hole. The size of the through hole is limited so that when the super-ultrasonic device is not in operation, liquid in the liquid chamber does not flow out of the through hole when continuous liquid flows through the liquid chamber. When the super-ultrasonic device is in operation, an acoustic beam flow is generated in the liquid in the liquid chamber toward the through hole, and at least a portion of the acoustic beam flow is ejected through the through hole to form ejected droplets.

[0524] In some embodiments, as shown in A in FIG64 , the cross-section at the through-hole is cylindrical. In some embodiments, as shown in B in FIG64 , the cross-section at the through-hole is contracted, such as conical. In some embodiments, as shown in C in FIG64 , the cross-section at the through-hole is divergent, such as trumpet-shaped. Among them, the interfacial tension of the liquid at the through-hole can prevent the liquid in the liquid cavity from flowing out through the through-hole. In addition, the outlet port is in an open state, and the flow resistance is much smaller than that at the through-hole, so that the liquid in the liquid cavity flows out from the outlet port. The provision of a through-hole on the liquid cavity also ensures the stability of the liquid surface at the through-hole relative to the distance of the ultra-ultrasonic device, thereby improving the overall attenuation of the sound wave and the uniformity of the sprayed droplets.

[0525] In some embodiments, the acoustic beam flows upward, and the through hole is located on the upper side of the liquid cavity. In other embodiments, the acoustic beam flows downward, and the through hole is located on the lower side of the liquid cavity. It is understood that the acoustic beam can also be tilted at a certain angle, and the through hole is located at a corresponding position in the liquid cavity.

[0526] In some embodiments, the liquid chamber can be tubular, either linear or curved, with the inlet and outlet ports located at both ends of the tubular liquid chamber. In other embodiments, the liquid chamber can be cylindrical, trapezoidal, conical, etc., with the inlet and outlet ports located on the sidewalls.

[0527] In some embodiments, the distance between the ultra-ultrasonic device and the through hole is set so that the energy of the ultra-ultrasonic device can be completely attenuated and converted into energy for droplet ejection, thereby achieving droplet ejection.

[0528] In some embodiments, the liquid cavity includes one or more inlet ports for introducing one or more liquids. In some embodiments, the liquid supply devices connected to these inlet ports can be controlled to supply liquid in a time-sharing manner so that the droplets sprayed at different times are different. In other embodiments, at least two liquid supply devices connected to these inlet ports can be controlled to supply liquid at the same time, and these liquids are mixed in the liquid cavity. In other embodiments, the inlet port of the liquid cavity is connected to the multiple liquid supply devices through a mixing cavity, and the liquids supplied by the multiple liquid supply devices are mixed in the mixing cavity before entering the liquid cavity.

[0529] In some embodiments, the through holes are multiple in an array, and the super-ultrasonic devices are correspondingly multiple, or multiple resonant chips are integrated on a super-ultrasonic device, and these resonant chips can share the positive and negative electrode ends of the super-ultrasonic device, for example, these resonant chips are in a parallel state in the circuit. These super-ultrasonic devices can be driven independently or share a driving device. The multiple through holes here refer to the through holes in a liquid chamber. In other embodiments, there are multiple liquid chambers, for example, multiple parallel ones, and each liquid chamber has one or more through holes in an array, and corresponding super-ultrasonic devices. When there are multiple liquid chambers, and each liquid chamber is connected to a different liquid supply device, it is possible to achieve simultaneous jet printing of liquids provided by different liquid supply devices.

[0530] When there are multiple through holes and corresponding super-ultrasonic devices, if high-throughput, large-area jet printing is required, multiple super-ultrasonic devices can be driven into working state. When high-precision, small-area printing is required, a small number or one super-ultrasonic device can be driven into working state.

[0531] In some embodiments, the droplet ejection component includes a substrate; the ultra-sonic device is located on the substrate; the liquid chamber is located on the substrate, and the substrate forms the bottom of the liquid chamber; and the through hole is located opposite the ultra-sonic device. In some embodiments, the ultra-sonic device can be fabricated on the substrate, and the liquid chamber can be bonded to the substrate.

