A method and apparatus for microparticle acoustic field manipulation for microfluidic networks

Abstract

The application discloses a method for manipulating particles in a microfluidic network with at least one branch, where at least one acoustic field with a predetermined shape is generated. When a particle flow is injected into the microfluidic network along a flow direction and passes through the branch, the shape of the acoustic field makes the particle flow prevented from entering a non-target flow channel, and the particle flow is guided by the acoustic field to enter a target flow channel of the branch. The shape of the acoustic field pressure is an arc shape, which is tangent to the center line of the target flow channel at the branch and covers the entrance of the non-target flow channel. The phase gradient of the acoustic field is superimposed inside the arc-shaped acoustic pressure, and the direction points to the target branch.

Description

Technical Field

[0001] The present invention belongs to the technical field of acoustic field control, and in particular relates to a method and device for controlling the acoustic field of particles in a microfluidic network. Background Art

[0002] In biomedicine, the manipulation of tiny substances has a wide range of applications, including cell assembly in tissue engineering, drug delivery, and the detection and separation of biochemical samples. Currently, a variety of methods for the directional manipulation of tiny substances based on external physical fields exist, including magnetic control, electric field control, optical field control, and ultrasonic field control. Magnetic fields have good penetration depth but limited precision, optical fields can precisely manipulate individual micron-sized substances but cannot penetrate opaque tissue, and electric field control can easily cause ionization damage to biological tissue. Ultrasonic manipulation, on the other hand, is a non-contact acoustic manipulation technology that uses ultrasonic mechanical effects (ultrasonic radiation force and acoustic streaming) to control the motion of objects. It is a manipulation method with good tissue penetration depth, excellent biocompatibility, high control precision, and a wide range of material applications. This technology utilizes the momentum exchanged between the sound wave and the particles caused by the reflection, refraction, and absorption of sound waves by particles in the acoustic field. The particles are then manipulated through the forces acting on them. This technology has been demonstrated to be applicable to the manipulation of microparticles both in vivo and in vitro, including alignment, mixing, separation, and aggregation. Summary of the Invention

[0003] The present disclosure proposes a method for manipulating the orientation of particles in a fluid network based on regulating the acoustic field, with the aim of solving the problem that existing acoustic manipulation methods are difficult to perform high-throughput directional manipulation of matter in complex fluid networks.

[0004] One embodiment of the present disclosure provides a method for controlling a microparticle acoustic field in a microfluidic network, wherein the microfluidic network has at least one branch, and at least one acoustic field of a preset shape is generated at the branch.

[0005] When a particle flow is injected into the microfluidic network along the fluid direction and passes through the branch, the shape of the acoustic field prevents the particle flow from entering a non-target flow channel and guides the particle flow into the target flow channel of the branch by the acoustic field.

[0006] The sound pressure field has an arc shape that is tangent to the centerline of the target flow channel at the branch and covers the entrance of the non-target flow channel. The phase gradient of the sound field is superimposed on the arc sound pressure and points to the target branch. BRIEF DESCRIPTION OF THE DRAWINGS

[0007] The above and other objects, features and advantages of the exemplary embodiments of the present invention will become readily apparent by reading the following detailed description with reference to the accompanying drawings, in which several embodiments of the present invention are shown by way of example and not limitation, in which:

[0008] Figure 1 Schematic diagram of a multi-branch network structure and fluid velocity distribution according to one embodiment of the present invention

[0009] Figure 2 Schematic diagram of the steps for regulating a shape-adaptive sound field according to one embodiment of the present invention.

[0010] Figure 3 Schematic diagram of a particle being directed to branch 2 in a multi-branch network according to one embodiment of the present invention.

[0011] Figure 4 Schematic diagram of a particle being directed to branch 1 in a multi-branch network according to one embodiment of the present invention.

[0012] Figure 5 Schematic diagram of a particle being directed to branch 3 in a multi-branch network according to one embodiment of the present invention.

[0013] Figure 6 Schematic diagram of a particle being directed to branch 4 in a multi-branch network according to one embodiment of the present invention.

[0014] Figure 7 Schematic diagram of particles being collected in a branch by an acoustic field without phase gradient according to one embodiment of the present invention.

[0015] Figure 8 Schematic diagram of a particle being manipulated in a branch to a target branch by a phase gradient acoustic field according to one embodiment of the present invention.

[0016] Figure 9 Schematic diagram of microparticle manipulation in rat liver blood vessels using a shape-adaptive acoustic field according to one embodiment of the present invention.

