Enrichment device

Abstract

The invention discloses an enrichment device, comprising: a piezoelectric substrate made of a piezoelectric material and comprising a sample placement area for storing a biological sample bearing container in which a biological sample solution to be enriched is placed; the transduction module is arranged on the piezoelectric substrate, an included angle between the transduction module and the vertical direction of the trimming of the piezoelectric substrate is a target angle, and the transduction module is used for converting the electric signal into mechanical vibration to generate surface acoustic waves; and the control module is connected with the transduction module and is used for adjusting a control parameter corresponding to the surface acoustic wave according to the target angle so as to adjust the vibration mode of the surface acoustic wave, so that the transducer transmits the surface acoustic wave to the biological sample bearing container, and the biological sample in the biological sample solution is enriched in the biological sample bearing container under the action of the surface acoustic wave. According to the device, through the synergistic effect of the piezoelectric substrate, the transduction module and the control module and by utilizing the physical characteristics of the acoustic surface waves, efficient enrichment of biological samples such as exosomes is achieved, and the separation purity and reliability of enrichment are improved.

Description

Technical Field

[0001] The invention belongs to the technical field of acoustofluidics, and in particular relates to an enrichment device. Background Art

[0002] In modern biomedical research and clinical diagnosis, biological sample enrichment technology plays a vital role. Biological sample enrichment refers to the extraction or concentration of specific types of biological samples from mixed biological samples for further analysis and research. Traditional biological sample enrichment techniques mainly include centrifugation, filtration and magnetic bead methods.

[0003] However, whether it is centrifugation, filtration or magnetic bead method, it involves multiple steps and complex operations, which increases the total time and cost of the experiment. Especially when a large number of samples need to be processed, traditional methods may cause damage to biological samples, affecting the reliability of experimental results and the subsequent use of biological samples. At the same time, when enriching specific biological sample types, such as exosomes, traditional methods have low separation efficiency and purity, and are prone to entrainment of non-target biological samples.

[0004] Therefore, there is an urgent need for an enrichment device to solve at least one of the above problems. Summary of the invention

[0005] The present application provides an enrichment device, which aims to solve the problem that traditional biological sample enrichment technology involves multiple steps and complex operations, which increases the total time and cost of the experiment. In particular, when a large number of samples need to be processed, traditional methods may cause damage to biological samples, affecting the reliability of experimental results and the subsequent use of biological samples. At the same time, when traditional methods are used to enrich specific biological sample types, such as exosomes, the separation efficiency and purity are low, and non-target biological samples are easily entrained.

[0006] The present application provides an enrichment device, comprising:

[0007] A piezoelectric substrate, wherein the piezoelectric substrate is made of a piezoelectric material and comprises a sample placement area, wherein the sample placement area is used to store a biological sample holding container, wherein a biological sample solution to be enriched is placed in the biological sample holding container;

[0008] A transducer module, wherein the transducer module is disposed on the piezoelectric substrate, wherein an angle between the transducer module and a vertical direction of a cut edge of the piezoelectric substrate forms a target angle, and is used for converting an electrical signal into a mechanical vibration to generate a surface acoustic wave;

[0009] A control module is connected to the transducer module, and the control module adjusts the control parameters corresponding to the surface acoustic wave according to the target angle to adjust the vibration mode of the surface acoustic wave. The transducer propagates the surface acoustic wave to the biological sample holding container, so that the cells in the biological sample solution are enriched in the biological sample holding container due to the action of the surface acoustic wave.

[0010] This application provides an enrichment device, which aims to solve the problems of multiple steps, complex operations, high cost, long time, biological sample damage, and low separation efficiency and purity in traditional biological sample enrichment technology. The technical content of the enrichment device mainly includes the following parts:

[0011] 1. The piezoelectric substrate is made of piezoelectric material and can convert electrical signals into mechanical vibrations. The piezoelectric substrate includes a sample placement area for storing biological sample holding containers, which can generate surface acoustic waves driven by electrical signals and enrich biological samples in biological sample solutions through vibration.

[0012] 2. The transducer module is arranged on the piezoelectric substrate, and the angle between the transducer module and the vertical direction of the cut edge of the piezoelectric substrate is a target angle. The surface acoustic wave is generated by converting the electrical signal into mechanical vibration.

[0013] 3. The control module is connected to the transducer module to control the electrical signal input of the transducer module. By adjusting the control parameters corresponding to the surface acoustic wave according to the target angle, the vibration mode of the surface acoustic wave is adjusted, and the transducer module is controlled to generate appropriate surface acoustic waves, so that the surface acoustic wave can be effectively propagated to the biological sample carrying container to achieve the enrichment of the biological sample. The control parameters include the frequency, amplitude and duration of the electrical signal, etc. These parameters can be adjusted according to different biological sample types and experimental requirements.

[0014] The enrichment device provided thereby has at least the following beneficial effects:

[0015] 1. Simplify the operation steps: Traditional biological sample enrichment technology usually requires multiple steps, such as centrifugation, washing, filtration, etc., which are complicated and time-consuming. This device reduces the operation steps and simplifies the experimental process through an integrated design.

[0016] 2. Reduce costs: Due to the reduction of operation steps and the improvement of automation, the total cost of the experiment is reduced. At the same time, the consumables and reagents required in the experiment are reduced, further saving expenses.

[0017] 3. Reduce damage to biological samples: Centrifugation and washing in traditional methods can easily cause damage to biological samples. This device reduces physical and chemical damage to biological samples through the action of surface acoustic waves, and improves the survival rate and functional integrity of biological samples.

[0018] 4. Improve enrichment efficiency and purity: Traditional methods have low separation efficiency and purity when enriching specific biological sample types, and are prone to carry non-target biological samples. This device can effectively enrich specific biological sample types and improve separation efficiency and purity by precisely controlling the frequency and amplitude of surface acoustic waves.

[0019] 5. Suitable for processing a large number of samples: The design of this device enables it to process multiple samples at the same time, greatly improving the throughput of the experiment. Especially when a large number of samples need to be processed, it can effectively reduce the experimental time.

[0020] At the same time, the enrichment device provided in this application can achieve excellent results in exosome enrichment. The principles of the device provided in this application to achieve exosome enrichment include:

[0021] 1. The effect of surface acoustic waves: The piezoelectric substrate generates surface acoustic waves through the transducer module, and the surface acoustic waves propagate in the biological sample container and act on the exosomes in the biological sample solution. Surface acoustic waves can form an acoustic field in the liquid, and through the effect of acoustic radiation force and acoustic flow, particles of different sizes and densities can produce different movements in the container.

[0022] 2. Characteristics of exosomes: Exosomes are microvesicles secreted by biological samples, with diameters usually between 30-150 nanometers. Due to their small size, it is more difficult for external physical fields to respond to them. The acoustic flow generated by surface acoustic waves of special vibration modes can achieve the enrichment of exosomes.

[0023] 3. Optimization of target angle: By adjusting the control parameters of the surface acoustic wave according to the target angle currently corresponding to the transducer module through the control module, specific surface acoustic wave vibration modes can be generated to improve the efficiency of exosome enrichment.

[0024] 4. Adjustment of control parameters: The control parameters generated by the control module according to the target angle may include but are not limited to any one of the frequency, amplitude and duration of the electrical signal. By precisely adjusting these parameters, the effect of the surface acoustic wave can be further optimized, so that the exosomes can be effectively enriched under specific conditions without entraining a large amount of non-target biological samples or impurities.

[0025] 5. Gentle enrichment process: Compared with traditional methods, the surface acoustic wave enrichment process is gentler and will not damage exosomes. Centrifugation and washing in traditional methods may destroy the structure and function of exosomes, while this device can achieve a gentler enrichment process through the action of surface acoustic waves, maintaining the integrity and biological activity of exosomes.

[0026] In summary, the provided enrichment device achieves efficient enrichment of biological samples and exosomes through the synergistic effect of the piezoelectric substrate, transducer module and control module, utilizing the physical properties of surface acoustic waves, while simplifying experimental operations, reducing costs, reducing damage to biological samples and exosomes, and improving the purity and reliability of separation. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] In order to more clearly illustrate the technical solutions of the embodiments of the present application, the drawings required for use in the description of the embodiments will be briefly introduced below. Obviously, the drawings described below are some embodiments of the present application. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying any creative work.

