WO2021227093A1

WO2021227093A1 - Non-contact ultrasonic pipetting device and method

Info

Publication number: WO2021227093A1
Application number: PCT/CN2020/091026
Authority: WO
Inventors: 邱维宝; 梁素姿; 张志强; 苏敏; 郑海荣
Original assignee: 中国科学院深圳先进技术研究院
Priority date: 2020-05-09
Filing date: 2020-05-19
Publication date: 2021-11-18
Also published as: CN111495455A

Abstract

A non-contact ultrasonic pipetting device and method. The device comprises an ultrasonic transduction unit (2), a source liquid carrying platform (4), and a target liquid carrying platform (5). The ultrasonic transduction unit (2) can generate a focused sound field under the action of an ultrasonic excitation system (1), and liquid drops can be accurately and quickly transferred from the source liquid carrying platform (4) to the target liquid carrying platform (5) without using gun head consumables. By controlling the relative position of the ultrasonic transduction unit (2) and the source liquid carrying platform (4) and the working state and parameters of the ultrasonic excitation system (1), the acting point of the focused sound field can be accurately positioned to the pipetting liquid level, and the volume of liquid drops in single pipetting is accurately adjusted. The picoliter-scale pipetting precision can be realized by using a high-frequency focused ultrasonic transducer, and the pipetting precision can be further randomly adjusted from the picoliter scale to the microliter scale by using the large-size focused ultrasonic transducer. By means of an ultrasonic coupling unit (3) between the ultrasonic transduction unit (2) and the source liquid carrying platform (4), energy can be spread to the maximum extent, and heat dissipation is achieved.

Description

Non-contact ultrasonic pipetting device and method

Technical field

The invention relates to the field of synthetic biology experiments, in particular to a non-contact ultrasonic pipetting device and method.

Background technique

In today's world, people are facing increasingly severe challenges such as diseases, environment, and energy. Synthetic biology is hailed as one of the world's three disruptive technologies to meet the challenges. The research goal of synthetic biology is to adopt the concept of engineering to design, transform and even re-synthesize organisms to create artificial life forms with non-natural functions.

At present, in the process of synthetic biology experiments, life verification experiments will be carried out based on a large number of biological experiments. Therefore, a large number of micropipetting operations are required for the preparation and processing of experiments. Pipetting is one of the most common operational tasks in synthetic biology laboratories. . Choosing the right pipette is a critical step in completing the experiment accurately.

At present, the most widely used method in the industry is to use a pipette to operate. It is a general biological and chemical laboratory equipment that can form a partial vacuum in the container above the liquid surface and absorb or discharge the liquid by selectively adjusting the vacuum volume. . Different types of pipettes can be designed to achieve different accuracy and precision. The types of pipettes range from simple pipettes made of a piece of glass to complex adjustable or electronically controlled pipettes. However, the accuracy of the measurement varies depending on the type. And the difference is huge. At the same time, because the pipette gun is a contact pipetting method, the sample sticks to the pipette tip during the pipetting process, resulting in an inaccurate amount of liquid transferred, which is prone to false negative results. In addition, because the pipette tip is a disposable consumable, in order to avoid cross-infection, special handling or replacement is required after each use, so a large number of consumables are required to support the experiment, which is expensive when used on a large scale.

Although the existing electromagnetic control-based non-contact pipetting technology can achieve non-contact pipetting between the pipette needle and the target reaction well, the pipetting liquid is still in contact with the pipette needle, which limits the type of liquid to be piped. Make the practical application of this technology limited. Therefore, non-contact micropipetting technology is a particularly important key technology in the field of biology.

Summary of the invention

In view of the shortcomings of the prior art, the present invention provides a non-contact ultrasonic pipetting device and method, which adopts a focused sound field to achieve non-contact pipetting, which avoids the expensive experimental costs and inconvenient pipetting caused by the use of pipette tip consumables. The problem of accuracy is that there is no need to contact the pipetting liquid and the type of the pipetting liquid can be not limited, thereby expanding the application range of the pipetting method.

In order to achieve the above objectives, the present invention adopts the following technical solutions:

A non-contact ultrasonic pipetting device includes an ultrasonic pipetting module, the ultrasonic pipetting module includes an ultrasonic transducer unit, a source liquid carrier platform, and a target liquid carrier platform; the ultrasonic transducer unit is used to move toward the source The liquid-carrying platform emits ultrasonic waves to generate a focused sound field, and moves relative to the source liquid-carrying platform to change the distance from the liquid level of the source liquid-carrying platform, and when the ultrasonic echo amplitude reaches a specific value, the target volume The droplets of are transferred from the source liquid carrier platform to the target liquid carrier platform.

