Particle sound field control method and device for microfluid network

Abstract

The invention discloses a particle sound field manipulation method for a microfluidic network, the microfluidic network is provided with at least one branch, and at least one sound field with a preset shape is generated at the branch. When a flow of particles is injected into the microfluidic network in a fluid direction through the branches, the sound field is shaped such that the flow of particles is prevented from entering a non-target flow channel, the flow of particles being directed by the sound field into a target flow channel of the branches. The sound field sound pressure is in an arc shape, and the shape is tangent to the center line of the target flow channel at the branch position and covers an inlet of a non-target flow channel. The phase gradient of the sound field is superposed in the arc-shaped sound 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 particle acoustic field control method and device for 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, detection and separation of biochemical samples, etc. At present, there are many methods for directional manipulation of tiny substances based on external physical fields, including magnetic control, electric field control, light field control, ultrasonic field control and other methods. Among them, the magnetic field has a good penetration depth but limited accuracy, the light field can accurately manipulate a single micron-level substance but cannot penetrate non-translucent tissues, and the electric field control is prone to cause ionization damage to biological tissues. Ultrasonic manipulation is a non-contact acoustic manipulation technology that uses ultrasonic mechanical effects (ultrasonic radiation force, acoustic flow) to control the movement of objects. It is a manipulation method with good tissue penetration depth, superior biocompatibility, high control accuracy, and wide application of materials. This technology uses the momentum caused by the reflection, refraction, absorption and other effects of particles in the sound field to exchange between sound waves and particles, and manipulates the particles through the force they are subjected to. It has been proven to be used for in vivo and in vitro particle control, including a series of manipulations such as arrangement, mixing, separation, and aggregation of particles. Summary of the invention

[0003] The present disclosure proposes a method for controlling the orientation of particles in a fluid network based on regulating the acoustic field, with the aim of solving the problem that existing acoustic control methods are difficult to control the orientation of substances in a complex fluid network with high throughput.

[0004] One embodiment of the present disclosure provides a method for controlling a particle 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 the particle flow is guided by the acoustic field to enter a target flow channel of the branch.

[0006] The shape of the sound field sound pressure 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 inside 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 understood by reading the detailed description below with reference to the accompanying drawings. In the accompanying drawings, several embodiments of the present invention are shown in an exemplary and non-limiting manner, in which:

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

[0009] Figure 2 A 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 directional manipulation of particles to branch 2 in a multi-branch network according to one embodiment of the present invention.

[0011] Figure 4 Schematic diagram of directional manipulation of particles to branch 1 in a multi-branch network according to one embodiment of the present invention.

[0012] Figure 5 Schematic diagram of directional manipulation of particles to branch 3 in a multi-branch network according to one embodiment of the present invention.

[0013] Figure 6 Schematic diagram of directional manipulation of particles 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] Fig. 9 Schematic diagram of particle manipulation in rat liver blood vessels using a shape-adaptive acoustic field according to one embodiment of the present invention.

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

[0018] Fig.11 A 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] Fig.12 Schematic diagram of the distribution of high-flux microparticles in a blood vessel under a shapeless adaptive acoustic field according to one embodiment of the present invention.

[0020] Fig.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] Fig.14 Schematic diagram of an experimental device according to one embodiment of the present invention. DETAILED DESCRIPTION

[0022] Ultrasonic manipulation is based on the acoustic effect. It can manipulate materials from micrometer to millimeter levels through the acoustic radiation force of sound waves on particles and the acoustic streaming effect caused by ultrasound in the medium. For example, in a standing wave acoustic field, the acoustic radiation force can push materials to wave nodes or antinodes to achieve personalized material distribution; the acoustic streaming effect formed by acoustic vortices can spirally lift materials from the bottom of the medium. At present, ultrasonic sound fields are gradually becoming a technical means for directional manipulation of materials in microfluidic networks.