[0017] Figure 10 Schematic diagram of modulating the acoustic field in the central artery of a rabbit ear to manipulate microparticles into a target blood vessel according to one embodiment of the present invention.

[0018] Figure 11 Schematic diagram of the trajectory of particles in a blood vessel under the action of a modulated acoustic field according to one embodiment of the present invention.

[0019] Figure 12 Schematic diagram of the distribution of high-flux microparticles in a blood vessel under a shape-free adaptive acoustic field according to one embodiment of the present invention.

[0020] Figure 13Schematic diagram of the distribution of high-flux microparticles in a blood vessel under a shape-adaptive acoustic field according to one embodiment of the present invention.

[0021] Figure 14 Schematic diagram of an experimental setup according to one embodiment of the present invention. DETAILED DESCRIPTION

[0022] Ultrasonic manipulation, based on acoustic effects, can manipulate materials ranging from micrometers to millimeters through the acoustic radiation force of sound waves on microparticles and the acoustic streaming effect induced by ultrasound in the medium. For example, in a standing wave acoustic field, the acoustic radiation force can propel materials toward wave nodes or antinodes, thereby achieving personalized material distribution; the acoustic streaming effect formed by acoustic vortices can spirally lift materials from the bottom of the medium. Currently, ultrasonic sound fields are gradually becoming a technical means for the directional manipulation of materials within microfluidic networks.

[0023] The study found that without the control of an external physical acoustic field, substances delivered within microfluidics would be randomly distributed in various branches within the fluid network along with the surrounding fluid. In contrast, through directional manipulation, substances can be delivered along specific paths in the fluid network, making it possible to selectively concentrate substances in the target area.

[0024] Microfluidics generally refers to the flow of fluids and chemical and biological processes carried out in channels or chambers ranging from micrometers to millimeters. It involves technologies for controlling and manipulating fluids at the microscopic scale. Microfluidics technology has applications in a variety of fields, including chemical analysis, biomedical research, drug screening, and environmental monitoring.

[0025] Currently, one method for directional acoustic manipulation of materials within microfluidics is to use surface acoustic waves to guide the material within a plane. The surface acoustic waves propagate along the plane into the fluid, generating acoustic radiation forces on the material, thereby changing its direction of motion. However, surface acoustic waves are limited to manipulating materials within a two-dimensional plane and cannot manipulate materials within complex three-dimensional fluids, resulting in a limited range of manipulation.

[0026] Another commonly used acoustic manipulation method is to use a bulk wave acoustic potential trap to capture matter in a fluid, and then drag the matter to move in three dimensions by moving the acoustic potential trap. However, acoustic potential traps are usually used to capture matter at a single point, which takes a long time and has low movement efficiency. In addition, the fluid network is often complex and diverse, making it difficult for acoustic potential traps to achieve rapid manipulation of high-throughput matter. In addition, bulk waves easily form standing waves or induce local acoustic flow between the interfaces of the fluid, causing matter to easily gather at the acoustic pressure distribution, blocking the fluid and limiting the directional manipulation of matter in the fluid. Therefore, the acoustic potential trap manipulation method is inefficient, time-consuming, and difficult to achieve parallel material control.

[0027] Therefore, the main challenges in microparticle manipulation in microfluidics are:

[0028] 1. Acoustic fields make it difficult to achieve high-throughput material manipulation in microfluidics;

[0029] 2. Due to the randomness of microfluidic structures, directional manipulation of materials requires an acoustic field whose shape is adapted to the fluid structure to achieve multi-point control;

[0030] 3. The accumulation of matter in the fluid in the acoustic field can easily reduce the control efficiency.

[0031] With the current development of acoustic manipulation technology for materials within microfluidic networks, ultrasonic manipulation of materials within multi-branched microfluidics often requires a multi-point acoustic field that is compatible with the fluid network structure. However, existing acoustic manipulation methods are unable to simultaneously implement multi-point parallel material manipulation. This disclosure utilizes acoustic holography technology to propose a solution for constructing precise acoustic fields that adapt to the shape of the fluid network and for manipulating materials within the fluid. This solution reconstructs multiple acoustic pressure distributions in space that are compatible with the microfluidic structure, enabling multi-point parallel, high-throughput acoustic manipulation of materials within the fluid network.

[0032] Example 1

[0033] A shape-adaptive acoustic field is used to manipulate the movement direction of particles. To achieve universal applicability of the manipulation method to microfluidic structures, this embodiment provides an acoustic manipulation strategy that provides a shape-adaptive acoustic field for directional manipulation of particles in multi-branched microfluidics.