[0028] Figure 1 It is a schematic diagram of the structure of an enrichment device provided in an embodiment of the present application;

[0029] Figure 2 is a schematic structural diagram of another enrichment device provided in an embodiment of the present application;

[0030] Figure 3 is a structural schematic diagram of a transducer module provided in an embodiment of the present application;

[0031] Figure 4 is a schematic structural diagram of another transducer module provided in an embodiment of the present application;

[0032] Figure 5 is a schematic diagram of a biological sample carrying container provided in an embodiment of the present application;

[0033] Figure 6 This is a schematic diagram of the effect of surface wave frequency on flow field provided in an embodiment of the present application;

[0034] Figure 7 This is a schematic diagram of the effect of particle size on enrichment position provided in an embodiment of the present application;

[0035] Figure 8 It is a schematic diagram of sample extraction of an enrichment device provided in an embodiment of the present application;

[0036] Fig. 9 It is a schematic diagram of a sample addition principle provided in an embodiment of the present application.

[0037] Description of main components and symbols:

[0038] 10. Enrichment device; 11. Piezoelectric substrate; 111. Biological sample carrying container; 112. Biological sample solution; 12. Transducer module; 13. Control module; 14. Compressing module.

[0039] It should be understood that the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the present application. DETAILED DESCRIPTION

[0040] The following will be combined with the drawings in the embodiments of the present application to clearly and completely describe the technical solutions in the embodiments of the present application. Obviously, the described embodiments are part of the embodiments of the present application, not all of the embodiments. Based on the embodiments in the present application, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of this application.

[0041] The flowcharts shown in the accompanying drawings are only examples and do not necessarily include all the contents and operations / steps, nor must they be executed in the order described. For example, some operations / steps may also be decomposed, combined or partially merged, so the actual execution order may change according to actual conditions.

[0042] It should be understood that the terms used in this application specification are only for the purpose of describing specific embodiments and are not intended to limit the application. As used in this application specification and the appended claims, unless the context clearly indicates otherwise, the singular forms "a", "an" and "the" are intended to include plural forms.

[0043] It should be understood that, in order to facilitate the clear description of the technical solutions of the embodiments of the present application, in the embodiments of the present application, the words "first", "second" and the like are used to distinguish the same items or similar items with substantially the same functions and effects. For example, the first support member and the second support member are only used to distinguish different support members, and the order thereof is not limited. Those skilled in the art can understand that the words "first", "second" and the like do not limit the quantity and execution order, and the words "first", "second" and the like do not necessarily limit them to be different.

[0044] It should be further understood that the term “and / or” used in the specification and appended claims refers to any combination and all possible combinations of one or more of the associated listed items, and includes these combinations.

[0045] In conjunction with the accompanying drawings, some embodiments of the present application are described in detail below. In the absence of conflict, the following embodiments and features in the embodiments can be combined with each other.

[0046] In modern biomedical research and clinical diagnosis, biological sample enrichment technology plays a vital role. Biological sample enrichment refers to the extraction or concentration of specific types of biological samples from mixed biological samples for further analysis and research. Traditional biological sample enrichment techniques mainly include centrifugation, filtration and magnetic bead methods.

[0047] However, whether it is centrifugation, filtration or magnetic bead method, it involves multiple steps and complex operations, which increases the total time and cost of the experiment. Especially when a large number of samples need to be processed, traditional methods may cause damage to biological samples, affecting the reliability of experimental results and the subsequent use of biological samples. At the same time, when enriching specific biological sample types, such as exosomes, traditional methods have low separation efficiency and purity, and are prone to entrainment of non-target biological samples.

[0048] Therefore, there is an urgent need for an enrichment device to solve at least one of the above problems.

[0049] To solve the above problems, please refer to Figures 1 to 5 The enrichment device 10 provided in the embodiment of the present application includes a piezoelectric substrate 11, a transducer module 12 and a control module 13. The piezoelectric substrate 11 is made of piezoelectric material. The piezoelectric substrate 11 includes a sample placement area, which is used to store a biological sample holding container 12. The biological sample holding container 12 contains a biological sample solution 112 to be enriched. The transducer module 12 is arranged on the piezoelectric substrate 11. The angle between the transducer module 12 and the vertical direction of the cut edge of the piezoelectric substrate 11 is a target angle, which is used to convert an electrical signal into a mechanical vibration to generate a surface acoustic wave. The control module 13 is connected to the transducer module 12. The control module 13 adjusts the control parameters corresponding to the surface acoustic wave according to the target angle to adjust the vibration mode of the surface acoustic wave. The transducer propagates the surface acoustic wave to the biological sample holding container 12, so that the biological sample in the biological sample solution 112 is enriched in the biological sample holding container 12 under the action of the surface acoustic wave.

[0050] Specifically, the present application provides a device for enriching biological samples, which achieves rapid, efficient and low-cost enrichment of biological samples through surface acoustic wave (SAW) technology. Surface acoustic wave is an elastic wave that propagates on the surface of a solid, and its energy is mainly concentrated within the surface wavelength range. Different types of biological samples respond differently to surface acoustic waves. By adjusting the frequency and intensity of the surface acoustic wave, a specific type of biological sample can be moved under the action of the surface acoustic wave, thereby achieving enrichment.

[0051] Among them, the piezoelectric substrate 11 can be any one of quartz, lithium niobate and lead zirconate titanate (PZT) according to the needs. For example, quartz has good thermal stability, piezoelectric effect and high mechanical strength, and is often used in high-frequency surface acoustic wave devices. Lithium niobate has high sensitivity and good frequency stability, and is suitable for scenes requiring high-precision control. Lead zirconate titanate (PZT) has a large piezoelectric constant and a high electromechanical coupling coefficient, and is suitable for occasions requiring higher power output. The actual piezoelectric substrate 11 can be selected according to the use requirements, and the embodiments of the present application are not limited to this.

[0052] The sample placement area is used to place the biological sample holding container 12. This area can be designed into different shapes and sizes to accommodate different types of biological sample holding containers 12. Electrodes are arranged on the surface of the piezoelectric substrate 11, usually interdigital transducers (IDT), which are used to receive electrical signals and convert them into mechanical vibrations. The cut edge is the edge of the piezoelectric substrate 11, which is used to determine the position and angle of the transducer module 12. When the electrode receives the electrical signal, the piezoelectric material vibrates mechanically and generates surface acoustic waves. The surface acoustic wave propagates on the surface of the substrate, and the vibration type can be controlled by adjusting the design of the electrode, the thickness of the piezoelectric substrate and the target angle. The transducer module 12 is fixed on the surface of the piezoelectric substrate 11, and the angle between it and the vertical direction of the cut edge of the piezoelectric substrate 11 is a target angle (such as 45 degrees). The target angle can be adjusted according to experimental requirements. For example, different types of biological samples respond differently to surface acoustic waves, and a specific angle is required to optimize the enrichment effect.

[0053] The IDT electrode is usually composed of a group of parallel metal finger electrodes. The input electrical signal generates an alternating electric field between the electrodes, thereby generating surface acoustic waves on the surface of the piezoelectric substrate 11. It is also possible to design multiple electrodes with different frequencies to achieve the generation of multi-band surface acoustic waves, further improving the enrichment efficiency and purity. The design of the transducer needs to consider its frequency response, power output and thermal stability to ensure that it can continue to work efficiently during the experiment.

[0054] The device generates surface acoustic waves on the surface of the piezoelectric substrate 11 through mechanical vibration, and the frequency and intensity of the surface acoustic waves can be controlled by the parameters of the electrical signal. The surface acoustic waves propagate in the biological sample holding container 12, and the biological sample in the biological sample solution 112 is enriched through the acoustic tweezers technology.

[0055] The control module 13 is connected to the transducer module 12 through an interface, which can be a physical interface (such as a cable) or a wireless interface (such as Bluetooth, Wi-Fi). The user can input the target biological sample type (such as exosomes) and the required enrichment parameters (such as frequency, intensity and time) through the control module 13. The control module 13 generates a corresponding electrical signal based on the input parameters and transmits it to the transducer module 12. The control module 13 can monitor the generation and propagation of the surface acoustic wave in real time to ensure the stability and effectiveness of the enrichment process. At the same time, an automated program can also be designed to automatically adjust and optimize the enrichment parameters to improve the enrichment efficiency.

[0056] The device integrates multiple enrichment steps into one, reducing the number of operating steps and complexity in the experiment. Through the automation program of the control module 13, one-key operation can be achieved, further simplifying the experimental process. Surface acoustic wave technology can complete the enrichment of biological samples in a short time, greatly shortening the experimental time.

[0057] At the same time, surface acoustic wave technology causes less damage to biological samples and does not cause mechanical damage to biological samples like centrifugation and filtration. Biological sample enrichment can be carried out under relatively mild conditions to maintain the integrity and activity of biological samples. By optimizing the frequency and intensity of surface acoustic waves, the target biological samples can be better protected and the entrainment of non-target biological samples can be reduced.

[0058] Surface acoustic waves have high resolution and can accurately separate different types of biological samples. By adjusting the parameters of the surface acoustic wave, specific types of biological samples can be selectively enriched to improve enrichment purity. The provided device does not require the use of markers (such as antibodies or magnetic beads), reducing additional processing steps and possible contamination.