[0023] The study found that without the control of external physical acoustic fields, the substances delivered in microfluidics will be randomly distributed in various branches within the fluid network along with the surrounding fluid. In contrast, through directional manipulation, the substances can be delivered along a specific path in the fluid network, and the substances can be selectively gathered in the target area.

[0024] Microfluidics usually refers to fluid flow and chemical and biological processes in channels or chambers at the micron to millimeter level, involving technologies for controlling and manipulating fluids at a microscopic scale. Microfluidics technology has applications in many fields, including chemical analysis, biomedical research, drug screening, environmental monitoring, etc.

[0025] At present, one way to perform directional acoustic manipulation of materials in microfluidics is to use surface acoustic waves to guide materials in a plane. Surface acoustic waves are transmitted into the fluid along the plane, which can produce acoustic radiation force on the material, thereby changing the direction of movement of the material. However, surface acoustic waves are limited to manipulating materials in a two-dimensional plane and cannot manipulate materials in a three-dimensional complex fluid, so the manipulation range is limited.

[0026] Another commonly used acoustic manipulation is to use body wave acoustic potential traps to capture substances in the fluid, and to drag the substances to move in three dimensions by moving the acoustic potential trap. However, acoustic potential traps are usually used to capture substances at a single point, which takes a long time and has low movement efficiency. In addition, the fluid network is often complex and diverse, and it is difficult for acoustic potential traps to achieve rapid manipulation of high-throughput substances. In addition, body waves easily form standing waves or induce local acoustic flows between the interfaces of the fluid, causing substances to easily gather at the sound pressure distribution, blocking the fluid and limiting the directional manipulation of substances 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 for the manipulation of particles in microfluidics are:

[0028] 1. It is difficult to achieve high-throughput material manipulation in microfluidics using acoustic fields;

[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] At present, according to the development of acoustic manipulation technology of materials in microfluidic networks, ultrasonic manipulation of materials in multi-branch microfluids often requires multi-point acoustic fields that are compatible with the fluid network structure, but existing acoustic manipulation methods cannot simultaneously implement multi-point parallel material manipulation. The present disclosure uses acoustic holography technology to propose a solution for the precise construction of acoustic fields that are compatible with the shape of the fluid network and the manipulation of materials in the fluid, reconstructing multiple sound pressure distributions that are compatible with the microfluidic structure in space, and realizing multi-point parallel, high-throughput acoustic manipulation of materials in the fluid network.

[0032] Embodiment 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, the acoustic manipulation strategy provided in this embodiment 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. The 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 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 from specific branches when there is no ultrasonic manipulation, the tributary velocities after each branch in the fluid are 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 branch 2 and branch 3 merge, they meet branch 1 at point B. The formed converging flow channel then meets branch 4 at point A to form the main flow channel. Figure 1The figure shows the difference in fluid velocity in different areas or branches. The color of the fluid velocity is given in the figure to indicate the difference. The flow velocity in the main channel is higher, and the fluid velocity in each branch is relatively small.

[0036] In terms of sound field setting, according to the target fluid area 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 to an arc. The arc is selected to enable particles on the side away from the target flow channel to better enter the target flow channel. Other selectable sound field graphics include linear, annular, circular, etc., and their main feature is that the phase gradient direction points to the target flow channel. The arc 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 superimposed phase gradient is located inside the arc sound pressure and points to the target branch. The target sound field will be generated by a focused transducer. The size of each arc sound field graphic is set to an outer diameter of 1mm and an inner diameter of 0.8mm, and the arc center angle is 90°.

[0037] 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 uneven. This uneven pressure distribution can generate force, namely, acoustic radiation force. The direction of the acoustic radiation force is usually related to the phase gradient of the sound wave, which can make the acoustic radiation force concentrated in a specific direction. This phenomenon is called beamforming or acoustic field focusing.