[0532] In some embodiments, other microfluidic chips can be located upstream of the liquid chamber to achieve the aforementioned mixing, as well as to aggregate, centrifuge, and align particles in the liquid supply, thereby enabling high-precision jet printing of droplets containing particles. In some embodiments, the particles include cells, molecules, molecular polymers, long-chain molecules, DNA nucleic acids, inorganic particles, metal particles, composite particles, magnetic particles, quantum dots, or microbeads (or microspheres, used for functional modification, such as modified proteins or specific substances). The size of the particles should be smaller than the through-holes.

[0533] In some embodiments, when there are multiple through holes, the shapes or sizes of the through holes can be the same or different. When the special ultrasonic devices and driving signals are the same, the resolution of the droplets sprayed is different due to the different shapes or sizes of the through holes. Accordingly, the special ultrasonic device corresponding to the through hole can be driven to operate according to the requirements of the jet printing resolution.

[0534] In some embodiments, when there are multiple super-ultrasonic devices, the resolution of the ejected droplets will be different under different super-ultrasonic devices, such as different shapes and / or resonant frequencies of the super-ultrasonic devices. Accordingly, the corresponding super-ultrasonic devices can be driven to work according to the requirements of the jet printing resolution.

[0535] In some embodiments, a super-ultrasonic device may produce different droplet resolutions when driven by different drive signals. Accordingly, a drive device may generate corresponding drive signals to drive the super-ultrasonic device according to the required inkjet printing resolution. Examples of different drive signals include drive signals of different powers, drive signals of different duty cycles, and drive signals of different drive periods.

[0536] In some embodiments, the size of the generated droplets is positively correlated with the power driving the hypersonic device. This can be explained by the fact that higher drive power results in a stronger acoustic beam, which in turn increases the amount of liquid released through the through-holes. Consequently, larger droplets are generated, resulting in lower droplet printing resolution.

[0537] In some embodiments, the size of the generated droplets is positively correlated with the duty cycle of the drive signal driving the ultra-ultrasonic device. This is explained by the fact that a larger duty cycle of the drive signal leads to a stronger acoustic beam, which in turn increases the amount of liquid that escapes through the through-holes, resulting in larger droplets.

[0538] In some embodiments, the size of the generated droplets is positively correlated with the size of the through-hole. This can be explained by the fact that the larger the through-hole size, the more liquid can be driven out of the through-hole, and thus the larger the size of the generated droplets.

[0539] In some embodiments, the size of the generated droplets is related to the physical properties of the liquid, such as viscosity, temperature, etc. Therefore, a heater can be placed close to the other side of the substrate to adjust the temperature of the liquid in the liquid chamber.

[0540] In some embodiments, the frequency of forming the droplets is positively correlated with the frequency of a driving signal driving the hypersonic device.

[0541] In some embodiments, the liquid supplied to the liquid chamber may be ink, various biological reagents such as DNA solution, a solution containing cells, or an inorganic solution.

[0542] In some embodiments, the super ultrasonic device is arranged on the same plane as the substrate, and the direction of the generated sound beam is facing the through hole. In other embodiments, the super ultrasonic device can also be placed on the substrate at an acute angle or an obtuse angle with the substrate, and the direction of the sound beam is toward the through hole.

[0543] In some embodiments, the ultra-sonic device is driven with a first power cycle to generate an acoustic beam flow in the first liquid, and the magnitude of the first power should also be such that the generated acoustic beam flow can break through the liquid surface tension at the through hole to form droplets.

[0544] In some embodiments, the above-mentioned droplet ejection component can be used as a droplet ejection head or a droplet printing head.

[0545] The twenty-fifth embodiment of the present application provides a printing device, as shown in the schematic diagram of Figure 65, including: a droplet ejection component as described in any one of the twenty-fourth embodiments; a liquid supply device, which is connected to the inlet port of the liquid cavity of the droplet ejection component through a pipeline, and can be used to continuously supply liquid to the liquid cavity. In this embodiment, the liquid supply device is realized by an injection pump; the outlet port of the liquid cavity of the droplet ejection component is connected to a liquid discharge pipeline; and a driving device of the super-ultrasonic device, which is used to drive the super-ultrasonic device to work.