[0034] In terms of flow channel design, the microfluidic structure refers to the common gradient multi-branched vascular network, and its flow channel size gradually decreases from 600 microns to 100 microns, and the height of the flow channel is 400 microns. The flow channel cross-section in this case is rectangular, the size here refers to the width of the microchannel, and the height of the flow channel refers to the height of the rectangle. The microchannel has four branch outlets, and each branch has a different angle. The angle here refers to the angle between the branch flow channel and the main flow channel. Without loss of generality, the angles of the three branches in this case are 60°, 45° and 30° respectively. At the same time, in order to prevent the particles from deviating to a specific branch when there is no ultrasonic manipulation, the tributary velocity after each branch in the fluid is equal. The structure of the flow channel and the fluid velocity are as follows Figure 1 As shown, according to the flow channel structure, from top to bottom, branch 1, branch 2, branch 3, and branch 4 are defined. Branch 2 is selected as the target flow channel for microparticle delivery.

[0035] Figure 1 This is a schematic diagram of a multi-branch network structure and fluid velocity distribution. Figure 1 In the figure, branch 2 and branch 3 meet at point C. After the flow of branches 2 and 3 converge, they meet branch 1 at point B. The resulting confluent flow channel then meets branch 4 at point A to form the main flow channel. Figure 1The velocity difference of the fluid in different regions or branches is shown, and the color representation of the fluid velocity size is given in the figure. The main flow channel has a higher flow velocity, and the fluid velocity in each branch is relatively small.

[0036] In terms of sound field setting, according to the target fluid region that the manipulated substance needs to reach, three branch points on the path are determined, and three corresponding sound pressure distributions are designed as the target sound field. Among them, the shape of each sound pressure is set as an arc shape. The arc shape is selected in order to make the particles away from the target flow channel side better enter the target flow channel. Other selectable sound field patterns include linear, ring-shaped, circular, etc., and the main feature is that the phase gradient direction points to the target flow channel. The arc shape is tangent to the center line of the target flow channel at the branch and covers the entrance of the non-target flow channel, and the superimposed phase gradient is located inside the arc-shaped sound pressure and points to the target branch. The target sound field will be generated by a focusing type transducer. The size of each arc-shaped sound field pattern is set as an outer diameter of 1 mm and an inner diameter of 0.8 mm, and the arc center angle is 90°.

[0037] The phase gradient (or phase difference) refers to the rate of change of the phase of a sound wave at different points in space. When the phase gradient of a sound wave is not zero, it means that the spatial distribution of pressure changes is not uniform. This non-uniform pressure distribution can generate force, i.e. acoustic radiation force. The direction of acoustic radiation force is usually related to the phase gradient of the sound wave, which can concentrate the acoustic radiation force in a specific direction. This phenomenon is called beam forming or acoustic focusing.

[0038] Therefore, by changing the phase gradient, the focusing of the sound wave beam can be achieved. In the focusing process, the wavefronts have the same phase at a specific point or region, so as to realize the superposition and enhancement of the waves. By adjusting the phase of different points on the wavefront, the direction and focusing characteristics of the beam can be changed. For example, during the propagation of a sound wave, the phase of the wave can be controlled by adjusting the emission source or using a phase delay device. To achieve focusing, a gradually increasing phase gradient needs to be created on the wavefront, so that the beam gradually converges to a focal point during propagation. This can be achieved through time delay or spatial delay. If a phased array is used, i.e. multiple emission transducers are used, each transducer can independently control the phase of its emission. By precisely adjusting the phase of each transducer, a beam with a specific directivity can be synthesized. When the phase gradient on the wavefront is properly adjusted, the beam will converge at a specific location to form a focal point. At the focal point, the amplitude of the wave is maximum and the energy is most concentrated. In practical applications, if it is necessary to dynamically adjust the phase gradient to track moving targets or adapt to environmental changes, a real-time feedback control system can be used to achieve this. Thus, by precisely controlling the phase gradient of the wavefront, precise focusing of the beam can be achieved.