[0059] The device can be applied to different types of biological samples, such as exosomes. It can process sample volumes from microliters to milliliters, suitable for different laboratory and clinical needs. It can also flexibly adjust the vibration mode, frequency and intensity of the surface acoustic wave according to different experimental needs to optimize the enrichment effect.

[0060] Now, an embodiment is used to illustrate the complete use process of the present device. Assuming that exosomes in a blood sample need to be enriched, the specific steps are as follows: a certain amount of blood sample is collected from a patient or an experimental animal. The blood sample is preliminarily processed, such as removing blood cells, to obtain a biological sample solution 112 containing exosomes. A suitable biological sample holding container 12 (such as a container processed based on PDMS material) is selected, and the biological sample solution 112 is placed in the container. The biological sample holding container 12 is placed in the sample placement area of ​​the piezoelectric substrate 11 to ensure that the container is in close contact with the surface of the substrate. According to the optimal enrichment angle of the exosome biological sample (for example, 60 degrees), the position of the transducer module 12 is adjusted so that the angle between it and the vertical direction of the cut edge of the piezoelectric substrate 11 is 60 degrees. The enrichment parameters of the exosomes are input into the control module 13, such as a surface acoustic wave frequency of 30MHz, a surface acoustic wave intensity of 3V, and an enrichment time of 1 minute. The control module 13 generates a corresponding electrical signal according to the input parameters and transmits it to the transducer module 12 through the interface. After the transducer module 12 receives the electrical signal, the transducer starts working and converts the electrical signal into a surface acoustic wave on the surface of the piezoelectric substrate 11, and the surface acoustic wave propagates along the set path to the biological sample holding container 12. The surface acoustic wave propagates in the biological sample solution 112, and the biological sample in the biological sample solution 112 is subjected to the acoustic flow, so that the exosomes are enriched in a specific area of ​​the container. The enrichment of exosomes in a specific area of ​​the container can be verified by microscopic observation or scanning electron microscopy. The enriched exosomes are taken out for further analysis or use, such as extraction of exosome RNA, protein analysis, etc.

[0061] The enrichment device 10 provided in the present application achieves efficient and low-damage enrichment of biological samples through surface acoustic wave technology. The device has significant advantages in simplifying the operation steps, reducing experimental costs, and improving enrichment efficiency and purity. It is particularly suitable for occasions where a large number of samples need to be processed and specific biological sample types need to be enriched. Through detailed parameter adjustment and optimization, the device can be widely used in medical research, biotechnology, clinical diagnosis and other fields.

[0062] In some embodiments, the transducer module 12 includes multiple transducer units, which are arranged on the piezoelectric substrate 11 and surround the biological sample holding container 12; the enrichment device 10 also includes: a compression module 14, which is arranged on at least one transducer unit, and the transducer unit corresponding to the compression module 14 is a target transducer unit, and the angle between the target transducer unit and the vertical direction of the cut edge of the piezoelectric substrate 11 is a target angle; wherein the control parameter is used to control the target transducer unit so that the target transducer unit transmits surface acoustic waves to the biological sample holding container 12.

[0063] like Figure 1 and Figure 2 As shown, in this embodiment, the transducer module 12 includes a plurality of transducer units, which are evenly arranged on the piezoelectric substrate 11 and surround the biological sample holding container 12. The surround design can realize multi-directional surface acoustic wave propagation, so that a transducer unit at an angle can be selected at will, or multiple transducer units can be selected at the same time for control, which greatly improves the flexibility of the device. At the same time, the transducer unit can be replaced very conveniently, reducing the maintenance cost of the device.

[0064] Multiple transducer units can generate surface acoustic waves in different directions, so that the biological sample in the biological sample solution 112 is enriched under the action of predetermined surface acoustic waves according to actual needs. According to different types of biological samples and experimental requirements, transducer units in different directions can be selected for control to achieve a more precise enrichment effect.

[0065] The compression module 14 is arranged on at least one transducer unit, which is called a target transducer unit. For example, the angle between the target transducer unit and the vertical direction of the cut edge of the piezoelectric substrate 11 is a target angle (such as 60 degrees) to optimize the propagation path of the surface acoustic wave.

[0066] The pressing module 14 can firmly press the target transducer unit onto the piezoelectric substrate 11 to ensure close contact between the transducer unit and the substrate surface. Through physical pressing, the energy loss during the propagation of the surface acoustic wave can be reduced, and the propagation efficiency and enrichment effect of the surface acoustic wave can be improved.

[0067] At the same time, by pressing the module 14, Figure 1 and Figure 2The transducer unit corresponding to any angle is tested, and then the most suitable target angle for the current biological sample enrichment is selected, the corresponding target transducer unit is determined, and the control parameters of the target transducer unit under the target angle are further adjusted to improve the efficiency of biological sample enrichment.

[0068] The control module 13 is connected to multiple target transducer units through an interface, and can control these transducer units separately or simultaneously. The control module 13 is embedded with a control algorithm, and can generate specific control signals according to the input parameters. The control module 13 generates corresponding electrical signals according to the input parameters and transmits them to the target transducer unit. In addition, one or more target transducer units can be controlled simultaneously to generate surface acoustic waves of specific vibration modes in different directions, thereby improving the enrichment effect.

[0069] Since multiple transducer units surround the biological sample holding container 12, surface acoustic waves can propagate from multiple directions, thereby improving the enrichment effect of the biological sample. The transducer units can work together to generate surface acoustic waves in different directions simultaneously or sequentially, greatly improving the enrichment efficiency. At the same time, the clamping module 14 ensures the close contact between the target transducer unit and the surface of the piezoelectric substrate 11, reducing the energy loss during the propagation of the surface acoustic wave and further improving the enrichment effect. Surface acoustic wave technology causes less damage to biological samples. By optimizing the frequency and intensity of the surface acoustic wave, biological sample enrichment can be performed under relatively mild conditions, further protecting the integrity and activity of the biological sample.

[0070] Accordingly, through the multi-unit control of the control module 13, specific types of biological samples can be selectively enriched according to the response characteristics of different biological sample types to the surface acoustic wave, thereby improving the enrichment purity. Multi-directional multi-mode surface acoustic waves can better separate target biological samples from non-target biological samples, reduce the entrainment of non-target biological samples, and improve the enrichment purity.

[0071] The control module 13 can flexibly adjust the frequency, intensity and direction of the surface acoustic wave, which is suitable for different types of biological samples and different experimental requirements. Through the built-in automatic control program, the enrichment parameters can be automatically optimized to improve the flexibility and repeatability of the experiment.

[0072] The above embodiment significantly improves the efficiency of biological sample enrichment by designing multiple transducer units surrounding the biological sample holding container 12 and the compression module 14, while reducing biological sample damage and improving enrichment purity. The device has obvious advantages in processing a large number of samples and specific biological sample types, and is suitable for a variety of experimental needs in the fields of medical research, biotechnology, clinical diagnosis, etc. Through flexible parameter adjustment and automated control procedures, the device can achieve efficient and low-damage biological sample enrichment and improve the reliability and repeatability of the experiment.

[0073] In some embodiments, the transducer module 12 is sputtered, evaporated, or 3D printed on the piezoelectric substrate 11 .

[0074] In this embodiment, the transducer module 12 is not an independent unit, but is directly sputtered or evaporated on the surface of the piezoelectric substrate 11. This integrated design can improve the overall performance and reliability of the device. The transducer module 12 sputtered or evaporated on the piezoelectric substrate 11 usually includes interdigital transducers (IDT), which can accurately control the generation and propagation of surface acoustic waves.

[0075] The transducer module 12 of sputtering, evaporation or 3D printing can convert the electrical signal into mechanical vibration and generate surface acoustic waves when receiving the electrical signal. Since the transducer module 12 is directly sputtered or evaporated on the piezoelectric substrate 11, the transducer module 12 is in close contact with the substrate, which reduces energy loss.

[0076] The transducer module 12 is directly formed on the piezoelectric substrate 11 by sputtering, evaporation or 3D printing, making the entire device more compact and integrated, reducing problems that may occur during the assembly process. The integrated design reduces the poor contact between the transducer module 12 and the piezoelectric substrate 11, and improves the reliability and stability of the device. At the same time, the transducer module 12 can also be formed on the piezoelectric substrate 11 by 3D printing.

[0077] By sputtering or evaporating the transducer module 12 on the piezoelectric substrate 11, an integrated design of the device is achieved, which improves the integration and stability. This design significantly reduces energy loss, improves enrichment accuracy and efficiency, and reduces manufacturing costs and maintenance costs of the device. The device has obvious advantages in processing a large number of samples and specific biological sample types, and is suitable for a variety of experimental needs in the fields of medical research, biotechnology, clinical diagnosis, etc. Through flexible parameter adjustment and automated control procedures, the device can achieve efficient and low-damage enrichment of biological samples and improve the reliability and repeatability of the experiment.