[0038] Therefore, the acoustic wave beam can be focused by changing the phase gradient. During the focusing process, the wavefront is made to have the same phase at a specific point or region to achieve wave superposition and enhancement. By adjusting the phase at different points on the wavefront, the direction and focusing characteristics of the beam can be changed. For example, during the propagation of the sound wave, the phase of the wave can be controlled by adjusting the transmitting source or using a phase delayer. To achieve focusing, it is necessary to create a gradually increasing phase gradient on the wavefront so that the beam gradually converges to a focus during propagation, which can be achieved by time delay or space delay. If a phased array is used, that is, multiple transmitting transducers are used, each transducer can independently control the phase of its emission. By accurately adjusting the phase of each transducer, a beam with a specific directionality can be synthesized. When the phase gradient on the wavefront is properly adjusted, the beam will converge at a specific position to form a focus. At the focus, the wave has the largest amplitude and the most concentrated energy. In practical applications, if the phase gradient needs to be dynamically adjusted to track a moving target or adapt to environmental changes, it can be achieved through a real-time feedback control system. Thus, by accurately controlling the phase gradient of the wavefront, precise focusing of the beam can be achieved.

[0039] In this embodiment, the transducer is a focusing transducer, the focusing distance is 20mm, and the aperture of the transducer is 18.4mm. In this embodiment, the target sound field is generated by using acoustic lens technology, and the acoustic lens is mounted on the surface of the transducer. The focusing transducer accurately controls the shape and size of the sound field, focusing the input sound wave or ultrasonic wave energy to a specific point or small area. The acoustic lens works on the principle of acoustics and can focus or diffuse sound waves like an optical lens. The acoustic lens imitates the function of an optical lens in design. Since the target sound field is formed by the regulation of the acoustic lens, as long as the positions of the transducer and the acoustic lens are fixed, the distribution of the target sound field in space is also determined. The specific position of the sound field in space can also be determined by measuring the sound pressure with a hydrophone; it can also be visualized by using a temperature-sensitive color film through the local heat generated by the sound field. Here, the acoustic lens is installed on the surface of the transducer, and the sound wave passes through the acoustic lens from the transducer to form a sound field at a preset height. As long as the transducer and the acoustic lens are fixed, the position 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, when performing acoustic field control, it is assumed that at least one of the three sound pressure graphs is located on the focal plane. The three acoustic field controls with phase gradients and adapted to the microfluidic branches, as well as the thickness information calculation of the lens, are completed by the following steps:

[0041] (1) The sound field including three sound pressure distributions of phase gradient 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) Transmitting the transmitted sound field with modified amplitude 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 reconstruction of the sound field is completed. Otherwise, compare the sound pressure ratios of the reconstructed sound field and the target sound field at each position, 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, the amplitude is increased 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, the amplitude is reduced at the same position of the input sound field.

[0045] (6) Retransmit the modified input sound field, i.e. repeat steps (2)-(5), and perform sound field transmission between the target plane and the transducer surface for multiple times, the number of transmissions is usually within 10 times. The reconstructed sound field will form a sound pressure distribution with uniform amplitude and phase gradient, such as Figure 2 The transducer here can be an acoustic lens transducer or a phased array transducer.

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

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

[0048] S201, setting the sound fields of three sound pressure distributions as input sound fields;

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

[0050] S203, performing homogenization processing on the amplitude of the transmitted sound field, which is helpful for subsequent sound field processing and analysis;

[0051] S204, propagating the transmitted sound field to the target plane to obtain a reconstructed sound field;

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

[0053] S206, replacing the original input sound field with the processed reconstructed sound field;

[0054] S207, the transducer surface emits a sound field with uniform amplitude for sound wave imaging or sound wave manipulation.

[0055] An acoustic lens is a component that uses the propagation characteristics of sound waves in different media to focus or diffuse sound waves, and uses phenomena such as refraction, reflection, and diffraction of sound waves in the medium to control the propagation path of sound waves. Acoustic lenses can have different thicknesses according to design requirements.