As one of the embodiments, the non-contact ultrasonic pipetting device further includes a moving module and a control module, the moving module is used to adjust the relative position of the ultrasonic transducer unit and the source liquid carrier platform; The control module is used to change the distance between the ultrasonic transducer unit and the liquid level of the source liquid platform according to the amplitude of the ultrasonic echo signal when the ultrasonic transducer unit is directly opposite to the source liquid carrier platform. When the echo amplitude reaches a specific value, the ultrasonic signal parameters of the ultrasonic waves emitted by the ultrasonic transducer unit are adjusted to adjust the volume of a single pipetting drop to the target volume.

As one of the embodiments, the ultrasonic transducer unit is an electronic phased array focusing transducer, and the control module further adjusts the parameters of the electronic phased array focusing transducer to enable the electronic phased array focusing transducer The focused beam synthesized by the energy device quickly moves on the source liquid-carrying platform to adjust the position of the focused focus on the liquid surface.

As one of the embodiments, the ultrasonic transducer unit is a large-size high-frequency focused ultrasonic transducer. Here, “large size” means that the diameter of the ultrasonic transducer unit is greater than or equal to 5 mm, and “high-frequency” means It means that the frequency of the ultrasonic transducer unit is greater than 1 MHz, the pipetting accuracy of the ultrasonic pipetting device is as high as the skin upgrade, and the pipetting accuracy can be adjusted arbitrarily within the range from the skin upgrade to the micro upgrade.

As one of the embodiments, the ultrasonic transducer unit is composed of one or more ultrasonic transducers, and/or, the working frequency of the ultrasonic transducer unit is one or more.

As one of the implementation manners, the ultrasonic transducer unit is a single element transducer, a linear array transducer, an area array transducer or a ring array transducer; and/or, the ultrasonic transducer unit includes When there are multiple sub-transducers, the arrangement shape of the sub-transducers is polygonal, circular or elliptical.

As one of the embodiments, the ultrasonic pipetting module further includes an ultrasonic coupling unit for transmitting ultrasonic energy. The ultrasonic coupling unit includes a housing and an acoustic wave couplant, and the acoustic wave couplant is filled in the housing and the The space enclosed by the ultrasonic transducer unit is used to contact the source liquid carrier platform.

As one of the embodiments, the housing includes an inner cylinder and an outer cylinder. The top end of the inner cylinder body closes the top end of the inner cylinder body; the inner cylinder body is arranged in the outer cylinder body and can move closer to or away from the outer cylinder body selectively In the source liquid-carrying platform, the acoustic wave coupling agent is filled between the outer cylinder and the top end of the inner cylinder.

As one of the embodiments, the ultrasonic coupling unit further includes a peristaltic pump and a cooling cavity communicating with the top end of the outer cylinder, the acoustic wave couplant is also filled in the cooling cavity, and the peristaltic pump drives the cooling cavity. The acoustic wave couplant circulates in the top end of the outer cylinder and the cooling cavity.

Another object of the present invention is to provide a non-contact ultrasonic pipetting method, including:

Ranging modes, including:

The ultrasonic transducer unit emits ultrasonic waves toward the source liquid-carrying platform to generate a focused sound field;

Change the distance between the ultrasonic transducer unit and the liquid level of the source carrier liquid platform according to the amplitude of the ultrasonic echo signal until the ultrasonic echo amplitude reaches a specific value;

Pipetting modes, including:

When the ultrasonic echo amplitude reaches a specific value, adjust the parameters of the ultrasonic excitation waveform to adjust the volume of the pipetting drop;

Increase the power of the ultrasonic transducer unit to transfer the droplets from the source liquid carrier platform to the target liquid carrier platform.

The non-contact ultrasonic pipetting device of the present invention can realize the liquid movement without contact by adopting the ultrasonic transducer unit. The ultrasonic transducer unit changes the distance from the liquid level of the source carrier liquid platform according to the amplitude of the ultrasonic echo signal, and When the ultrasonic echo amplitude reaches a specific value, a focused sound field is generated, and the liquid droplets can be accurately and quickly transferred from the source carrier liquid platform to the target liquid carrier platform without the use of pipette head consumables to produce the target volume of liquid. The liquid addition method is not only direct and accurate And the repeatability is excellent.

In addition, by controlling the relative position of the ultrasonic transducer unit and the source liquid-carrying platform and the working state and parameters of the ultrasonic excitation system, the action point of the focused sound field can be accurately positioned to the pipetting surface, and the single pipetting can be precisely adjusted Drop the volume to the target volume. By using a high-frequency focused ultrasound transducer, the pipetting accuracy can be upgraded. On this basis, by adopting a large-size focused ultrasound transducer, the pipetting accuracy can be further upgraded from the skin to the micro-upgrade range. Adjustable; with the help of the ultrasonic coupling unit between the ultrasonic transducer unit and the source liquid-carrying platform, the maximum spread of energy and heat dissipation can be achieved.