[0078] In some embodiments, the control parameters include at least frequency and power. The frequency and power of the transducer module 12 are determined according to the diameter, density, compression coefficient and the target angle of the biological sample to be enriched in the biological sample solution 112 .

[0079] In this embodiment, the control parameters generated by the control module 13 include at least the frequency and power of the surface acoustic wave. These parameters are determined according to the type of piezoelectric material, the wavelength of the surface acoustic wave corresponding to the transducer module 12, and the target angle. The frequency parameter determines the wavelength and propagation speed of the surface acoustic wave. By adjusting the frequency, the response of the surface acoustic wave to a specific biological sample can be optimized. The power parameter determines the intensity of the surface acoustic wave. By adjusting the power, the size of the acoustic field generated by the surface acoustic wave to the biological sample in the biological sample solution 112 can be controlled. Biological samples of different diameters and volumes respond differently to the surface acoustic wave. By adjusting the frequency and power, efficient enrichment of specific biological samples can be achieved.

[0080] By automatically adjusting the frequency and power according to the diameter, density, compression coefficient and the target angle through the control module 13, the enrichment effect of the surface acoustic wave on the target biological sample can be significantly improved. At the same time, by accurately adjusting the frequency and power of the surface acoustic wave, the biological sample can be enriched under relatively mild conditions, reducing mechanical damage to the biological sample. Biological samples of different diameters and volumes respond differently to the surface acoustic wave. By optimizing the frequency and power, specific types of biological samples can be enriched more accurately. The optimized parameters can better separate the target biological sample and the non-target biological sample, reduce the entrainment of the non-target biological sample, and improve the enrichment purity.

[0081] In some embodiments, the transducer includes at least one IDT, and a ratio of a wavelength range of a surface acoustic wave emitted by the IDT to a finger width range of the IDT is within a preset ratio range.

[0082] In the present embodiment, the transducer module 12 includes at least one interdigital transducer. The interdigital transducer is composed of a series of interdigital electrodes, which can convert electrical signals into surface acoustic waves (SAW, Surface Acoustic Wave). The interdigital transducer is composed of a plurality of parallel comb-shaped electrodes, which are arranged in parallel to form an interdigital structure. The finger width of the interdigital transducer refers to the width of each electrode finger, which is usually at the micron level. When the interdigital transducer receives an electrical signal, the electrical signal generates an alternating electric field between the interdigital electrodes, thereby driving the mechanical vibration of the surface of the piezoelectric substrate 11 and generating a surface acoustic wave. The generated surface acoustic wave propagates along the substrate surface, and the target biological sample in the biological sample solution 112 is enriched to a specific area through the action of the surface acoustic wave.

[0083] According to specific application requirements, multiple IDTs can be set to achieve multi-directional surface acoustic wave propagation. After receiving the electrical signal, the IDT converts the electrical signal into mechanical vibration to generate surface acoustic waves. Multiple IDTs can generate surface acoustic waves from multiple directions simultaneously or individually, improving the enrichment efficiency.

[0084] The ratio of the wavelength range of the surface acoustic wave emitted by the IDT to the finger width range of the IDT is within a preset ratio range, and the specific ratio range can be adjusted according to experimental requirements and biological sample characteristics to optimize the enrichment effect.

[0085] By adjusting the finger width of the interdigital transducer, the wavelength of the generated surface acoustic wave can be controlled, thereby optimizing the response of the surface acoustic wave to a specific biological sample. A suitable wavelength to finger width ratio can ensure that the surface acoustic wave propagates more effectively in the biological sample solution 112, thereby improving the accuracy of biological sample enrichment.

[0086] For example, Figure 3 As shown, the shape of each interdigital transducer on the piezoelectric substrate 11 is a trapezoid. Each interdigital transducer is in the shape of a trapezoid, that is, the length of the electrode finger gradually changes on the surface of the substrate. The layout of the trapezoidal electrode can be an isosceles trapezoid, and the specific layout is designed according to the experimental requirements. The trapezoidal interdigital electrode can generate surface acoustic waves within a specific range through its length gradient design, thereby achieving efficient enrichment of different biological samples.

[0087] The design of the trapezoidal electrode can generate a more complex acoustic field, allowing biological samples to be more accurately enriched in the target area under the action of sound. The multi-mode surface acoustic wave field of the trapezoidal design can adapt to biological samples of different diameters, densities and compression coefficients, improving the versatility and adaptability of the device. At the same time, the length gradient design of the trapezoidal electrode can optimize the propagation of surface acoustic waves on the surface of the piezoelectric substrate and improve the enrichment efficiency.

[0088] For example, Figure 4 As shown, the shape of each interdigital transducer on the piezoelectric substrate 11 is an arc. The shape of each interdigital transducer on the piezoelectric substrate 11 is an arc, also known as a focusing transducer. That is, the arrangement of the electrode fingers is in the shape of an arc. The layout of the arc-shaped electrode is a plurality of concentric arcs, and the specific layout is designed according to the experimental requirements. The design of the arc-shaped electrode can focus the surface acoustic wave on the central area of ​​the container, thereby achieving the enrichment of the target biological sample and improving the enrichment efficiency. The arc-shaped acoustic field can enrich the biological sample in the central area of ​​the container, which is convenient for subsequent processing and analysis. The central enrichment design reduces the interference of background biological samples and impurities, and improves the enrichment purity. By adjusting the parameters of the arc-shaped electrode, it can flexibly adapt to different types of biological samples and experimental requirements.

[0089] Exemplarily, the preset ratio range is 1 / 8 to 1 / 2. The ratio of the wavelength range of the surface acoustic wave emitted by the interdigital transducer to the finger width range of the interdigital transducer is in the range of 1 / 8 to 1 / 2. According to the characteristics of the biological sample to be enriched, the finger width and the interval width of the interdigital transducer are adjusted to ensure that the ratio is within the preset range. By adjusting the finger width of the interdigital transducer, the wavelength of the generated surface acoustic wave can be accurately controlled to optimize the response of the surface acoustic wave to the target biological sample.

[0090] The design of the ratio range of 1 / 8 to 1 / 2 can ensure that the propagation of the surface acoustic wave in the biological sample solution 112 is more efficient and improves the enrichment efficiency. The optimized wavelength to finger width ratio can reduce mechanical damage to the biological sample and protect the integrity and activity of the target biological sample. This ratio range is applicable to a variety of different types of biological samples, improving the versatility and adaptability of the device. By optimizing the ratio, the propagation efficiency of the surface acoustic wave can be improved, the energy loss can be reduced, and the enrichment effect can be improved.

[0091] Exemplarily, the wavelength of the surface acoustic wave is 20 to 1000 μm. The wavelength range of the surface acoustic wave emitted by the interdigital transducer is 20 to 1000 μm. According to the required wavelength range, the appropriate interdigital electrode finger width and electrical signal frequency are designed. The wavelength range of 20 to 1000 μm can cover a variety of biological samples of different sizes and is suitable for enrichment of different types of biological samples. By adjusting the frequency of the electrical signal, surface acoustic waves can be generated in different wavelength ranges to form a multi-mode surface acoustic wave field and improve the enrichment efficiency. By adjusting the wavelength range, the interference of background biological samples and impurities can be reduced and the enrichment purity can be improved.

[0092] In some embodiments, the control parameter includes at least a frequency, and the frequency corresponds to a frequency range of 10 MHz to 150 MHz.

[0093] The frequency range of the surface acoustic wave emitted by the IDT is 10 MHz to 150 MHz. According to the frequency range, the electrode finger width, electrode spacing and other parameters of the IDT are adjusted to ensure that the surface acoustic wave can be effectively generated within the frequency range. The frequency range of 10 MHz to 150 MHz can cover a variety of biological samples of different sizes and types to meet different enrichment needs. For example, when the target angle is 0 degrees, the frequency is 19.8 MHz. When the target angle is 30 degrees, the frequency is 18.6 MHz. When the target angle is 60 degrees, the frequency is 32.2 MHz. When the target angle is 90 degrees, the frequency is 34.4 MHz.

[0094] By adjusting the frequency of the electrical signal, surface acoustic waves of different vibration modes can be generated to form a multi-mode sound field, thereby improving the diversity and flexibility of enrichment.

[0095] In some embodiments, it also includes: an extraction module (not shown in the figure), which is oriented toward the sample placement area and is used to extract the enriched target concentrated sample; the control module 13 obtains the vibration shape of the surface acoustic wave and the liquid surface characteristic information of the biological sample solution 112, and confirms the enrichment position information corresponding to the target concentrated sample in the biological sample holding container 111 according to the vibration shape and the liquid surface characteristic information, so as to control the extraction module according to the enrichment position information to complete the automatic extraction of the target concentrated sample.