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

[0057] Therefore, each position of the transmitted sound field corresponds to a thickness value, which determines the structure of the lens. The 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, and the ultrasonic waves emitted by the transducer reconstruct multiple sound pressure distributions in the target plane after passing through the acoustic lens on the surface.

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

[0063] Different from the flow channel design in Example 1, in this embodiment, the microchannel is set to be 600 microns wide, 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 shape and the transducer used to reconstruct the sound field are the same as in Example 1. The sound field generation method for a single sound pressure distribution is similar to the sound field control in Example 1, except that only one sound field pattern needs to be set on the target plane. Here, the sound field pattern used is arc-shaped like the sound field pattern in Example 1. The transducer used to generate the sound field is also the 4MHz transducer in Example 1.

[0064] Different from the sound field setting in the first embodiment, the key to the sound field with phase gradient in this embodiment is to set the phase gradient on the sound pressure graph. The value of the phase gradient in this embodiment is set to 3rad / mm. At the same time, the sound field control process is similar to the sound field control in the first embodiment, except that the phase gradient needs to be added to the sound pressure distribution. As a comparison, another sound field does not set the phase gradient in its sound pressure distribution.

[0065] After the particles enter the microfluidic system, an acoustic field with or without a gradient is applied to 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 the particles into the target fluid without aggregation.

[0066] Embodiment 3

[0067] This embodiment provides a method for controlling microparticles in a vascular network using a shape-adaptive acoustic field. Different from the flow channel design in Embodiment 1, this embodiment uses a vascular micronetwork from rat liver. The liver vascular network is obtained by decellularization technology, and the size of the blood vessels where the microparticles are controlled is 500μm to 1200μm. The vascular network retains the original vascular structure and can be used to verify the control effect of the acoustic field 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 particles in the corresponding two blood vessel branches. In this embodiment, the particles enter the liver blood vessel network, and the particles are controlled by the acoustic field and enter the predetermined blood vessel branches, such as Fig. 9 .

[0069] Embodiment 4

[0070] This embodiment provides a method for controlling microparticles in a living blood vessel network using a shape-adaptive acoustic field. Different from the flow channel design in the first embodiment, the central artery of the rabbit ear of a New Zealand white rabbit is used as a microvessel to control microparticles in this embodiment. The blood vessel size of the central artery of the rabbit ear is within 1000 μm. This fluid network is a real blood vessel, which is used to verify the control effect of the acoustic field on microparticles in the real blood vessels of a living body.

[0071] Different from the sound field setting in the first embodiment, the sound field setting in this embodiment is a single sound pressure distribution. This embodiment manipulates a single blood vessel branch particle. The focusing distance of the focusing transducer used in this embodiment is 60 mm, and the aperture of the transducer is 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.

[0073] Embodiment 5

[0074] This embodiment provides a method for high-throughput manipulation of microparticles in a living vascular network using a shape-adaptive acoustic field. Different from the microparticle injection in embodiment 4, the particle size of the microparticles injected in this embodiment is 20 μm. A large number of particles can enter the branch of the central artery of the rabbit ear.

[0075] After the particles enter the blood vessels, their distribution in the conditions of non-modulated and modulated sound fields is displayed by the image silhouette method. Fig.12 , Fig.13 It is shown in the figure 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] Embodiment 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 an input sound field, and is transmitted to the transducer surface through a 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 area of ​​the reconstructed sound field, and using the increased amplitude as the new amplitude of the input sound field, but 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 surface of the transducer when synthesizing the target sound field. This phase value can be modulated by the height information of the acoustic lens, synthesized by phased array technology, or obtained by other technologies such as metamaterials. After the sound field on the surface of the ultrasonic transducer is modulated in the above manner, multiple target sound fields with controllable sound pressure distributions can be reconstructed in space.

[0082] The ultrasonic frequency applicable to the acoustic field modulation is between 0.01MHz and 10MHz. The acoustic field modulation method is applicable to planar transducers and focused transducers. The shape of the modulated acoustic field is controllable and can present linear, arc, annular and other structures. The acoustic field can contain multiple sound pressure distributions, and the position of each high sound pressure area in space is controllable.