[0039] In this embodiment, the transducer is a focused transducer with a focusing distance of 20 mm and an aperture of 18.4 mm. In this embodiment, acoustic lens technology is used to generate the target sound field, with the acoustic lens mounted on the surface of the transducer. A focused transducer precisely controls the shape and size of the sound field, focusing the input acoustic or ultrasonic energy onto a specific point or small area. The acoustic lens, operating on acoustic principles, can focus or diffuse sound waves like an optical lens, mimicking the function of an optical lens in its design. Because the target sound field is regulated and formed by the acoustic lens, the spatial distribution of the target sound field is determined as long as the transducer and acoustic lens are fixed. The specific location of the sound field in space can also be determined by measuring the sound pressure with a hydrophone or by visualizing the localized heat generated by the sound field using temperature-sensitive color film. Here, the acoustic lens is mounted on the surface of the transducer. As sound waves travel from the transducer through the acoustic lens, a sound field is formed at a predetermined height. As long as the transducer and acoustic lens are fixed, the location of the sound field is determined. In addition, if the sound field needs to be visualized or precisely located in space, a hydrophone can be used to measure the sound pressure in the space, or temperature-sensitive color-changing glue / paper can be used to display the position of the sound field.

[0040] In terms of acoustic field control, it is assumed that at least one of the three sound pressure patterns is located on the focal plane. The three acoustic field controls with phase gradients and adapted to the microfluidic branches, as well as the calculation of the lens thickness information, are completed by the following steps:

[0041] (1) The sound field containing three sound pressure distributions with phase gradients is set as the target sound field and the first input sound field.

[0042] (2) The input sound field is transferred to the transducer surface using the time reversal method to obtain the transmitted sound field on the transducer surface. (3) Since the sound field on the transducer surface has a uniform amplitude, the amplitude of the transmitted sound field is homogenized, but the phase information of the transmitted sound field is retained.

[0043] (4) The transmitted sound field with modified amplitude is transmitted back to the target plane to obtain the reconstructed sound field.

[0044] (5) Compare the reconstructed sound field with the target sound field. If the sound pressure formed by the reconstructed sound field is uniform, the sound field reconstruction is completed. Otherwise, compare the sound pressure ratios at each position of the reconstructed sound field and the target sound field, and correct the amplitude of the input sound field according to the difference in amplitude. Specifically, if the amplitude of the reconstructed sound field at a certain position is lower than that of the target sound field, then increase the amplitude at the same position of the input sound field; conversely, if the reconstructed sound field has a higher sound pressure amplitude than the target sound field at a certain position, then reduce the amplitude at the same position of the input sound field.

[0045] (6) The modified input sound field is re-sound field transmitted, i.e. repeating steps (2)-(5), through multiple sound field transmissions between the target plane and the transducer surface, usually within 10 times. The reconstructed sound field will form a sound pressure distribution with uniform amplitude and phase gradient, as shown in Figure 2 The transducer here can be a sound lens transducer or a phased array transducer.

[0046] The time reversal algorithm (TRA) is an algorithm for signal reconstruction based on the principle that the propagation of waves in a medium has time reversal symmetry, which is used to iteratively focus waveforms and achieve acoustic focusing.

[0047] Figure 2 The steps of shape-adaptive sound field regulation are described, including:

[0048] S201, the sound field of three sound pressure distributions is set as an input sound field;

[0049] S202, the input sound field is transmitted to the transducer surface using the time reversal algorithm, which is regarded as the transmitting sound field of the transducer surface;

[0050] S203, the amplitude of the transmitting sound field is uniformly processed, which is helpful for subsequent sound field processing and analysis;

[0051] S204, the transmitting sound field is propagated to the target plane to obtain a reconstructed sound field;

[0052] S205, the phase and amplitude of the reconstructed sound field are replaced to achieve sound field distribution or focusing effect;

[0053] S206, the original input sound field is replaced by the processed reconstructed sound field;

[0054] S207, the transducer surface transmits a sound field with uniform amplitude, which is used for acoustic imaging or acoustic manipulation.

[0055] A sound lens is a device that uses the propagation characteristics of sound waves in different media to focus or diffuse sound waves. It uses refraction, reflection, and diffraction of sound waves in media to control the propagation path of sound waves. The sound lens can have different thicknesses according to design requirements.

[0056] According to the phase information of the transmitting sound field, the thickness information of the sound lens is converted. The lens has an initial thickness According to the phase value of each position of the transmitting sound field (0-2π), its thickness becomes Here, the lens has an initial thickness H0. Based on the desired phase (φ) at each position of the acoustic lens (each point on the acoustic lens can be a pixel, and each position here refers to each point on the acoustic lens), the thickness is reduced to H1.

[0057] Therefore, each position in the transmitted sound field corresponds to a thickness value, which determines the structure of the lens. This lens structure is prepared using 3D printing technology and mounted on the transducer surface to construct the required sound field on the target plane.