[0096] Extraction module: facing the sample placement area, responsible for automatically extracting the enriched target concentrated sample under the instruction of the control module 13. This module can be a micro-needle, micro-pump or other forms of micro-extraction module.

[0097] The control module 13 analyzes the vibration shape and liquid surface characteristic information, determines the enrichment position information of the target concentrated sample, and controls the extraction module to complete the automatic extraction accordingly. The control module 13 can use sensors and algorithms to monitor and adjust the enrichment process in real time to ensure the stability and efficiency of the enrichment effect.

[0098] Suppose we need to enrich a specific cell type, such as white blood cells, from a blood sample. The operation process can be:

[0099] Prepare the sample: place the blood sample solution in a biological sample holding container 111 (such as a microfluidic chip), and place the container in the sample placement area of ​​the piezoelectric substrate 11 .

[0100] Start-up device: The control module 13 is powered on and starts to send electrical signals to the transducer module 12. The transducer module 12 converts the electrical signals into mechanical vibrations to generate surface acoustic waves.

[0101] Enrichment process: The surface acoustic wave propagates in the microfluidic chip, and the white blood cells in the blood sample are enriched in a specific area through vibration. The control module 13 detects the vibration shape of the surface acoustic wave and the liquid surface characteristic information in real time through the sensor to ensure that the white blood cells are enriched in the predetermined position.

[0102] Confirming the enrichment position: The control module 13 determines the exact position of the target concentrated sample (enriched leukocytes) based on the detected vibration shape and liquid surface characteristic information.

[0103] Automated extraction: The control module 13 instructs the extraction module (such as a microneedle) to extract the target concentrated sample from the enrichment location and transfer it to another container or detection device for subsequent analysis or processing.

[0104] The entire enrichment and extraction process does not require human intervention, and the intelligent scheduling of the control module 13 realizes automated operation, reduces human errors, and improves the stability of the enrichment effect. Utilizing the precise manipulation ability of surface acoustic waves, biological samples can be efficiently enriched on a microscale, and the purity and concentration of the target concentrated samples are higher, which is conducive to subsequent high-precision analysis and detection. The control module 13 can monitor the vibration shape and liquid surface characteristic information of the surface acoustic wave in real time, and dynamically adjust the parameters of the electrical signal according to this information to ensure the optimal effect of the enrichment process. The device is not only suitable for the enrichment of cells, but also can be used for the enrichment of other biological samples, such as proteins, DNA, RNA, etc., and has broad application prospects. Compared with traditional manual enrichment methods, the device is easy to operate, has high enrichment efficiency, can greatly reduce experimental time and labor costs, and is suitable for large-scale production and clinical applications.

[0105] Exemplarily, the control module 13 also obtains the frequency corresponding to the surface acoustic wave, the sample volume corresponding to each addition of the biological sample carrying solution, and the size of the micro-nanoparticles contained in the biological sample solution 112; the control module 13 determines the enrichment position information based on the frequency, sample volume, micro-nanoparticle size, vibration shape and the liquid surface characteristic information.

[0106] The control module 13 not only obtains the vibration shape and liquid surface characteristic information of the surface acoustic wave, but also can monitor the frequency of the surface acoustic wave. Frequency is one of the key parameters that affect the characteristics of the surface acoustic wave and the enrichment effect of the biological sample. The control module 13 can obtain the volume of the biological sample solution 112 added each time. The added volume will affect the height of the liquid level and the propagation path of the surface acoustic wave, thereby affecting the enrichment effect. The control module 13 can also obtain the size of the micro-nano particles contained in the biological sample solution 112. Different particle sizes respond differently to the surface acoustic wave, so the particle size is an important parameter that affects the efficiency and accuracy of the enrichment.

[0107] The control module 13 comprehensively analyzes the influence of these parameters on the enrichment effect based on the acquired frequency, sample volume, micro-nano particle size, vibration shape and liquid surface characteristic information, thereby determining the accurate enrichment position of the target concentrated sample. The control module 13 integrates an intelligent algorithm, which can adjust the frequency and amplitude of the electrical signal in real time according to the above parameters to ensure that the surface acoustic wave works under the best conditions, thereby achieving high-efficiency and high-precision enrichment.

[0108] like Figure 6 Show, Figure 6The effect of different surface wave frequencies on the flow field. By monitoring and adjusting the frequency of the surface acoustic wave, it can be ensured that the surface acoustic wave works at the optimal frequency, thereby improving the enrichment effect of biological samples. The optimal frequency can make the vibration energy of the surface acoustic wave most effectively transmitted to the biological sample, achieving efficient enrichment. The monitoring and control of the sample volume ensures that the liquid level and shape of each sample are consistent, reducing the interference of the liquid level change on the propagation path of the surface acoustic wave, and improving the stability and accuracy of the enrichment. Figure 7 The control module 13 can adjust the parameters of the surface acoustic wave according to the size of the micro-nano particles in the biological sample solution 112, so that particles of different sizes can be effectively enriched. This adaptability improves the efficiency of enrichment, especially for complex samples. By real-time monitoring and adjusting the electrical signal, the control module 13 can dynamically optimize the enrichment process to avoid the problem of insufficient enrichment or unstable enrichment effect caused by parameter mismatch.

[0109] The multi-parameter monitoring and intelligent algorithm of the control module 13 make the entire enrichment process more automated, reducing the manual intervention process, thereby greatly reducing human errors. Due to the precise control of parameters and automated operation, the enrichment process of the device has high repeatability and is suitable for large-scale and high-throughput biological sample enrichment.

[0110] Through multi-parameter comprehensive analysis, the device can adapt to a variety of biological samples and different experimental conditions, with higher versatility and flexibility. It can handle micro-nanoparticles of different sizes, expanding the scope of application and being suitable for the enrichment of various biological samples such as cells, proteins, DNA, and RNA.

[0111] The user only needs to add the biological sample solution 112 into the carrying container and start the device to complete the enrichment and extraction process. The operation is simple and suitable for laboratory technicians and clinical applications. The enrichment and extraction process is completed in a short time, which improves the experimental efficiency and shortens the research and detection time.

[0112] Exemplarily, the formula corresponding to the enriched position information may include:

[0113] x=a·f+b·V+c·D+d·φ+e·1 / h+g·R+i;

[0114] a is the coefficient of frequency f, which is used to describe the effect of frequency on the enrichment position. b is the coefficient of sample volume V, which describes the effect of sample volume on the enrichment position. c is the coefficient of micro-nanoparticle size D, which describes the effect of particle size on the enrichment position. d is the coefficient of vibration shape φ, which describes the effect of vibration shape on the enrichment position. e is the reciprocal coefficient of liquid level h, which describes the effect of the reciprocal of liquid level on the enrichment position. g is the coefficient of the curvature radius R of the liquid surface shape, which describes the effect of the liquid surface shape on the enrichment position. i is a constant term, which represents the default enrichment position when all parameters are zero.

[0115] High-frequency surface acoustic waves are usually beneficial for more precise manipulation, so a is usually a positive value, indicating that the frequency has a positive correlation with the enrichment position. The larger the sample volume, the higher the liquid level, and the propagation path and energy distribution of the surface acoustic wave change, so b is usually a negative value, indicating that the sample volume has a negative correlation with the enrichment position. Smaller micro-nanoparticles are more easily enriched by surface acoustic waves, so c is usually a negative value, indicating that the particle size has a negative correlation with the enrichment position. The vibration shape directly affects the propagation mode of the surface acoustic wave, so d is usually a positive value, indicating that the vibration shape has a positive correlation with the enrichment position. The reciprocal of the liquid level can better describe the effect of the liquid surface on the propagation of the surface acoustic wave, so e is usually a positive value, indicating that the reciprocal of the liquid level has a positive correlation with the enrichment position. The radius of curvature of the liquid surface shape affects the reflection and refraction of the surface acoustic wave on the liquid surface, so g is usually a negative value, indicating that the radius of curvature of the liquid surface shape has a negative correlation with the enrichment position. The constant term i represents the default enrichment position when all parameters are zero, which can be adjusted according to actual experimental conditions. The above formula is fitted by experimental data to determine the specific values ​​of each coefficient, and linear regression, nonlinear regression or machine learning algorithm can be used for fitting. The formula can more accurately predict the enrichment position information of the surface acoustic wave in the biological sample holding container 111 through comprehensive analysis of multiple parameters, thereby improving the accuracy and efficiency of enrichment. Through fitting and verification of experimental data, the coefficients of the formula can be further optimized to make it more reliable in practical applications.

[0116] It should be noted that the control module 13 determines the flow field characteristics corresponding to the biological sample solution 112 according to the frequency and the sample volume, so as to determine the number of eddies in the biological sample solution 112 under the action of the surface acoustic wave according to the flow field characteristics; the control module 13 determines the enrichment position information according to the number of eddies, the size of micro-nanoparticles, the vibration shape and the liquid surface characteristic information.