[0546] In some embodiments, the liquid discharge pipeline is connected to a recovery chamber, and the liquid in the recovery chamber can be transported to the liquid supply device by a pump, thereby realizing liquid recycling.

[0547] In some embodiments, the printing process further includes a table for placing the printed substrate, and the droplet ejection component and the table are movable relative to each other. In some embodiments, the table is immovable, and the droplet ejection component is mounted on the end of a robotic arm (such as a three-axis robotic arm, a manipulator, a six-axis robotic arm, etc.). In the embodiment shown in Figure 65, the droplet ejection component is immovable, and the table is a movable table, specifically a table on a three-axis translation stage. In other embodiments, both the droplet ejection component and the table are movable.

[0548] In some embodiments, the system further includes a camera facing the liquid drop ejecting component, configured to acquire a liquid surface image of the ejection port of the liquid drop ejecting component.

[0549] In some embodiments, the method further includes a camera facing the printing carrier for acquiring an image of the printed object.

[0550] In some embodiments, a fill light is also included to provide fill light for the camera to capture images.

[0551] In some embodiments, a control and display device is also included. The control device receives user operation instructions, controls the actions of other devices, and displays process data, including images captured by the camera.

[0552] The embodiment of the printing device shown in FIG65 is a downward printing structure, that is, the droplet ejection component is located above the table and ejects droplets downward. In other embodiments, an upward printing structure is also possible, where the printed substrate is detachably fixed to the lower surface of the table, and the droplet ejection component is located below the table and ejects droplets upward.

[0553] The twenty-sixth embodiment of the present application provides a printing method, which performs printing based on the above-mentioned printing device, and the method includes:

[0554] continuously supplying liquid to the liquid chamber through the liquid supply device;

[0555] When the ultra-ultrasonic device is driven to work by the driving device, the ultra-ultrasonic device drives the liquid in the liquid chamber to generate an acoustic beam flow toward the through hole, and at least a portion of the acoustic beam flow is ejected through the through hole to form ejected liquid droplets;

[0556] When the ultra-ultrasonic device is in a suspended working state, the liquid continuously supplied into the liquid cavity flows out from the liquid discharge pipeline.

[0557] When the ultra-sonic device is in a suspended state, the droplet ejection component is moved to another target position. In some embodiments, this situation corresponds to printing at a different target position. After moving to the target position, the ultra-sonic device is driven to enter the operating state again.

[0558] In some embodiments, the control of the ejected droplets, such as controlling the resolution of the droplets, can be achieved by controlling the driving signal of the driving device that drives the ultra-ultrasonic device. For details, please refer to the previous embodiments and will not be repeated here.

[0559] In the several embodiments provided in this 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. In addition, the terms "first, second, third, etc." or module A, module B, module C, and 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 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.

[0560] In the above description, the numbers representing the steps, such as S10, S20, etc., do not necessarily mean that the steps must be executed in this manner. If permitted, the order of the steps can be interchanged or they can be executed simultaneously.

[0561] 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.

[0562] References in this specification to "one embodiment" or "an embodiment" mean that a particular feature, structure, or characteristic described in connection 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 throughout this specification do not necessarily refer to the same embodiment, but may refer to the same embodiment. Furthermore, in one or more embodiments, the particular features, structures, or characteristics can be combined in any suitable manner, as would be apparent to one of ordinary skill in the art from this disclosure.

[0563] Note that the above are only preferred embodiments of the present application and the technical principles employed. 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 has been described in more detail through the above embodiments, the present application is not limited to the above embodiments and may include many other equivalent embodiments without departing from the scope of protection of the present application, all of which fall within the scope of protection of the present application.