[0083] The acoustic field can control the direction of movement of matter. The acoustic field can redirect the movement of matter through the acoustic radiation force, the phase gradient in the acoustic field can drive the movement of matter, and the acoustic field can generate acoustic flow along the phase gradient to manipulate particles.

[0084] Acoustic manipulation can be applied to microfluidics with different branch structures, including different branch angles and branch widths. Alternatively, it can be applied to multi-point control of substances in microfluidics with multiple branch structures, enabling selective delivery of substances in fluid networks. Alternatively, it can be used for substance control in vascular networks, enabling selective delivery of substances to sub-millimeter-level vascular branches.

[0085] Acoustically manipulated materials can be used for targeted delivery of materials within living blood vessels. The size of acoustically manipulated materials is between 0.1 microns and 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 accurately 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, according to the branching structure of the microfluidic, 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 accurately 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 sound field to change the direction of the substance in the fluid branch so that it reaches the selected target area, wherein the position of the sound field manipulation is at each branch of the fluid. The present disclosure has a sound field with multiple sound pressure distributions, and the regulation of the sound field is realized by phase modulation technology. The phase value of the sound field on the surface of the transducer is regulated by means of phased array, acoustic lens, acoustic metamaterial, etc., so as to reconstruct the required sound pressure distribution on the target plane. The regulated sound field can manipulate the substance at any sound pressure distribution, so it can quickly achieve high-throughput directional delivery of substances in microfluids. At the same time, a phase gradient can be superimposed on the sound pressure that is adapted to the shape of the microfluid branch. The existence of the phase gradient can cause an acoustic streaming effect within the sound field range, and exert an acoustic radiation force along the phase gradient on the manipulated object. The modulated sound field can effectively avoid the aggregation of particles at the sound 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 disclosed in the present disclosure is 100 microns, and the microfluidic structure is also 100 to 600 microns, so a general optical microscope can be used to observe the microfluidic network. The determination of the position of the sound field can be achieved by measuring the sound pressure with a hydrophone, or by using a temperature-sensitive color-changing film / temperature-sensitive color-changing liquid crystal film to display the position of the sound field. In addition, the sound field can be reconstructed in space, and each lens corresponds to a specific sound field graph. The sound field is bound to the sound lens, that is, each sound lens can only correspond to one sound field. Therefore, the sound field generated by the sound lens is fixed, and the position is also fixed, and the manipulation of the particles will not affect the sound field structure. As long as the branch point of the microchannel corresponds to the position of the sound field, the particles can be seen being manipulated, and this process does not require real-time feedback on the sound field.

[0089] Multi-point sound pressure can also be achieved through an acoustic lens, and only one transducer is needed, but each acoustic lens can only produce a corresponding sound pressure. For example, the acoustic lens in Example 2 can only produce one arc-shaped sound pressure; the acoustic lens in Example 1 can produce three arc-shaped sound pressures, that is, the number of sound pressure points can be designed. However, the acoustic lens needs to be replaced every time the sound 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 first needs to be able to fit well on the surface of the transducer, so the shape of the bottom of the acoustic lens is the shape of the transducer surface. Secondly, the acoustic lens visualization is composed of voxels of different heights. These voxels are responsible for regulating the phase of the ultrasonic wave. Each different voxel height will adjust the ultrasonic phase to a different value. The acoustic lens needs to be replaced every time the sound field is changed.

[0090] exist Figure 2The control steps of the shape-adaptive sound field are described, which includes the phase reconstruction method. The size of the phase gradient is set manually. The sound pressure of the sound field is calculated with the normalized sound pressure amplitude, that is, the sound pressure in the target sound field graph is set to 1 (this 1 is a uniform value, representing the sound pressure intensity index, 1 means the strongest, 0 means no, it does not represent the specific sound pressure value), while the actual sound field sound pressure is determined by the output power of the transducer, and the actual sound pressure value does not need to be considered in the calculation process. When calculating the sound field, evaluate whether the reconstructed sound field graph has uniform sound pressure. The sound pressure intensity index of each point in the sound field graph can be compared. When the maximum and minimum values ​​of the sound pressure intensity index in the sound field graph are close to 1 (the sound pressure intensity is between 0.75 and 1), the sound field can be considered to be a uniform value.