[0117] The control module 13 further refines the method for determining the enriched position information through comprehensive analysis of multiple parameters. The specific technical content includes the following steps:

[0118] The control module 13 determines the flow field characteristics of the biological sample solution 112 according to the frequency of the surface acoustic wave and the sample volume of the biological sample solution 112. The frequency affects the propagation speed and energy distribution of the surface acoustic wave, while the sample volume affects the height and shape of the liquid surface, which together determine the flow field distribution in the solution.

[0119] The control module 13 calculates the number of eddies in the biological sample solution 112 under the action of the surface acoustic wave according to the determined flow field characteristics. The eddies are local vortices generated by the surface acoustic wave in the solution, which can promote the enrichment of the biological sample. The number and distribution pattern of the eddies have a significant impact on the enrichment effect.

[0120] The control module 13 comprehensively considers the number of eddies, the size of micro-nanoparticles, the vibration shape of the surface acoustic wave and the liquid surface characteristic information (such as the liquid level height and the curvature radius of the liquid surface shape), and determines the enrichment position information of the target concentrated sample through mathematical models and algorithms.

[0121] Determining the flow field characteristics by frequency and sample volume can more accurately describe the propagation and energy distribution of surface acoustic waves in the solution, thereby improving the accuracy of the enrichment position. The calculation of the eddy number provides a quantitative description of the local vortex in the solution, which helps to more accurately determine the enrichment position of the biological sample in the vortex.

[0122] By comprehensively considering the number of eddies, the size of micro-nano particles, vibration shape and liquid surface characteristic information, the control module 13 can dynamically adjust the parameters in the enrichment process to optimize the enrichment efficiency. In particular, under different particle sizes and different liquid surface conditions, this multi-parameter comprehensive method can provide a more flexible and efficient enrichment scheme. The control module 13 can monitor the changes of the above parameters in real time and adjust the electrical signal according to the changes to ensure that the enrichment process is always carried out under the best conditions.

[0123] The entire enrichment and extraction process is highly automated, reducing the number of manual operations, thereby significantly reducing human errors. The intelligent algorithm of the control module 13 can automatically optimize parameters to avoid unstable enrichment effects caused by improper manual settings.

[0124] This method is not only applicable to a single type of biological sample, but can also process a variety of micro-nanoparticles of different sizes, which enhances the adaptability and versatility of the device. Through the calculation of flow field characteristics and the number of eddy currents, this method can adapt to different experimental conditions, such as different sample volumes and liquid surface characteristics, and improves the applicability of the device in different environments. The user only needs to add the biological sample solution 112 to the carrying container and start the device to complete the enrichment and extraction process. It is easy to operate and suitable for laboratory technicians and clinical applications. The control module 13 can provide enrichment position information in real time, and the user can quickly obtain the enrichment results, shortening the time of experiments and detection.

[0125] Exemplarily, it includes: an image acquisition module, used to collect liquid surface characteristic information of the biological sample carrying solution; wherein the liquid surface characteristic information also includes aggregated particle information corresponding to the micro-nanoparticles in the biological sample solution 112; the aggregated particle information at least includes aggregated particle color and aggregated particle shape.

[0126] like Figure 8 As shown, the image acquisition module can capture the liquid surface characteristic information of the biological sample carrying solution, including the height and shape of the liquid surface and the aggregation information of the micro-nano particles in the solution. The module can use a high-resolution camera or imaging device, and can transmit image data to the control module 13 in real time for analysis. The image acquisition module can determine the height of the liquid surface, which has a direct impact on the propagation path and energy distribution of the surface acoustic wave. The radius of curvature of the liquid surface shape affects the reflection and refraction of the surface acoustic wave on the liquid surface, further affecting the enrichment effect. The image acquisition module can identify the aggregation color of micro-nano particles in the solution, and particles of different colors may have different properties and responses. The image acquisition module can identify the aggregation shape of micro-nano particles in the solution, and different shapes also respond differently to the surface acoustic wave.

[0127] The control module 13 receives the liquid surface characteristic information and aggregated particle information transmitted by the image acquisition module, combines the existing frequency, sample volume, micro-nano particle size and vibration shape, and determines the enrichment position information through complex algorithms and models.

[0128] Exemplarily, the surface acoustic wave includes a first-stage surface wave and a second-stage surface wave; the control module 13 controls the transducer module 12 to sequentially generate the first-stage surface wave and the second-stage surface wave; the first-stage surface acoustic wave is used to form a plurality of vortices in the biological sample solution 112, so that the micro-nanoparticles close to the side wall of the biological sample holding container 111 are gathered at a plurality of gathering points away from the side wall; the second-stage surface acoustic wave is used to form a single vortex in the biological sample solution 112, so as to gather the plurality of micro-nanoparticles at the center position of the biological sample holding container 111.

[0129] The surface acoustic wave includes two stages of surface waves: a first stage surface wave and a second stage surface wave. The control module 13 generates the two stages of surface waves in sequence through the energy conversion module 12 to achieve efficient enrichment of micro-nano particles.

[0130] The first-stage surface wave is used to form multiple vortices in the biological sample solution 112, so that the micro-nano particles close to the side wall of the biological sample holding container 111 are gathered at multiple gathering points away from the side wall. The control module 13 sends the first-stage electrical signal to the transducer module 12, and the transducer module 12 generates the first-stage surface wave according to the signal. The design of the first-stage surface wave causes multiple local vortices to be generated on the liquid surface, and these vortices are distributed at different positions of the container, gradually guiding the particles close to the side wall to multiple gathering points near the center of the container.

[0131] The second-stage surface wave is used to form a single vortex in the biological sample solution 112, further concentrating the micro-nano particles in the multiple aggregation points to the center of the biological sample holding container 111. After the first-stage surface wave is completed, the control module 13 sends the second-stage electrical signal to the transducer module 12, and the transducer module 12 generates the second-stage surface wave according to the signal. The design of the second-stage surface wave causes a central vortex to be generated on the liquid surface, which has a strong enrichment ability, and further concentrates the particles in the multiple aggregation points formed in the first stage to the center of the container.

[0132] Through two stages of surface waves, micro-nanoparticles can be more efficiently concentrated in the center of the container. In the first stage, multiple vortices are formed to initially guide the particles from the side walls to the middle. In the second stage, a single central vortex is used to further concentrate the particles. This multi-stage enrichment strategy significantly improves the enrichment efficiency. Compared with single-stage enrichment, multi-stage enrichment can complete the enrichment process in a shorter time, thereby speeding up experiments and detection.

[0133] The multiple vortices in the first stage initially concentrate the particles to multiple gathering points, reducing the uneven distribution of particles on the side walls. The single central vortex in the second stage concentrates the particles in these gathering points to a central point, improving the accuracy of enrichment. Through multi-stage enrichment, the process of particles gradually enriching from the side walls to the center reduces cross-contamination between different particles and ensures the purity of the enriched sample.

[0134] The surface waves in the first and second stages can be adjusted according to the size of different particles to adapt to different types of biological samples. The multi-stage enrichment strategy can adapt to biological sample carrying containers 111 of different shapes and sizes, thereby improving the versatility and flexibility of the device.

[0135] The entire enrichment process is automatically controlled by the control module 13, which reduces the number of manual operations and greatly reduces human errors. The control module 13 can dynamically adjust the parameters of the electrical signal according to actual conditions to ensure that the enrichment process is always carried out under optimal conditions.

[0136] The user only needs to add the biological sample solution 112 into the carrying container and start the device to complete the enrichment and extraction process. The operation is simple and suitable for laboratory technicians and clinical applications. The control module 13 can monitor the generation and enrichment process of the surface wave in real time. The user can intuitively see the process status through the display screen or software interface, which improves the transparency and operability of the experiment. The data in the enrichment process can be recorded and subsequently analyzed to provide data support for the verification and optimization of the experimental results.

[0137] Assuming that specific white blood cells need to be enriched from a blood sample, the device of Example 3 can be specifically operated as follows: Prepare the sample: add a certain volume (for example, V = 50 μL) of blood sample solution into the biological sample holding container 111 and place it in the sample placement area of ​​the piezoelectric substrate 11.

[0138] The control module 13 is powered on and starts to send electrical signals. The control module 13 first sends the first-stage electrical signals to the transducer module 12, and the transducer module 12 generates the first-stage surface waves.