Claims

1. A method for generating a micro-scale columnar high-speed acoustic beam in a liquid environment, characterized in that: include: Liquid environment; a high-frequency resonator that generates 0.5-30 GHz ultrasonic waves to act on the liquid environment to generate directional fluid motion at the solid-liquid interface along the direction of sound wave propagation in the liquid, wherein the directional fluid motion includes a focused columnar acoustic beam flow; The high-frequency resonator is driven at a first power to operate for at least one driving cycle, each driving cycle comprising a first stage and a second stage, wherein the high-frequency resonator is driven to operate to generate 0.5-30 GHz ultrasonic waves in the first stage, and the high-frequency resonator is stopped from being driven in the second stage; The magnitude of the first power enables the high-frequency resonator to generate the acoustic beam flow in the first stage.

2. The method according to claim 1, characterized in that The duration of the first stage at the first power is less than a second threshold or the duty cycle of the first stage in one driving cycle is less than the first threshold, so that the temperature of the high-frequency resonator is within a third threshold; or The duration of the first stage at the first power is less than a second threshold or the duty cycle of the first stage in one driving cycle is less than the first threshold, so as to suppress the high-frequency resonator from generating a secondary flow in the liquid environment.

3. The method according to claim 1 or 2, characterized in that increasing the intensity of the first power to increase the intensity of the acoustic beam flow, or The duration of the first stage or the duty cycle in a driving cycle is reduced, and the intensity of the first power is increased to increase the intensity of the acoustic beam flow.

4. A method for directional transmission based on acoustic beam flow, characterized in that: include: Generating an acoustic beam flow in a liquid based on the method according to any one of claims 1 to 3, wherein the direction of the acoustic beam flow is the direction of the directional transport; The liquid acted upon by the high-frequency resonator, or the particles in the acted liquid, are directionally transported by the dragging force of the acoustic beam.

5. The method according to claim 4, characterized in that The liquid environment includes one or two layers of liquid, wherein the two layers of liquid include a first layer of liquid in contact with the interface of the high-frequency resonator and a second layer of liquid away from the interface of the high-frequency resonator and in contact with the first layer of liquid; The directional transport includes: moving particles in a direction in the first layer of liquid by using an acoustic beam flow or directionally transporting particles in the first layer of liquid to the second layer of liquid.

6. The method according to claim 5, characterized in that Also included is a target substance, wherein the liquid environment is included between the target substance and the interface of the high-frequency resonator; The directional transport includes: transporting the first layer of liquid or particles in the first layer of liquid in a directional manner to the target substance through an acoustic beam flow.

7. A particle control method based on acoustic beam flow, characterized in that: include: Allowing a fluid including particles to flow into a first flow channel of the microfluidic channel, wherein the particles include first particles; The first ultra-ultrasonic device is not activated so that the particles flowing through it flow downstream; wherein the first ultra-ultrasonic device is a high-frequency resonator and is disposed closely to the first flow channel; The first ultra-sonic device is started to generate an acoustic beam flow of desired intensity based on the method according to any one of claims 1 to 3, so as to deviate the moving direction of the first particles passing through the acoustic beam flow.

8. A particle sorting method based on acoustic beam flow, characterized in that: include: Allowing a fluid including particles to flow into a first flow channel of a microfluidic channel, wherein the particles include first particles; wherein the microfluidic channel further includes a second flow channel and a third flow channel connected to the downstream of the first flow channel; The first ultra-sonic device is not activated so that the particles flowing through it flow toward the downstream third flow channel; wherein the first ultra-sonic device is a high-frequency resonator and is disposed closely to the first flow channel; The first ultra-sonic device is started to generate an acoustic beam flow of desired intensity based on the method described in any one of claims 1 to 3, and the moving direction of the first particles flowing through the acoustic beam flow is deviated so as to flow toward the second flow channel downstream.

9. A method for treating cells based on acoustic beam flow, characterized in that: include: The ultra-ultrasonic device and the target cells are relatively fixed in position, and at least the ultra-ultrasonic device is placed in a liquid environment, and the target cells are within the effective range of the acoustic beam of the ultra-ultrasonic device; wherein the ultra-ultrasonic device is a high-frequency resonator; The ultra-ultrasonic device is driven based on the method according to any one of claims 1 to 3 to generate an acoustic beam in the liquid environment, and the acoustic beam acts on a target position of the target cell to change the state of the target cell.