[0058] In terms of sound field construction, the frequency of the ultrasonic signal is 4 MHz, a sinusoidal wave signal. The ultrasonic waves emitted by the transducer pass through the acoustic lens on the surface and reconstruct multiple sound pressure distributions in the target plane.

[0059] In terms of particle injection, polymethyl methacrylate (PMMA) particles with a particle size of 100 μm were selected as the manipulation object, and the particles were injected into the fluid network using a microinjection pump. After the particles enter the fluid, they are manipulated by the shape-adapted sound pressure at each branch. Because the sound field produces acoustic effects at the branches, including the acoustic streaming effect and the acoustic radiation force of the sound field on the particles, the particles are manipulated into the target fluid, thereby ultimately achieving the effect of selective delivery, such as Figure 3 By changing the target branch and modulating the corresponding shape to adapt to the sound field, the directional control of particles in the other three branches can be achieved, such as Figure 4 , Figure 5 , Figure 6 .

[0060] exist Figure 3 in Figure 1 Based on the structure, particles are injected from the main channel, and three shape-adaptive sound fields are set at points A, B, and C, respectively, so that the particles enter branch 2. Figure 4 In the example, the particle enters branch 1 by setting the shape at points A and B to adapt to the acoustic field. Figure 5 In the example, the shape is set at points A, B, and C to adapt to the acoustic field so that the particle enters branch 3. Figure 6 In the example, the shape is set at point A to adapt to the acoustic field so that the particles enter branch 4.

[0061] Example 2

[0062] The shape-adaptive acoustic field can superimpose a phase gradient at the sound pressure distribution to improve the efficiency of material manipulation. This embodiment provides a comparison of manipulating the directional motion of particles at a fluid branch using an acoustic field containing a phase gradient and an acoustic field without a phase gradient.

[0063] Different from the flow channel design in Example 1, in this embodiment, the microchannel is set to be 600 microns wide and 400 microns deep, with a single branch and a branch angle of 60 degrees. The branch angle here refers to the angle between the two branch flow channels formed after the flow channel bifurcates. Different from the multiple sound pressure distributions in Example 1, in this embodiment, one sound pressure distribution without gradient and one sound pressure distribution in the sound field with phase gradient are set. The rest of the sound field shapes and the transducers used to reconstruct the sound field are the same as in Example 1. The sound field generation method of a single sound pressure distribution is similar to the sound field control in Example 1, the difference is that only one sound field graph needs to be set on the target plane. Here, the sound field graph used is arc-shaped, just like the sound field graph in Example 1. The transducer used to generate the sound field is also the 4MHz transducer in Example 1.

[0064] Unlike the sound field setting in Example 1, the key to the sound field with a phase gradient in this embodiment is to set a phase gradient on the sound pressure graph. In this embodiment, the phase gradient value is set to 3 rad / mm. The sound field control process is similar to that in Example 1, differing only in that a phase gradient is added to the sound pressure distribution. For comparison, another sound field is used without a phase gradient set within its sound pressure distribution.

[0065] After the particles enter the microfluidics, an acoustic field with or without gradient is applied at the branch of the fluid. Figure 7 As shown in Figure 2, the acoustic field without phase gradient causes aggregation at the branch point and cannot manipulate the particles into the target fluid. Figure 8 The acoustic field containing a phase gradient can manipulate particles into the target fluid without aggregation.

[0066] Example 3

[0067] This embodiment provides a method for manipulating microparticles within a vascular network using a shape-adaptive acoustic field. Unlike the flow channel design in Example 1, this embodiment utilizes a vascular micronetwork derived from rat liver. The liver vascular network was obtained using decellularization technology, and the vessels where the microparticles are manipulated range in size from 500μm to 1200μm. This vascular network retains the original vascular structure and can be used to verify the effectiveness of acoustic field manipulation on microparticles in real blood vessels.

[0068] Different from the acoustic field setting in the first embodiment, the acoustic field setting in this embodiment is set according to the specific blood vessel branches. In this embodiment, two sound pressure distributions are used to control the microparticles in the corresponding two blood vessel branches. In this embodiment, the microparticles enter the liver blood vessel network and are controlled by the acoustic field to enter the predetermined blood vessel branches, such as Figure 9 .