[0139] The first-stage surface wave forms multiple vortices in the biological sample solution 112, so that the white blood cells close to the side wall of the container gradually gather at multiple aggregation points away from the side wall. For example, assuming that the frequency of the first-stage electrical signal is 100 MHz, the control module 13 confirms the multiple aggregation points formed in the first stage through the sensor or image acquisition module to ensure that the initial enrichment effect is good. The control module 13 sends the second-stage electrical signal to the transducer module 12, and the transducer module 12 generates the second-stage surface wave. The second-stage surface wave forms a single central vortex in the biological sample solution 112, further concentrating the white blood cells in the multiple aggregation points formed in the first stage to the center of the container. For example, assuming that the frequency of the second-stage electrical signal is 50 MHz, the central vortex formed has a higher energy density.

[0140] In some embodiments, the system further includes: a loading module (not shown in the figure), wherein the biological sample solution 112 is stored in the loading module, and the loading pipette head of the loading module faces the sample placement area; when the control module 13 controls the transducer module 12 to generate the surface acoustic wave, and the biological sample in the biological sample solution 112 is enriched in the biological sample holding container 111 under the action of the surface acoustic wave, the control module 13 obtains the container height of the biological sample holding container 111 and the solution level information of the biological sample solution 112 in the biological sample holding container 111; the control module 13 determines the loading amount corresponding to the loading module according to the container height of the biological sample holding container 111; the control module 13 determines the loading position according to the solution level information; the control module 13 controls the loading module to load the biological sample holding container 111 according to the loading amount and the loading position.

[0141] Sample loading module: biological sample solution 112 is stored inside. It includes a liquid loading pipette, which faces the sample placement area and is used to accurately control the loading amount and loading position. The control module 13 is responsible for controlling the transducer module 12 to generate surface acoustic waves. The sensor obtains the container height and solution level information of the biological sample holding container 111. According to the container height and solution level information, the loading amount and loading position are determined. Finally, the sample loading module is controlled to perform accurate loading.

[0142] Exemplarily, if the control module 13 determines, based on the solution level information, that the liquid level of the biological sample solution 112 increases inwardly along the side wall of the biological sample holding container 111 , the sample adding position is the position of the highest point of the liquid level corresponding to the biological sample holding container 111 .

[0143] The control module 13 monitors the changes in the liquid level in the biological sample holding container 111 in real time through the sensor. When the sensor detects that the liquid level increases inward along the side wall of the container, it means that the liquid surface in the container has formed a specific shape with a highest point. The control module 13 uses image processing technology or sensor data to accurately determine the position of the highest point of the liquid surface. For example, the image sensor can take an image of the liquid surface and determine the coordinates of the highest point through an image processing algorithm; the laser ranging sensor can find the highest liquid surface position through multi-point measurement. Once the position of the highest point of the liquid surface is determined, the control module 13 can set the sample loading position at the highest point. This design can ensure that the liquid surface contacted by the pipette tip is the highest when loading the sample, thereby reducing the risk of the pipette tip sucking empty air or sucking up less sample.

[0144] By determining the highest point of the liquid surface, the sample loading module can locate the sample loading position more accurately, thereby reducing the sample loading error. It ensures that the amount and position of each sample loading meet the experimental requirements, and improves the reliability and repeatability of the sample loading. In the traditional sample loading method, the unevenness of the liquid surface may cause the suction head to absorb the sample at the low liquid surface, resulting in sample loss. This embodiment ensures that the suction head can absorb the most samples by locating the highest point of the liquid surface, thereby reducing the loss of samples. The highest point of the liquid surface is often the position with the best enrichment effect, because the propagation of surface acoustic waves and the aggregation effect of samples are most significant there. Setting the sample loading position at the highest point of the liquid surface can ensure that the enriched sample is effectively transferred to the target container, thereby improving the efficiency and purity of the enrichment. This method does not depend on the specific shape of the container and is applicable to various biological sample carrying containers 111 of different designs. As long as the liquid level increases inward along the side wall of the container, the control module 13 can accurately determine the highest point of the liquid surface, and has strong adaptability.

[0145] Assume that it is necessary to enrich proteins from a biological sample solution 112 containing a specific protein and accurately transfer the enriched protein solution to another container: select a suitable biological sample holding container 111, put the diluted protein solution into the container, and place it in the sample placement area of ​​the piezoelectric substrate 11. The control module 13 sends an electrical signal to the transducer module 12 to generate a surface acoustic wave. Under the action of the surface acoustic wave, the protein is enriched on one side or the bottom of the container, forming a distribution in which the liquid level increases inward along the side wall of the container. Through an image sensor or a laser ranging sensor, the control module 13 monitors the height change of the liquid level in real time. The control module 13 determines the position of the highest point of the liquid level. The control module 13 calculates the volume of the enriched protein solution based on the height of the container and the position of the highest point of the liquid level. Determine the sample addition amount and sample addition position to ensure that the pipette tip can contact the highest point of the liquid level during sample addition. The control module 13 controls the liquid addition pipette tip of the sample addition module to move to the position of the highest point of the liquid level. The sample addition module accurately absorbs the enriched protein solution and transfers it to the target container.

[0146] By accurately positioning the highest point of the liquid surface in the embodiment, the enrichment device 10 exhibits higher accuracy during the sample addition process, reduces sample loss, improves enrichment efficiency, and is suitable as an efficient tool in modern biomedical research and clinical diagnosis.

[0147] For example, Fig. 9 As shown, after the addition of the biological sample solution 112 , the liquid surface adjacent to the side wall of the biological sample holding container 111 is flush with the side wall of the biological sample holding container 111 .

[0148] The control module 13 monitors the liquid level and position in the biological sample holding container 111 in real time through sensors. Based on the sensor data, the control module 13 can determine whether the liquid level after adding the sample is flush with the side wall of the container.

[0149] The control module 13 calculates the amount of sample to be added based on the height and liquid level information of the container to ensure that the liquid level after adding the sample is flush with the side wall of the container. This requires the control module 13 to have accurate calculation capabilities and real-time adjustment capabilities to dynamically adjust the amount and position of sample addition.

[0150] By controlling the amount and position of the sample added, the liquid level is kept flush with the side wall of the container after the sample is added, which can effectively reduce the fluctuation and unevenness of the liquid level. This step ensures that the liquid level in the container remains stable during subsequent operations.

[0151] The design of the liquid surface after adding the sample is flush with the side wall of the container, which significantly improves the flatness and consistency of the liquid surface. This helps to reduce liquid level fluctuations and ensure the stability and accuracy of subsequent operations.

[0152] The flatness of the liquid surface can reduce the uneven distribution of samples in the container and avoid sample loss caused by the uneven liquid surface. Since the liquid surface is flush with the side wall of the container, the tip of the sample loading module can be more accurately positioned at the appropriate position of the liquid surface. This helps to reduce loading errors and improve the reliability and repeatability of loading. The design of the liquid surface being flush with the side wall of the container can ensure that the propagation path and intensity of the surface acoustic wave in the container are consistent, so that the enrichment effect of the biological sample is more uniform and efficient. This helps to improve the purity and quality of the enriched sample, which is suitable for high-precision biomedical research and clinical diagnosis.

[0153] At the same time, if Fig. 9 As shown, when the maximum volume of the biological sample carrying container is 100uL, the volume of the solution is controlled to be 50-100uL by the device. Fig. 9 The leftmost liquid surface can only be added at the center of the circle, so that the droplet does not touch the inner wall of the PDMS ring. After running for a period of time, due to the vibration of the liquid surface, the droplet contacts the inner wall of the ring, making the liquid surface more gentle, and the enrichment effect is better. The liquid surface situation is as follows Fig. 9 From left to right. By bringing the sample level to the same level as the ring, rapid enrichment can also be achieved.

[0154] Exemplarily, the expression of the sample addition position includes: z=h-0.5n·λ; wherein z is the sample addition position, n is the position of the wave node corresponding to the surface acoustic wave, the liquid level of the solution is h, and the wavelength of the surface acoustic wave is λ. The main purpose of selecting the wave node position n is to avoid the sample addition position being located at the antinode, thereby reducing the disturbance caused by vibration and ensuring that the sample can be quickly and evenly distributed below the liquid surface after the sample is added.

[0155] Exemplarily, the expression of the sample loading volume includes: V = (1-h / H)·k·Vmax; wherein V is the sample loading volume, H is the container height, the solution liquid level height is h, and the wavelength of the surface acoustic wave is λ. k is a dynamic adjustment factor. The value of k can be dynamically adjusted according to the properties of the biological sample (such as viscosity, density) to optimize the sample loading volume. The maximum volume of the biological sample holding container is Vmax. The value range of k is 0.1 to 0.3 to ensure that the liquid level will not approach the top of the container after loading, and there is also enough sample volume for enrichment. At the same time, if the sample loading volume is large, a multi-point loading strategy can be designed to divide the sample loading volume into multiple small portions and load the sample from different positions to ensure uniform distribution of the sample. During the loading process, the liquid level and the sample distribution in the container are monitored in real time by sensors, and the loading position and loading volume are dynamically adjusted to adapt to any unexpected situations.