10. The method according to claim 9, characterized in that The step of driving the ultra-ultrasonic device to generate an acoustic beam in the liquid environment, wherein the acoustic beam acts on a target position of the target cell to change the state of the target cell, includes: The ultra-sonic device is periodically driven to generate a pulsed acoustic beam in the liquid environment, wherein the acoustic beam acts on a first position on the surface of the target cell, causing the first position on the surface of the target cell to be impacted by the pulsed acoustic beam, thereby causing at least one of the following changes: deformation of the surface of the target cell, generation of pores on the surface of the target cell, generation of pores at the first position, cutting at the first position, or entering a corresponding state in response to stimulation; Among them, the target cell enters a corresponding state in response to stimulation, including at least one of the following: activating the cell's mechanical gate channel, reorganizing the cytoskeleton, activating the signal transduction pathway, and changing the secretory activity.

11. The method according to claim 10, characterized in that Also includes at least one of the following: allowing a substance in the liquid environment to enter the interior of the target cell through the pore or the mechanical gate channel; A substance in the liquid environment is transmitted by the acoustic beam flow, passes through the pore or the mechanical gate channel, and enters the interior of the target cell.

12. The method according to claim 9, characterized in that The step of driving the ultra-ultrasonic device to generate an acoustic beam in the liquid environment, wherein the acoustic beam acts on a target position of the target cell to change the state of the target cell, includes: The ultra-ultrasonic device is periodically driven to generate a pulsed acoustic beam in the liquid environment. The acoustic beam acts on a second position on the surface of the target cell, where the second position is located at the binding position between the target cell and the binding object, so that the second position is impacted by the pulsed acoustic beam and separated from the binding object.

13. A method for realizing micro water hammer effect based on acoustic beam flow, characterized in that: include: The ultra-ultrasonic device is a high-frequency resonator, which generates an acoustic beam in a liquid environment based on the method described in any one of claims 1 to 3, and The duty cycle of the second phase in at least one driving cycle is adjusted to intermittently generate an acoustic beam flow, and the duration of the intermittent generation is greater than a threshold value, and the intermittently generated acoustic beam flow below the threshold value produces a micro water hammer effect.

14. The method according to claim 13, characterized in that The liquid environment is located in a cavity, a hollow needle extending outward is provided on the wall of the cavity, and the acoustic beam generated by the ultra-ultrasonic device is facing the hollow needle; The hollow needle is used to extend the action distance of the micro water hammer effect and / or maintain the directionality of the micro water hammer effect.

15. The method according to claim 13 or 14, characterized in that Also includes: The target object on which the acoustic beam flow of the generated micro water hammer effect acts includes at least one of the following: a first particle, an epidermis or surface, or a tissue located within the range of the micro water hammer effect; The liquid environment includes second particles, and the acoustic beam flow generated by the micro water hammer effect carries the second particles.

16. A method for continuously generating droplets, characterized in that: include: introducing at least two immiscible fluids into the first flow channel, wherein the at least two-phase fluids include a first liquid and a second liquid in laminar flow, and a laminar interface is formed between the first liquid and the second liquid; The ultra-ultrasonic device is driven with a first power cycle, the ultra-ultrasonic device being a high-frequency resonator. Based on the method described in any one of claims 1 to 3, the ultra-ultrasonic device is caused to periodically generate an acoustic beam flow toward the laminar interface in at least the second liquid, the acoustic beam flow breaking through the laminar interface into the first liquid and forming droplets in the first liquid, wherein the droplets are composed of the second liquid.

17. A method for continuously generating droplets, characterized in that: include: introducing at least two immiscible fluids into the first flow channel, the at least two-phase fluids comprising a first liquid, a second liquid, and a third liquid in laminar flow, wherein a first laminar interface is formed between the first liquid and the second liquid, and a second laminar interface is formed between the second liquid and the third liquid; The ultra-ultrasonic device is driven with a first power cycle, the ultra-ultrasonic device being a high-frequency resonator. Based on the method described in any one of claims 1 to 3, the ultra-ultrasonic device is caused to periodically generate an acoustic beam flow toward the second laminar flow interface at least in the third liquid. The acoustic beam flow breaks through the second laminar flow interface and the first laminar flow interface into the first liquid and forms droplets in the first liquid. The droplets are composed of the second liquid enclosing the third liquid, or the droplets are composed of two closely adjacent droplets that are integrated, and the two droplets are composed of the second liquid and the third liquid.