Description of the drawings

Fig. 1 is a structural block diagram of a non-contact ultrasonic pipetting device according to an embodiment of the present invention;

2 is a block diagram of a non-contact ultrasonic pipetting method according to an embodiment of the present invention;

3 is a schematic diagram of the working flow of the non-contact ultrasonic pipetting device according to the embodiment of the present invention;

4 is a schematic diagram of the principle of liquid transfer of the ultrasonic transducer unit according to the embodiment of the present invention;

5 is a schematic diagram of a laminated structure of an ultrasonic transducer unit according to an embodiment of the present invention;

6 is a schematic diagram of a part of the structure of a non-contact ultrasonic pipetting device according to an embodiment of the present invention;

The label description in the figure is as follows:

1-ultrasonic excitation system; 100-ultrasonic pipetting module; 2-ultrasonic transducer unit; 21-backing; 22-piezoelectric layer; 23-matching layer; 3-ultrasonic coupling unit; 31-space; 32-cooling cavity ; 4-source liquid-carrying platform; 5-target liquid-carrying platform; 6-mobile module; 61-loading liquid mobile module; 62-transducer mobile module; 7-control module; 9-inner cylinder; 10-outer cylinder Body; 11-seal ring.

Detailed ways

In order to make the objectives, technical solutions, and advantages of the present invention clearer, the following further describes the present invention in detail with reference to the accompanying drawings and embodiments. It should be understood that the specific embodiments described here are only used to explain the present invention, but not used to limit the present invention.

1, an embodiment of the present invention provides a non-contact ultrasonic pipetting device, which mainly includes an ultrasonic pipetting module 100. The ultrasonic pipetting module 100 may specifically include an ultrasonic excitation system 1, an ultrasonic transducer unit 2, and an ultrasonic coupling unit. 3 and the source liquid carrier platform 4 and the target liquid carrier platform 5 arranged above the ultrasonic transducer unit 2 from bottom to top. The ultrasonic excitation system 1 is connected to the ultrasonic transducer unit 2, which can be used to drive the ultrasonic transducer unit 2 to generate ultrasonic waves. The sound field is focused to realize the effect of ultrasonic radiation force on the liquid transfer surface at a predetermined position on the source liquid carrier platform 4, the source liquid carrier platform 4 and the target liquid carrier platform 5 are arranged directly opposite, and the source liquid carrier platform 4 has a liquid transfer surface Under the action of the focused sound field, the droplets can be transferred from the source liquid carrier platform 4 to a specific position on the target liquid carrier platform 5 without contact. Both the source liquid carrier platform 4 and the target liquid carrier platform 5 can have a multi-well plate structure, and both have holes in an array. Under the action of ultrasonic radiation force, it can be transferred to the target liquid-carrying platform 5 to realize pipetting.

Among them, the ultrasonic excitation system 1 includes an ultrasonic signal generator and a power amplifier. The control module 7 can arbitrarily adjust the ultrasonic signal parameters of the ultrasonic excitation system 1 (including ultrasonic frequency, ultrasonic energy, ultrasonic pulse length, ultrasonic pulse repetition frequency, etc.). The signal parameters correspond to the ultrasonic signal parameters of the ultrasonic waves emitted by the ultrasonic transducer unit 2. By adjusting the ultrasonic signal parameters of the ultrasonic waves, the droplet volume of a single pipetting can be adjusted, thereby realizing high-precision pipetting. The ultrasonic coupling unit 3 is configured to be arranged between the ultrasonic transducer unit 2 and the source liquid carrier platform 4 to ensure that the ultrasonic energy emitted by the ultrasonic transducer unit 2 is better transmitted to the source liquid carrier platform 4.

It is understandable that, in other embodiments, the ultrasonic excitation system 1 may not be included in the ultrasonic pipetting device, but a separate structure, which can be assembled into the ultrasonic pipetting device when needed to exchange energy with the ultrasonic pipetting device. Unit 2 is connected.

In addition to the ultrasonic pipetting module 100, the non-contact ultrasonic pipetting device can also include a moving module 6 and a control module 7. The control module 7 serves as the control center of the entire pipetting device and can control the ultrasonic excitation system 1, the ultrasonic transducer unit 2. , The working status and parameter modulation of the source liquid carrier platform 4, the target liquid carrier platform 5, and the mobile module 6, etc., can realize fully automatic control.

Wherein, the mobile module 6 can be relatively fixed to at least one of the ultrasonic transducer unit 2 and the source liquid carrier platform 4. By adjusting the relative position of the ultrasonic transducer unit 2 and the source liquid carrier platform 4, the focused sound field of the ultrasonic transducer unit 2 The action point of is positioned to the liquid transfer surface of the predetermined position of the source liquid carrier platform 4, so as to facilitate the next liquid transfer action.