[0069] Example 4

[0070] This example provides a method for manipulating microparticles within a living vascular network using a shape-adaptive acoustic field. Unlike the flow channel design in Example 1, this example uses the central ear artery of a New Zealand white rabbit as a microvessel for microparticle manipulation. The central ear artery of a rabbit has a size of less than 1000 μm. This fluid network represents a real blood vessel, used to verify the effectiveness of acoustic field manipulation of microparticles within a living vascular network.

[0071] Unlike the acoustic field setting in Example 1, this embodiment uses a single acoustic pressure distribution. This embodiment manipulates microparticles within a single blood vessel branch. The focused transducer used in this embodiment has a focal distance of 60 mm and an aperture of 56.5 mm.

[0072] Different from the sound field construction in the first embodiment, the electric signal amplitude of the driving transducer in this embodiment is a sine signal with a 2 MHz amplitude.

[0073] Example 5

[0074] This example provides a method for high-throughput manipulation of microparticles within a living vascular network using a shape-adaptive acoustic field. Unlike the microparticle injection in Example 4, the injected microparticles in this example were 20 μm in diameter. These microparticles were able to enter the branches of the central artery in the rabbit ear in significant numbers.

[0075] After the particles enter the blood vessels, their distribution in the non-modulated and modulated acoustic fields is displayed by the image silhouette method. Figure 12 , Figure 13 The figure shows that when there is no modulated acoustic field, the grayscale corresponding to the particles is distributed in the two blood vessels; when there is a modulated acoustic field, the particles are mainly distributed in the target blood vessel branches, indicating that the modulated acoustic field can achieve high-throughput intravascular particle manipulation.

[0076] Example 6

[0077] A method for modulating an ultrasonic sound field with multi-point sound pressure distribution, the modulation principle and implementation of which include the following steps: (a) a sound field with uniform amplitude is used as the input sound field, which is transmitted to the transducer surface through the time inversion method to obtain a propagation sound field located on the transducer surface.

[0078] (b) The median amplitude of the propagating sound field is reassigned to the same value, the phase information is retained, and the modified propagating sound field is then transmitted back to the target plane to obtain the reconstructed sound field.

[0079] (c) Comparing the amplitudes of the input sound field and the reconstructed sound field, increasing the amplitude by a corresponding proportion in the low sound pressure region of the reconstructed sound field, and using the increased amplitude as the new amplitude of the input sound field, while retaining the original phase information in the input sound field.

[0080] (d) Repeat steps (a) to (c) for the new input sound field until the reconstructed sound field has a uniform amplitude and a set phase gradient.

[0081] (e) The phase information in the propagating sound field is the phase value required on the transducer surface to synthesize the target sound field. This phase value can be modulated using the height information of the acoustic lens, synthesized using phased array technology, or obtained through other technologies such as metamaterials. By modulating the sound field on the ultrasonic transducer surface in this manner, multiple target sound fields with controllable sound pressure distributions can be reconstructed in space.

[0082] Acoustic field modulation is applicable to ultrasonic frequencies between 0.01MHz and 10MHz. This method is suitable for planar and focused transducers. The modulated sound field shape is controllable and can exhibit linear, arc-shaped, and annular structures. The sound field can contain multiple sound pressure distributions, and the spatial location of each high-pressure area can be controlled.

[0083] Acoustic fields can control the direction of motion of matter. Through the acoustic radiation force, acoustic fields can redirect the motion of matter. Phase gradients in the acoustic field can drive the movement of matter, and acoustic fields can generate acoustic currents along the phase gradient to manipulate particles.

[0084] Acoustic manipulation can be applied to microfluidics with diverse branching structures, including varying branch angles and widths. Alternatively, it can be applied to multi-point control of substances within microfluidics with multiple branches, enabling selective delivery of substances within fluid networks. Furthermore, it can be used to control substances within vascular networks, enabling selective delivery of substances to submillimeter-scale vascular branches.

[0085] Acoustically manipulated materials can be used for targeted delivery within living blood vessels. The size of acoustically manipulated materials ranges from 0.1 microns to 1 centimeter.

[0086] In summary, the present disclosure proposes a method for controlling an acoustic field that is adapted to the shape of a microfluidic network. The acoustic field can be precisely formed at the branches in the flow channel network, and the phase gradient in the acoustic field points to the target flow channel. At the same time, based on the branching structure of the microfluidic network, a multi-point acoustic field distribution is established to achieve a multi-point, high-throughput control effect of the acoustic field on the substance. Here, shape adaptation means that the acoustic field pattern can be precisely modulated to the flow channel bifurcation point, and the phase gradient in the acoustic field points to the target flow channel.