18. A method for continuously generating droplets, characterized in that: include: introducing at least two immiscible fluids into the first flow channel, wherein the at least two-phase fluids include a first liquid and a second liquid in laminar flow, and a laminar interface is formed between the first liquid and the second liquid; The ultra-ultrasonic device is driven with a first power cycle, the ultra-ultrasonic device being a high-frequency resonator. Based on the method described in any one of claims 1 to 3, the ultra-ultrasonic device is caused to periodically generate an acoustic beam flow along the laminar interface at the laminar interface, the acoustic beam flow inducing a portion of the second liquid to enter the first liquid and form droplets in the first liquid, wherein the droplets are composed of the second liquid.

19. The method according to claim 16, 17 or 18, characterized in that When the acoustic beam enters the first liquid, droplets are formed in the first liquid by one of the following methods: When the ultra-sonic device is driven in a first power cycle, the acoustic beam is formed into the liquid droplet based on the driving energy in the first stage of the driving cycle; or When the velocity difference between the two-phase flow of the first liquid and the second liquid is such that the first laminar interface shear force exceeds a threshold value, the acoustic beam is formed into the liquid droplets under the control of the velocity difference.

20. The method according to any one of claims 19, characterized in that: The particle size of the droplets formed is controlled by at least one of the following parameters: The first power, wherein the magnitude of the first power is positively correlated with the size of the droplet particle size; The duration of the first stage in the driving cycle is positively correlated with the size of the droplet; a shear force generated by a flow velocity difference in the two-phase flow of the first liquid and the second liquid, wherein the flow velocity is negatively correlated with the droplet size; The physical properties of the first liquid.

21. A device for continuously generating droplets, characterized in that: include: First flow channel; At least two sample flow channels located upstream of the first flow channel are used to pass at least two immiscible fluids, wherein the at least two-phase fluids include a first liquid and a second liquid, and are in a vertical laminar flow within the first flow channel, with a horizontal laminar interface formed between the first liquid and the second liquid; A super-ultrasonic device is provided at the bottom of the first flow channel, and the super-ultrasonic device is a high-frequency resonator. Based on the method described in any one of claims 1 to 3, the super-ultrasonic device is driven with a first power cycle, so that the super-ultrasonic device periodically generates an acoustic beam flow toward the laminar interface in at least the second liquid. The acoustic beam flow breaks through the laminar interface and enters the first liquid, and forms droplets in the first liquid, and the droplets are composed of the second liquid.

22. A device for continuously generating droplets, characterized in that: include: First flow channel; At least two sample flow channels located upstream of the first flow channel are used to pass at least two immiscible fluids, wherein the at least two-phase fluids include a first liquid and a second liquid, and are laminar flowed in the first flow channel in a horizontal direction, with a vertical laminar interface formed between the first liquid and the second liquid; A special ultrasonic device is provided at the bottom of the first flow channel, which is a high-frequency resonator. Based on the method described in any one of claims 1 to 3, the special ultrasonic device is facing the laminar interface position, and the special ultrasonic device is driven with a first power cycle, so that the special ultrasonic device generates an acoustic beam flow along the laminar interface periodically at the laminar interface. The acoustic beam flow induces a portion of the second liquid to enter the first liquid and form droplets in the first liquid, and the droplets are composed of the second liquid.