As shown in FIGS. 2 to 4, the working modes of the non-contact ultrasonic pipetting device of this embodiment include the distance measurement mode S01 and the pipetting mode S02. In the distance measurement mode S01, the power of the ultrasonic transducer unit 2 is lower. The droplet will not be ejected, only the focus of the focused sound field on the liquid surface is achieved; in the pipetting mode S02, the power of the ultrasonic transducer unit 2 can be increased by adjusting the parameters of the ultrasonic excitation system 1 through the control module 7 to remove the droplet from The liquid level is shot out.

The following will specifically describe the non-contact ultrasonic pipetting method of this embodiment:

Initially, the positions of the ultrasonic transducer unit 2 and the source liquid-carrying platform 4 in the horizontal direction and the vertical direction are not aligned.

First, as shown in step a in Figure 3, the control module 7 controls the movement module 6 to work and adjusts the distance between the ultrasonic transducer unit 2 and the source liquid carrier platform 4 so that they are close to each other. Finally, the ultrasonic transducer unit 2 moves to the source. The liquid carrying platform 4 is directly below the specific pipetting liquid surface.

Subsequently, as shown in step b in Figure 3, in the ranging mode S01, the control module 7 controls the operation of the ultrasonic transducer unit 2 to position the longitudinal distance between the ultrasonic transducer unit 2 and the pipetting liquid surface, and the mobile module 6 can be measured according to The ultrasonic transducer unit 2 is moved longitudinally (for example, the source liquid-carrying platform 4 can also be moved). When the ultrasonic echo amplitude reaches a certain value, it means that the focal point of the ultrasonic transducer unit 2 is located at a predetermined position. Of the pipetting liquid surface. Here, "specific value" means a specific value, and does not necessarily refer to the absolute maximum value of the echo amplitude. In the actual process, the specific value can be adjusted according to the actual situation, that is, the "specific value" can be an absolute value. The maximum value may also be a value close to the absolute maximum value, for example, 80% of the absolute maximum value. Specifically, in the ranging mode S01, the ultrasonic transducer unit 2 emits ultrasonic waves toward the upper source liquid-carrying platform 4, and receives the ultrasonic echo in real time, and the control module 7 adjusts the distance between the ultrasonic transducer unit 2 and the source liquid-carrying platform 4 When the ultrasonic echo amplitude reaches the specific value, it is judged that the action point of the focused sound field has been positioned on the pipetting liquid surface at the predetermined position. In this way, the work corresponding to the ranging mode S01 is completed, and the liquid droplet can be switched to the pipetting mode S02 at any time. As shown in Figure 4, it is a schematic diagram of the state of pipetting after the focused sound field is positioned to the pipetting liquid surface.

Next, the control module 7 switches the working state of the pipetting device to the pipetting mode S02 by increasing the power of the ultrasonic transducer unit 2, as shown in step c in Figure 3, the control module 7 first adjusts the ultrasonic excitation system 1 The parameter of the signal adjusts the volume of the droplet in a single pipetting to the target volume. Then, the droplet is ejected from the source carrier platform 4 under the action of the focused sound field (step d in Figure 3). Through this series of steps, In turn, a high-precision pipetting process can be ensured.

Here, the adjustment process of the volume of a single pipetting droplet can be specifically realized by adjusting the parameters of the excitation waveform of the ultrasonic excitation system 1, such as the voltage amplitude, the number of cycles, and the number of cycles.

Since this embodiment adopts the ultrasonic transducer unit 2 as the core pipetting part of the ultrasonic pipetting module 100, in the actual pipetting process, only the ultrasonic transducer unit 2 needs to be moved to a predetermined position of the source liquid carrier platform 4 to achieve alignment. After that, the ultrasonic pipetting module 100 can be used to generate a focused sound field to realize a non-contact pipetting process. Samples can be added from a source position of the source liquid carrier platform 4 to a target of the target liquid carrier platform 5 without using pipette tip consumables. The position not only reduces the replacement of consumables, reduces the cost, but also avoids the sample sticking to the pipette tip, and realizes the precise pipetting process. In addition, since this embodiment first aligns the ultrasonic transducer unit with the source carrier liquid platform, and then adjusts the focus of the ultrasonic transducer unit to the pipetting liquid surface, the volume of a single pipette droplet can be adjusted as needed before liquid injection. , So that the final pipetting accuracy is guaranteed.

This embodiment shows a situation where the mobile module 6 is fixed to the ultrasonic transducer unit 2 and the source liquid-carrying platform 4 at the same time, and can move both horizontally and vertically independently. Specifically, the mobile module 6 includes a loading liquid moving module 61 and a transducer moving module 62. The loading liquid moving module 61 can drive the target liquid carrier platform 5 and the source liquid carrier platform 4 to move and transport within the pipetting device. The transducer The moving module 62 can drive the ultrasonic transducer unit 2 to move at any position in the pipetting device, and the moving accuracy of the moving module 6 is controlled within 1 μm. Under the control of the control module 7, the moving module 6 can work to adjust the relative position of the ultrasonic transducer unit 2 and the source carrier liquid platform 4 accordingly. For example, only the ultrasonic transducer unit 2 can be moved, or only the source carrier liquid can be moved. The platform 4, or move the ultrasonic transducer unit 2 and the source liquid carrier platform 4 at the same time, so that the ultrasonic transducer unit 2 and the source liquid carrier platform 4 are close to and away from each other as required.