[0087] The main ultrasonic manipulation mechanism of the present disclosure is to use the acoustic field to change the orientation of the substance in the fluid branch so that it reaches the selected target area, wherein the position of the acoustic field manipulation is at each branch of the fluid. The present disclosure has multiple acoustic pressure distribution acoustic fields, and the regulation of the acoustic field is realized by phase modulation technology. The phase value of the surface acoustic field of the transducer is regulated by phased array, acoustic lens, acoustic metamaterial, etc., so as to reconstruct the required acoustic pressure distribution in the target plane. The regulated acoustic field can manipulate the substance at any acoustic pressure distribution, so it can quickly realize the directional delivery of high-throughput substance in the microfluid. At the same time, the acoustic pressure suitable for the shape of the microfluid branch can be superimposed with a phase gradient. The existence of the phase gradient can cause acoustic streaming effect in the acoustic field range and exert an acoustic radiation force along the phase gradient on the manipulated object. The modulated acoustic field can effectively avoid the aggregation of microparticles at the acoustic pressure, thereby improving the efficiency of directional manipulation.

[0088] It should be noted that in the present disclosure, an optical microscope can be used for the microfluidic network structure. The particle diameter used in the case of the present disclosure is 100 microns, and the microfluid channel structure is also 100-600 microns, so a general optical microscope can be used to observe the microfluidic network. The determination of the position of the acoustic field can be realized by measuring the acoustic pressure with a hydrophone, or a temperature-sensitive color-changing film / temperature-sensitive color-changing liquid crystal sheet can be used to display the position of the acoustic field. In addition, the acoustic field can be reconstructed in space, and each lens corresponds to a specific acoustic field pattern. The acoustic field is bound to the acoustic lens, that is, each acoustic lens can only correspond to one acoustic field. Therefore, the acoustic field generated by the acoustic lens is fixed, and the position is also fixed, and the manipulation of the microparticles will not affect the structure of the acoustic field. As long as the branch point of the microfluid channel corresponds to the position of the acoustic field, the microparticles can be seen to be manipulated, and this process does not require real-time feedback of the acoustic field.

[0089] The acoustic pressure of multiple points can also be realized by the acoustic lens, and only one transducer is needed, but each acoustic lens can only generate one kind of acoustic pressure. For example, the acoustic lens in Example 2 can only generate an arc-shaped acoustic pressure; the acoustic lens in Example 1 can generate three arc-shaped acoustic pressures, that is, the number of acoustic pressure points can be designed. However, the acoustic lens needs to be replaced each time the acoustic field is changed. The specific structure of the acoustic lens is a layer of material with different voxel heights covering the surface of the transducer. The acoustic lens needs to be well fitted on the surface of the transducer, so the shape of the bottom of the acoustic lens is the shape of the surface of the transducer. Secondly, the acoustic lens is visualized by voxels with different heights, which are responsible for regulating the phase of the ultrasonic wave. Each time the acoustic field is changed, the acoustic lens needs to be replaced.

[0090] In Figure 2The modulation steps of the shape-adaptive sound field are described, which includes the method of phase reconstruction. The size of the phase gradient is artificially set. The sound pressure of the sound field is calculated in the normalized sound pressure amplitude, that is, the sound pressure in the target sound field pattern is set to 1 (this 1 is a normalized value, which represents the sound pressure intensity index, 1 represents the strongest, 0 represents none, and it does not represent the specific sound pressure value), and the actual sound pressure of the sound field is determined by the output power of the transducer, which does not need to be considered in the calculation process. In the calculation of the sound field, whether the reconstructed sound field pattern has uniform sound pressure is evaluated, and the sound pressure intensity index of each point in the sound field pattern can be compared. When the maximum and minimum values of the sound pressure intensity index in the sound field pattern are close to 1 (the sound pressure intensity is between 0.75 and 1), it can be considered that the sound field is uniform.

[0091] As Figure 14 The experimental device system of the present disclosure is a microfluidic chip experimental device for observing the dynamics of microparticles in a microfluidic channel through a microscope. The device system includes a syringe pump, a signal generator, a power amplifier, a transducer, an acoustic lens, a water cavity, a microfluidic chip, and a microscope. The syringe pump is used to accurately control the injection of fluid, ensuring that the fluid enters the microfluidic channel at a constant flow rate and flow. The signal generator is used to generate acoustic signals, which are transmitted to the microfluidic channel through the power amplifier, acoustic lens, and transducer. The acoustic signals have been modulated and have specific frequencies and amplitudes. They pass through the water in the water cavity and are transmitted to the microfluidic chip to manipulate the microparticles in the microfluidic channel. The acoustic lens is used to focus the acoustic waves, and the transducer converts electrical signals into acoustic signals. The power amplifier is used to enhance the power of the acoustic signals, ensuring that the acoustic waves can effectively manipulate the microparticles in the microfluidic channel. The transducer can be an acoustic lens transducer or a phased array transducer, or a phased array transducer equipped with an acoustic lens.