23. A device for continuously generating droplets, characterized in that: include: a first flow channel and a second flow channel, wherein the first flow channel and the second flow channel include a first position closely disposed to each other, and the first position includes a through hole connecting the first flow channel and the second flow channel; The first flow channel and the second flow channel are used to respectively introduce a first liquid and a second liquid; A super-ultrasonic device capable of acting on the first liquid in the first flow channel, wherein the super-ultrasonic device is a high-frequency resonator. When the super-ultrasonic device is driven with a first power cycle based on the method described in any one of claims 1 to 3, an acoustic beam flow toward the through hole is generated in the first liquid. The acoustic beam flow enters the second liquid through the through hole and forms droplets composed of the first liquid in the second liquid.

24. The device according to claim 23, characterized in that The first liquid includes at least one substance different from the first liquid, so that at least one of the droplets includes the substance.

25. A method for continuously generating droplets, characterized in that: Using the device for continuous droplet generation according to any one of claims 23 or 24, the method comprises: introducing a first liquid and a second liquid into the first flow channel and the second flow channel respectively; The ultra-ultrasonic device is driven with a first power cycle, where the ultra-ultrasonic device is a high-frequency resonator. Based on the method described in any one of claims 1 to 3, an acoustic beam flow toward a through hole is generated in a first liquid, where the acoustic beam flow enters the second liquid through the through hole, and forms droplets composed of the first liquid in the second liquid.

26. The method according to claim 25, characterized in that Also includes at least one of the following: Adjusting the power of driving the ultra-ultrasonic device to adjust the size of the droplets, wherein the size of the droplets is positively correlated with the power of driving the ultra-ultrasonic device; adjusting a duty cycle of a driving signal for driving the ultra-ultrasonic device to adjust a size of the liquid droplet, wherein the size of the liquid droplet is positively correlated with the duty cycle of the driving signal for driving the ultra-ultrasonic device; adjusting the flow rate of the second liquid to adjust the size of the droplets, wherein the size of the droplets is inversely correlated with the flow rate of the second liquid; adjusting the size of the through-hole to adjust the size of the liquid droplet, wherein the size of the liquid droplet is positively correlated with the size of the through-hole; The frequency of the driving signal driving the ultra-ultrasonic device is adjusted to adjust the frequency of forming the droplets, wherein the frequency of forming the droplets is positively correlated with the frequency of the driving signal driving the ultra-ultrasonic device.

27. A droplet ejecting component, characterized in that: including a liquid chamber and a super ultrasonic device; The liquid cavity includes an inlet port and an outlet port, and a through hole is formed in a wall of the liquid cavity. The size of the through hole is limited so that when the ultra-ultrasonic device is not working, the liquid in the liquid cavity does not flow out of the through hole when the liquid continuously flows through the liquid cavity. The ultra-ultrasonic device is a high-frequency resonator. Based on the method described in any one of claims 1 to 3, when the ultra-ultrasonic device is in an operating state, an acoustic beam flow is driven in the liquid in the liquid chamber toward the through hole, and at least a portion of the acoustic beam flow is ejected through the through hole to form ejected droplets.

28. A printing device, characterized in that: include: The droplet ejecting component according to claim 27; a liquid supply device, connected to the inlet port of the liquid chamber through a pipeline, and capable of continuously supplying liquid to the liquid chamber; The outlet port of the liquid chamber is connected to a liquid discharge pipeline; The driving device of the ultra-ultrasonic device is used to drive the ultra-ultrasonic device to work.

29. The device according to claim 28, characterized in that Also includes at least one of the following: a recovery chamber, the liquid discharge pipeline being connected to the recovery chamber, and the liquid in the recovery chamber being transported to the liquid supply device; A table is provided for placing the printed carrier, and the droplet ejecting component and the table are movable relative to each other.

30. A printing method, characterized in that: Printing is performed based on the printing device according to any one of claims 28 or 29, and the method includes: continuously supplying liquid to the liquid chamber through the liquid supply device; When the ultra-ultrasonic device is driven to work by a driving device, the ultra-ultrasonic device drives the liquid in the liquid chamber to generate an acoustic beam toward the through hole based on the method of any one of claims 1 to 3, and at least a portion of the acoustic beam is ejected through the through hole to form ejected liquid droplets; When the ultra-ultrasonic device is in a suspended working state, the liquid continuously supplied into the liquid cavity flows out from the liquid discharge pipeline.

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