It is understandable that in other embodiments, the mobile module 6 may also include only one of the loading liquid moving module 61 and the transducer moving module 62, which can also perform similar adjustments to the ultrasonic transducer unit and the source liquid carrier platform. There is no restriction on the effect of relative position.

In order to better ensure the accuracy of pipetting, the ultrasonic transducer unit 2 of the non-contact ultrasonic pipetting device of this embodiment is a large-size high-frequency focused ultrasonic transducer. Here, "large size" refers to the ultrasonic transducer unit 2 The diameter of is greater than or equal to 5mm, "high frequency" means that the frequency of the ultrasonic transducer unit 2 is greater than 1MHZ. Further, the frequency range of the ultrasonic transducer unit 2 can be 1MHz to 1GHz, and the bandwidth is above 50%. This large-size, high-frequency focused ultrasonic transducer not only has a smaller focus size, but also has a larger focus size. The output acoustic radiation force. Among them, the high-frequency characteristics of the ultrasonic transducer ensure that the pipetting accuracy can reach the highest level. The high-bandwidth characteristics of the ultrasonic transducer can also ensure that the transducer has a relatively high frequency in a larger frequency range. High output acoustic radiation power, while satisfying both of these requirements, realizes the arbitrarily adjustable pipetting accuracy from skin upgrade to micro upgrade within a larger range. By precisely controlling the ultrasonic acoustic parameters, the pipetting device can modulately control the sound wave energy in a larger range, and intelligently select the size of each sample droplet according to the user's experimental needs.

It should be noted that the ultrasound transducer unit 2 can work with one focused ultrasound transducer, or multiple focused ultrasound transducers can work together; it can work at a single frequency, or it can work at multiple frequencies. According to the focusing method of the ultrasonic transducer, the ultrasonic transducer is a physical focusing transducer or an electronic phased array focusing transducer. The focusing method of the physical focusing transducer is acoustic lens focusing, self-focusing and other focusing modes such as acoustic Ultra-structure focusing and other ultrasonic transducers with different focusing methods. When the electronic phased array focusing transducer is selected as the ultrasonic transducer, the electronic phased array focusing method can be used for focusing and transducing the electronic phased array through the control module 7. The adjustment of the parameters of the electronic phased array focus transducer enables the focused beam synthesized by the electronic phased array focus transducer to quickly move on the source carrier liquid platform without moving or rotating the ultrasonic transducer unit to adjust the position of the focus focus on the liquid surface. Accurate and rapid focus positioning, but also better to achieve automatic control. According to the type of ultrasonic transducer, the ultrasonic transducer unit 2 includes but is not limited to piezoelectric ultrasonic transducer, capacitive micromachined ultrasonic transducer (cMUT), piezoelectric micromachined ultrasonic transducer (pMUT) and other types Ultrasonic transducer.

The ultrasonic transducer unit 2 can be a single element transducer, a linear array transducer, an area array transducer or a ring array transducer. When the ultrasonic transducer unit 2 includes multiple sub-transducers, the sub-transducers The arrangement shape of the energy devices can be square, round, ellipse, etc., but is not limited to this.

As shown in Fig. 5, shown is a schematic structural diagram of a piezoelectric ultrasonic transducer. The ultrasonic transducer unit 2 mainly includes a backing 21, a piezoelectric layer 22, and a matching layer 23. The outer surface of the matching layer 23 may also be provided with a protective layer (not shown). The piezoelectric layer 22 and the matching layer 23 are in order from bottom to top. Set above the backing 21. The matching layer 23 may include a one-layer or multi-layer structure.

The ultrasonic coupling unit 3 includes a housing (not shown in the figure) and an acoustic wave couplant (not shown in the figure). As shown in FIG. 1 and FIG. The agent is filled in the space 31. When the ultrasonic coupling unit 3 is moved to a proper position under the source liquid carrier platform 4, the housing contacts the source liquid carrier platform 4, and the acoustic wave couplant in the space 31 is filled between the ultrasonic transducer unit 2 and the source liquid carrier platform 4. As the ultrasonic coupling medium between the ultrasonic transducer unit 2 and the source liquid-carrying platform 4, it can reduce the attenuation of the sound wave energy in the propagation process. At the same time, the sound wave couplant also acts as a heat dissipation medium, opposing the ultrasonic transducer placed in the space 31 Unit 2 dissipates heat, and it serves multiple purposes. The acoustic coupling agent can be water, oil, and similar flowable ultrasonic coupling agents.