[0156] In some embodiments, the control parameters include at least that the thickness of the piezoelectric substrate 11 is 0.1 to 10 mm; and / or, the material of the biological sample holding container 12 is polydimethylsiloxane, and the thickness of the side wall of the biological sample holding container 12 decreases upward along the piezoelectric substrate 11. The piezoelectric substrate 11 is generally made of piezoelectric materials such as quartz, lithium niobate (LN), and lithium tantalate (LT). These materials have high electromechanical coupling coefficients and good surface acoustic wave propagation performance. The material of the biological sample holding container 12 is polydimethylsiloxane (PDMS). The thickness of the side wall of the biological sample holding container 12 decreases upward along the piezoelectric substrate 11. Since PDMS has good biocompatibility, transparency and softness, it is suitable for the cultivation and enrichment of biological samples. The design of the side wall thickness of the biological sample holding container 12 decreasing upward along the piezoelectric substrate 11 can optimize the propagation of surface acoustic waves in the container, reduce energy loss, and improve enrichment efficiency. At the same time, the decrease can be a linear decrease or a decrease such as Figure 5 The nonlinear decrease shown is preferably adopted in this application.

[0157] In summary, the thickness of the piezoelectric substrate 11 and the design of the biological sample holding container 12 have a significant impact on the enrichment effect of the biological sample. Since the thickness of the piezoelectric substrate 11 ranges from 0.1 to 10 mm, the appropriate thickness can be selected according to the experimental requirements to optimize the propagation speed of the surface acoustic wave and improve the enrichment efficiency. The transparency and biocompatibility of the PDMS material, as well as the design of the biological sample holding container 12 with the side wall thickness decreasing upward along the piezoelectric substrate 11, can optimize the propagation of the surface acoustic wave in the container, reduce energy loss, and improve the enrichment efficiency. This design is particularly suitable for processing mixed samples containing multiple types of biological samples, and can achieve accurate enrichment of different biological samples at different frequencies and directions, thereby improving the reliability and repeatability of the experiment.

[0158] For example, Figure 5 As shown, the decrease of the biological sample holding container 111 is nonlinear. During the propagation of the surface acoustic wave, its energy distribution will be affected by the side wall of the container. The change in the thickness of the side wall will affect the propagation efficiency and path of the sound wave, thereby affecting the enrichment effect of the biological sample. From the bottom to the top, the thickness of the side wall of the container gradually decreases, but it is not a linear decrease, but decreases according to a specific nonlinear function. This design can optimize the propagation path of the sound wave so that the sound wave can be more evenly distributed at different heights in the container. The uniform distribution of the sound wave can reduce the fluctuation and unevenness of the liquid surface, thereby improving the consistency and flatness of the liquid surface. This is very important for the subsequent sample addition operation, which can ensure the accuracy of the sample addition position.

[0159] Due to the nonlinear decreasing design of the container side wall thickness, the propagation of sound waves on the liquid surface is more uniform, reducing the fluctuation of the liquid surface. This makes the liquid surface remain flatter and more consistent during the enrichment process, reducing the problem of sample loss and uneven enrichment caused by uneven liquid surface.

[0160] The uniform distribution of sound waves at different heights can better enrich specific biological samples and reduce the uneven distribution during the enrichment process. This improves the efficiency and purity of the enrichment, making the enriched samples more suitable for subsequent analysis and research. The flatness and consistency of the liquid surface allow the tips of the sample loading module to be more accurately positioned at the predetermined loading position. This helps to reduce loading errors and ensure that the amount and position of each loading meet the experimental requirements. Due to the improved flatness and consistency of the liquid surface, a larger throughput of samples can be processed without the problem of low loading efficiency caused by liquid surface fluctuations in traditional methods. It is suitable for processing high-throughput samples and improves the overall processing capacity of the laboratory. The nonlinear decreasing design of the side wall allows the device to better adapt to different types of biological samples and containers. Whether it is a small-volume microcentrifuge tube or a large-volume culture dish, the enrichment effect can be optimized by adjusting the decreasing function of the side wall thickness. Since the liquid surface remains flat and consistent, the overflow and mixing of samples in the container are reduced, thereby reducing the risk of cross contamination. Assume that a biological sample solution 112 containing specific cells needs to be enriched and transferred: select a container with a side wall thickness that decreases nonlinearly from the bottom to the top, put the diluted cell suspension into the container, and place it in the sample placement area of ​​the piezoelectric substrate 11. The control module 13 sends an electrical signal to the transducer module 12 to generate a surface acoustic wave. The surface acoustic wave propagates evenly in the container, so that the cells are enriched on one side or the bottom of the container. Monitor the height and liquid level information of the container: Through the laser ranging sensor and the pressure sensor, the control module 13 obtains the height and liquid level position information of the container. Based on the acquired information, the control module 13 calculates the volume of the enriched cell solution and determines the amount and position of the cell solution to be transferred. The control module 13 controls the liquid addition pipette of the sample addition module to move to the specified sample addition position, accurately absorbs the enriched cell solution, and transfers it to the target container. Through the design of the nonlinear decreasing side wall in the embodiment, the enrichment device 10 exhibits higher liquid level consistency and flatness when processing high-throughput biological samples, thereby significantly improving the efficiency and accuracy of enrichment and sample addition. This has important application value for modern biomedical research and clinical diagnosis.

[0161] The serial numbers of the embodiments of the present application are for description only and do not represent the advantages and disadvantages of the embodiments. The above are only specific implementation methods of the present application, but the protection scope of the present application is not limited thereto. Any technician familiar with the technical field can easily think of various equivalent modifications or replacements within the technical scope disclosed in the present application, and these modifications or replacements should be included in the protection scope of the present application. Therefore, the protection scope of the present application shall be based on the protection scope of the claims.

Claims

1. An enrichment device, characterized in that: include: A piezoelectric substrate, wherein the piezoelectric substrate is made of a piezoelectric material and comprises a sample placement area, wherein the sample placement area is used to store a biological sample holding container, wherein a biological sample solution to be enriched is placed in the biological sample holding container; A transducer module, wherein the transducer module is disposed on the piezoelectric substrate, wherein an angle between the transducer module and a vertical direction of a cut edge of the piezoelectric substrate forms a target angle, and is used for converting an electrical signal into a mechanical vibration to generate a surface acoustic wave; A control module is connected to the transducer module, and the control module adjusts the control parameters corresponding to the surface acoustic wave according to the target angle to adjust the vibration mode of the surface acoustic wave. The transducer propagates the surface acoustic wave to the biological sample holding container, and the biological sample in the biological sample solution is enriched in the biological sample holding container under the action of the surface acoustic wave.

2. The device according to claim 1, characterized in that The transducer module includes a plurality of transducer units, and the plurality of transducer units are disposed on the piezoelectric substrate and surround the biological sample holding container; The enrichment device also includes: A pressing module, wherein the pressing module is arranged on at least one of the transducer units, the transducer unit corresponding to the pressing module is a target transducer unit, and an angle between the target transducer unit and a vertical direction of the cut edge of the piezoelectric substrate is the target angle; The control parameter is used to control the target transducer unit to generate a surface acoustic wave, so that the target transducer unit propagates the surface acoustic wave toward the biological sample holding container.

3. The device according to claim 1, characterized in that The energy conversion module is processed on the piezoelectric substrate by sputtering, evaporation or 3D printing.

4. The device according to claim 1, characterized in that The control parameters include at least frequency and power. The frequency and power of the transducer module are determined according to the diameter, density, compression coefficient and target angle of the biological sample to be enriched in the biological sample solution.

5. The device according to claim 1, characterized in that The transducer comprises at least one interdigital transducer, and a ratio of a wavelength range of a surface acoustic wave emitted by the interdigital transducer to a finger width range of the interdigital transducer is within a preset ratio range.

6. The device according to claim 5, characterized in that The shape of each of the interdigital transducers on the piezoelectric substrate is a trapezoid; or, Each of the interdigital transducers on the piezoelectric substrate is in an arc shape.

7. The device according to claim 5, characterized in that The preset ratio range is 1 / 8 to 1 / 2; and / or, The wavelength of the surface acoustic wave is in the range of 10 to 500 μm.

8. The device according to claim 1, characterized in that The control parameter at least includes frequency, and the frequency corresponding to the frequency range is 5 MHz to 400 MHz.

9. The device according to claim 8, characterized in that If the wavelength of the surface acoustic wave is in the range of 180 to 220 μm, the frequency is negatively correlated with the wavelength.

10. The device according to claim 1, characterized in that The thickness of the piezoelectric substrate is 0.1 to 10 mm; and / or, The thickness of the side wall of the biological sample holding container decreases upward along the piezoelectric substrate.

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