[0091] like Fig.14 , is an experimental device system disclosed in the present invention, a microfluidic chip experimental device, which is used to observe the dynamics of particles in the 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 chamber, a microfluidic chip and a microscope. The injection pump is used to accurately control the injection of the fluid to ensure that the fluid enters the microfluidic channel at a constant flow rate and flow rate. The signal generator is used to generate acoustic wave signals, which are transmitted to the microfluidic channel through the power amplifier, the acoustic lens and the transducer. The acoustic wave signals are modulated and have a specific frequency and amplitude. They are transmitted to the microfluidic chip through the water in the water chamber and are used to manipulate the particles in the microfluidic channel. The acoustic lens is used to focus the sound wave, and the transducer converts the electrical signal into an acoustic wave signal. The power amplifier is used to enhance the power of the acoustic wave signal to ensure that the sound wave can effectively manipulate the particles 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] Fig.14 Case 1 in the figure is a multi-branch microfluidic channel with multiple branches. Case 2 is a single-branch microfluidic channel. Compared with the multi-branch microfluidic channel, the single-branch microfluidic channel has a simpler structure and is suitable for the study of a single fluid path. Case 3 is a decellularized liver vascular, which simulates the decellularized liver vascular environment in a microfluidic channel for drug screening or pathology 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 inversion algorithm. The spatial sound field control technology can form multiple accurate sound pressure distributions in three-dimensional space. The steps of sound field generation are simple and low in cost, and the modulated sound field can be applied to a variety of fluid structures.

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

[0096] 3. The sound field can have high sound pressure amplitude and phase gradient at the same time. This kind of sound field characteristic can change the movement direction of substances in the microfluidic network through acoustic radiation force and acoustic flow effect, and can efficiently control the movement of substances in the microfluidic network.

[0097] 4. This acoustic manipulation technology can avoid the accumulation of matter in the acoustic field, and is applicable to a variety of fluid velocities, fluid structures, and high-throughput material control.

[0098] 5. The modulated acoustic field can be applied in real vascular networks and can be used to manipulate substances in living blood vessels.

[0099] It is worth noting that, although the foregoing content has described the spirit and principle of the invention with reference to several specific embodiments, it should be understood that the invention is not limited to the disclosed specific embodiments, and the division of various aspects does not mean that the features in these aspects cannot be combined, and such division is only for the convenience of expression. The invention 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 particles 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 to enter a target flow channel of the branch.

2. The method according to claim 1, characterized in that The shape of the sound field sound pressure is arc, line, ring or circle.

3. The method according to claim 2, characterized in that The sound field sound pressure has 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 sound field is superimposed inside the arc sound pressure and points to the target branch.

4. 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.

5. The method according to claim 4, characterized in that The ultrasonic sound field is generated by a transducer.

6. The method according to claim 5, characterized in that The transducer surface has an acoustic lens, through which the ultrasonic waves are focused on a target area.

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

8. The method according to claim 1, characterized in that The sound field generation step comprises: The expected sound field is set, and the expected sound field is calculated and processed using the time reversal algorithm, and the amplitude of the expected sound field is homogenized. 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 reconstruction of the sound field, and the original input sound field is replaced by the processed sound field.

9. A particle 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 preset shape in one or more target areas in the microfluidic network; The main controller controls the transducer to generate a sound field pressure of a preset shape in one or more microfluidic network target areas according to the microfluidic network branch target position obtained from the image sensor and the particle fluid flow target.

10. The device according to claim 9, characterized in that The transducer is an acoustic lens transducer or a phased array transducer.

Images