As shown in FIG. 6, the housing may specifically include an inner cylinder body 9 and an outer cylinder body 10. The top ends of the inner cylinder body 9 and the outer cylinder body 10 are directly opposite to the source liquid carrier platform 4 above, and the ultrasonic transducer unit 2 is fixed inside The top end of the cylinder 9 closes the top end of the inner cylinder 9. The top end surface of the outer cylinder 10 is in contact with the source liquid-carrying platform 4, and the inner cylinder 9 is arranged in the outer cylinder 10 and can move closer to or away from the source liquid-carrying platform with respect to the axial movement of the outer cylinder 10 4. The inner cylinder body 9, the ultrasonic transducer unit 2, and the outer cylinder body 10 enclose a space 31 that can contain the acoustic coupling agent. When the ultrasonic transducer unit 2 is close to the source liquid carrier platform 4, the outer cylinder body 10 contacts the source When the liquid-carrying platform 4 is used, the acoustic wave coupling agent is filled between the ultrasonic transducer unit 2 and the source liquid-carrying platform 4.

Here, the inner cylinder body 9 and the outer cylinder body 10 are combined in a threaded manner. Specifically, the outer circumferential surface of the inner cylinder body 9 is provided with an outer thread, and the inner circumferential surface of the outer cylinder body 10 is provided with an inner thread. During the rotation of 9 relative to the outer cylinder 10, the inner cylinder 9 moves along the axial direction of the outer cylinder 10, so that the ultrasonic transducer unit can be accurately adjusted in the direction away from or away from the source liquid carrier platform 4 according to actual requirements. 2The distance from the liquid surface, so as to easily locate the action point of the focused sound field to the liquid surface.

Specifically, a through hole may be opened at the top of the inner cylinder 9, and the ultrasonic transducer unit 2 is inserted into the through hole from below and the through hole is closed. The through hole may be a stepped hole with a large inside and a small outside. 2 abuts against the inner surface of the stepped hole of the through hole.

In order to ensure the sealing effect of the acoustic coupling agent between the inner cylinder 9 and the outer cylinder 10, the ultrasonic coupling unit 3 further includes a sealing ring 11, which is sleeved on the outer peripheral surface of the inner cylinder 9 and is elastically compressed on Between the inner cylinder 9 and the outer cylinder 10. Wherein, the outer circumferential surface of the inner cylinder 9 is provided with a recessed annular groove, and the sealing ring 11 is elastically compressed in the annular groove by the outer cylinder 10 to prevent the sealing ring 11 from falling out. It can be understood that this embodiment does not limit the number of the sealing ring 11, and the number of the sealing ring 11 can be more.

As shown in Figure 6, the ultrasonic coupling unit 3 also includes a peristaltic pump (not shown) and a cooling cavity 32 connected to the space 31. The acoustic coupling agent is filled in the cooling cavity 32 in addition to the space 31, and the peristaltic pump drives The acoustic wave couplant circulates in the space 31 and the cooling cavity 32. The cooling cavity 32 is connected to both ends of the space 31 at the same time. Under the action of the peristaltic pump, the sonic couplant flowing out of the space 31 flows into the cooling cavity 32 from an interface at one end, and flows through the cooling cavity 32 to radiate heat from the other end of the space 31. In this way, the circulating flow of the heat dissipation medium is realized. The heat dissipation speed can be controlled by controlling the flow rate of the heat dissipation medium by the peristaltic pump. The acoustic wave couplant takes away the heat generated during the working process of the ultrasonic transducer unit 2, and then flows in again after being dissipated by the cooling cavity 32. Quickly circulate heat.

The space 31 is formed at the top of the inner cylinder 9 and the outer cylinder 10. The interface between the cooling cavity 32 and the space 31 may be located on the wall of the outer cylinder 10 near the top, and the end of the ultrasonic transducer unit 2 protrudes inside. Outside the end surface of the cylinder 9, the acoustic coupling agent flowing through the two opposite sides of the top end of the outer cylinder 10 can take away the heat generated during the operation of the ultrasonic transducer unit 2 in time, and the heat dissipation effect is better.

When the mobile module 6 works so that the ultrasonic transducer unit 2 and the source liquid carrier platform 4 are close to each other, the ultrasonic transducer unit 2 directly faces the pipetting liquid surface of the source liquid carrier platform 4 above and focuses the sound field in the distance measurement mode. The point of action is positioned to the liquid transfer surface, and then, the control module 7 drives the ultrasonic transducer unit 2 to generate a focused sound field by adjusting the working state and parameters of the ultrasonic excitation system 1 The liquid carrier platform 4 is transferred to the target liquid carrier platform 5. During this process, the control module 7 controls the flow rate of the acoustic coupling agent circulating in the space 31 and the cooling cavity 32 by controlling the parameters of the peristaltic pump, thereby controlling the heat dissipation speed.