[0092] Figure 14 Case 1 in the above is a multi-branch microfluidic channel with multiple branches. Case 2 is a single-branch microfluidic channel, which is opposite to the multi-branch microfluidic channel. The single-branch microfluidic channel structure is simpler and is suitable for the study of a single fluid path. Case 3 is a decellularized liver blood vessel, which simulates the environment of a decellularized liver blood vessel in a microfluidic channel and is used for drug screening or pathological research.

[0093] The beneficial effects of the present disclosure include:

[0094] 1. The modulation principle of the sound field is mainly based on the iterative time reversal algorithm. The spatial sound field modulation technology can form multiple sound pressure distributions in three-dimensional space. The steps of generating the sound field are simple, the cost is low, and the modulated sound field can be applied to various fluid structures.

[0095] 2. The sound field can accurately correspond to the manipulation position in the microfluidic network, and can solve the need for multiple sound pressure distributions in the current acoustic manipulation.

[0096] 3. The sound field can have both high sound pressure amplitude and phase gradient, which can change the direction of the motion of the substance in the microfluidic by the acoustic radiation force and acoustic streaming effect, and can efficiently control the motion of the substance in the microfluidic network.

[0097] 4. The acoustic manipulation technique can avoid the aggregation of the substance at the position of the sound field, and is suitable for a variety of fluid velocities, fluid structures, and high-throughput substance control.

[0098] 5. The modulated sound field can be applied in real blood vessel networks and can be used for substance manipulation in living blood vessels.

[0099] It should be noted that, although the foregoing has described the spirit and principles of the present application with reference to a number of specific embodiments, it should be understood that the present application is not limited to the disclosed specific embodiments, and the division of aspects does not mean that the features in these aspects cannot be combined, and the division is only for the convenience of expression. The present application is intended to cover various modifications and equivalent arrangements included in the spirit and scope of the appended claims.

Claims

1. A method for controlling the acoustic field of microparticles in a microfluidic network, characterized in that: The microfluidic network has at least one branch, generating at least one sound field of a preset shape at the branch, When a particle flow is injected into the microfluidic network along the fluid direction and passes through the branch, the shape of the acoustic field prevents the particle flow from entering a non-target flow channel and the particle flow is guided by the acoustic field into the target flow channel of the branch. The shape of the sound field sound pressure is arc, line, ring or circle, The shape of the sound pressure field is an arc, which is tangent to the center line of the target flow channel at the branch and covers the entrance of the non-target flow channel. The phase gradient of the sound field is superimposed on the interior of the arc-shaped sound pressure, and is directed toward the target branch.

2. The method according to claim 1, characterized in that The sound field is an ultrasonic sound field with a frequency between 0.01 MHz and 10 MHz.

3. The method according to claim 2, characterized in that The ultrasonic sound field is generated by a transducer.

4. The method according to claim 3, characterized in that The transducer surface has an acoustic lens, through which the ultrasonic waves are focused on a target area.

5. The method according to claim 3, characterized in that The transducer is a phased array transducer having a plurality of transducer units.

6. The method according to claim 1, characterized in that The sound field generating step comprises: Set the expected sound field, calculate and process the expected sound field using the time reversal algorithm, and then homogenize the amplitude of the expected sound field. The homogenized acoustic field is transmitted to the target plane of the microfluidic network through the transducer. The phase and amplitude of the sound field in the target plane are replaced to achieve the reconstruction of the sound field, and the original input sound field is replaced by the processed sound field.

7. A microparticle acoustic field manipulation device for a microfluidic network, characterized in that: An image sensor is used to obtain the channel distribution structure and particle flow state of the microfluidic network; a transducer for generating an acoustic field of a predetermined shape in one or more target areas in the microfluidic network; The main controller controls the transducer to generate a preset shape of sound field pressure in one or more microfluidic network target areas using any method according to claims 1 to 6 based on the microfluidic network branch target position and the microfluidic flow target obtained from the image sensor.

8. The device according to claim 7, characterized in that The transducer is an acoustic lens transducer or a phased array transducer.

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