The non-contact ultrasonic pipetting device of the present invention can realize the liquid movement without contact by using the ultrasonic transducer unit, and change the distance from the liquid level of the source liquid carrier according to the amplitude of the ultrasonic echo signal, and the ultrasonic echo amplitude When a specific value is reached, a focused sound field is generated, and the droplets can be accurately and quickly transferred from the source carrier liquid platform to the target carrier liquid platform without the use of pipette head consumables to produce the target volume of liquid. The liquid addition method is not only direct, accurate and repeatable Excellent. In addition, by controlling the relative position of the ultrasonic transducer unit and the source liquid-carrying platform and the working state and parameters of the ultrasonic excitation system, the present invention can accurately locate the action point of the focused sound field to the liquid transfer surface, and precisely adjust the single transfer The volume of the droplet. By using a high-frequency focused ultrasound transducer, the pipetting accuracy can be upgraded. On this basis, by adopting a large-size focused ultrasound transducer, the pipetting accuracy can be further upgraded from the skin to the micro-upgrade range. Adjustable; with the help of the ultrasonic coupling unit between the ultrasonic transducer unit and the source liquid-carrying platform, the maximum spread of energy and heat dissipation can be achieved.

The above are only specific implementations of this application. It should be pointed out that for those of ordinary skill in the art, without departing from the principles of this application, several improvements and modifications can be made, and these improvements and modifications are also Should be regarded as the scope of protection of this application.

Claims

A non-contact ultrasonic pipetting device, which includes an ultrasonic pipetting module, the ultrasonic pipetting module includes an ultrasonic excitation system, an ultrasonic transducer unit, a source liquid carrier platform, and a target liquid carrier platform; the ultrasonic transducer unit Used to emit ultrasonic waves toward the source liquid-carrying platform under the drive of the ultrasonic excitation system to generate a focused sound field, and move relative to the source liquid-carrying platform to change the distance from the liquid level of the source liquid-carrying platform , And when the ultrasonic echo amplitude reaches a specific value, the droplet of the target volume is transferred from the source liquid carrier platform to the target liquid carrier platform.
The non-contact ultrasonic pipetting device according to claim 1, further comprising a moving module and a control module, the moving module is used to adjust the relative position of the ultrasonic transducer unit and the source liquid carrier platform, so The control module is used to change the distance between the ultrasonic transducer unit and the liquid level of the source liquid carrier platform according to the amplitude of the ultrasonic echo signal when the ultrasonic transducer unit is directly opposite to the source liquid carrier platform. When the ultrasonic echo amplitude reaches a specific value, the ultrasonic signal parameters of the ultrasonic excitation system are adjusted to adjust the volume of a single pipetting drop to the target volume.
The non-contact ultrasonic pipetting device according to claim 2, wherein the ultrasonic transducer unit is an electronic phased array focusing transducer, and the control module further adjusts the electronic phased array focusing transducer The parameters make the focused beam synthesized by the electronic phased array focus transducer move quickly on the source liquid carrier platform to adjust the position of the focus focus on the liquid surface.
The non-contact ultrasonic pipetting device according to claim 2, wherein the ultrasonic transducer unit is a large-size high-frequency focused ultrasonic transducer, the diameter of the ultrasonic transducer unit is greater than or equal to 5 mm, and the ultrasonic transducer The frequency of the transducer unit is greater than 1MHZ; the pipetting accuracy of the ultrasonic pipetting device is as high as the skin upgrade, and the pipetting accuracy can be adjusted arbitrarily from the skin upgrade to the micro upgrade range.
The non-contact ultrasonic pipetting device according to claim 2, wherein the ultrasonic transducer unit is composed of one or more ultrasonic transducers, and/or, the working frequency of the ultrasonic transducer unit is one Or multiple.
The non-contact ultrasonic pipetting device according to claim 2, wherein the ultrasonic transducer unit is a single-element transducer, a linear-array transducer, an area-array transducer, or a ring-array transducer; and /Or, when the ultrasonic transducer unit includes a plurality of sub-transducers, the arrangement shape of the sub-transducers is polygon, circle or ellipse.
The non-contact ultrasonic pipetting device according to claim 2, wherein the ultrasonic pipetting module further comprises an ultrasonic coupling unit for transmitting ultrasonic energy, and the ultrasonic coupling unit includes a housing and an acoustic wave couplant, and the acoustic wave The couplant is filled in the space enclosed by the housing and the ultrasonic transducer unit for contact with the source liquid carrier platform.
The non-contact ultrasonic pipetting device according to claim 7, wherein the housing comprises an inner cylinder and an outer cylinder, and the top ends of the inner cylinder and the outer cylinder are facing the source liquid carrying platform , The ultrasonic transducer unit is fixed on the top end of the inner cylinder to close the top end of the inner cylinder; the inner cylinder is arranged in the outer cylinder and can be opposite to the axis of the outer cylinder Moving toward and selectively approaching or away from the source liquid-carrying platform, the acoustic wave coupling agent is filled between the top end of the outer cylinder and the inner cylinder.
The non-contact ultrasonic pipetting device according to claim 7, wherein the ultrasonic coupling unit further comprises a peristaltic pump and a cooling cavity communicating with the top end of the outer cylinder, and the acoustic wave couplant is also filled in the In the cooling cavity, the peristaltic pump drives the sonic coupling agent to circulate in the top end of the outer cylinder and the cooling cavity.
The non-contact ultrasonic pipetting device according to claim 3, wherein the ultrasonic pipetting module further comprises an ultrasonic coupling unit for transmitting ultrasonic energy, and the ultrasonic coupling unit includes a housing and an acoustic wave couplant, and the acoustic wave The couplant is filled in the space enclosed by the housing and the ultrasonic transducer unit for contact with the source liquid carrier platform.
The non-contact ultrasonic pipetting device according to claim 10, wherein the housing includes an inner cylinder and an outer cylinder, and the top ends of the inner cylinder and the outer cylinder are facing the source liquid carrying platform , The ultrasonic transducer unit is fixed on the top end of the inner cylinder to close the top end of the inner cylinder; the inner cylinder is arranged in the outer cylinder and can be opposite to the axis of the outer cylinder Moving toward and selectively approaching or away from the source liquid-carrying platform, the acoustic wave coupling agent is filled between the top end of the outer cylinder and the inner cylinder.
The non-contact ultrasonic pipetting device according to claim 10, wherein the ultrasonic coupling unit further comprises a peristaltic pump and a cooling cavity communicating with the top end of the outer cylinder, and the acoustic wave couplant is also filled in the In the cooling cavity, the peristaltic pump drives the sonic coupling agent to circulate in the top end of the outer cylinder and the cooling cavity.
The non-contact ultrasonic pipetting device according to claim 4, wherein the ultrasonic pipetting module further comprises an ultrasonic coupling unit for transmitting ultrasonic energy, and the ultrasonic coupling unit includes a housing and an acoustic wave couplant, and the acoustic wave The couplant is filled in the space enclosed by the housing and the ultrasonic transducer unit for contact with the source liquid carrier platform.
The non-contact ultrasonic pipetting device according to claim 13, wherein the housing includes an inner cylinder and an outer cylinder, and the top ends of the inner cylinder and the outer cylinder are facing the source liquid carrying platform , The ultrasonic transducer unit is fixed on the top end of the inner cylinder to close the top end of the inner cylinder; the inner cylinder is arranged in the outer cylinder and can be opposite to the axis of the outer cylinder Moving toward and selectively approaching or away from the source liquid-carrying platform, the acoustic wave coupling agent is filled between the top end of the outer cylinder and the inner cylinder.
The non-contact ultrasonic pipetting device according to claim 13, wherein the ultrasonic coupling unit further comprises a peristaltic pump and a cooling cavity communicating with the top end of the outer cylinder, and the acoustic wave couplant is also filled in the In the cooling cavity, the peristaltic pump drives the sonic coupling agent to circulate in the top end of the outer cylinder and the cooling cavity.
The non-contact ultrasonic pipetting device according to claim 2, wherein the ultrasonic transducer unit is a piezoelectric ultrasonic transducer, and the piezoelectric ultrasonic transducer includes a backing, a piezoelectric layer, and a matching The matching layer includes a multilayer structure.
A non-contact ultrasonic pipetting method, which includes:

Ranging modes, including:

The ultrasonic transducer unit emits ultrasonic waves toward the source liquid-carrying platform to generate a focused sound field;

Change the distance between the ultrasonic transducer unit and the liquid level of the source carrier liquid platform according to the amplitude of the ultrasonic echo signal until the ultrasonic echo amplitude reaches a specific value;

Pipetting modes, including:

When the ultrasonic echo amplitude reaches a specific value, adjust the parameters of the ultrasonic excitation waveform to adjust the volume of the pipetting drop;

Increase the power of the ultrasonic transducer unit to transfer the droplets from the source liquid carrier platform to the target liquid carrier platform.
The non-contact ultrasonic pipetting method according to claim 17, wherein in the step of adjusting the parameters of the ultrasonic excitation waveform, the adjusted parameters include at least one of voltage amplitude, number of cycles, and number of cycles.
The non-contact ultrasonic pipetting method according to claim 17, wherein, before the distance measurement mode, the position of the ultrasonic transducer unit and the source liquid carrier platform in the horizontal direction are not aligned, and the non-contact ultrasonic pipetting The liquid method further includes: adjusting the distance between the ultrasonic transducer unit and the source liquid-carrying platform, so that the ultrasonic transducer unit is moved to a predetermined position of the source liquid-carrying platform directly below the pipetting liquid surface.
The non-contact ultrasonic pipetting method according to claim 17, further comprising: driving the acoustic wave couplant to circulate in the space enclosed by the housing and the ultrasonic transducer unit and the cooling cavity connected to both ends of the space.