WO2019169573A1 - 声表面波微流控芯片及微米尺寸的声焦域形成方法 - Google Patents

声表面波微流控芯片及微米尺寸的声焦域形成方法 Download PDF

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WO2019169573A1
WO2019169573A1 PCT/CN2018/078252 CN2018078252W WO2019169573A1 WO 2019169573 A1 WO2019169573 A1 WO 2019169573A1 CN 2018078252 W CN2018078252 W CN 2018078252W WO 2019169573 A1 WO2019169573 A1 WO 2019169573A1
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acoustic wave
fluid
surface acoustic
interdigital transducer
microfluidic
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PCT/CN2018/078252
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English (en)
French (fr)
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王晶晶
陈艳
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中国科学院深圳先进技术研究院
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Priority to PCT/CN2018/078252 priority Critical patent/WO2019169573A1/zh
Publication of WO2019169573A1 publication Critical patent/WO2019169573A1/zh

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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N29/00—Investigating or analysing materials by the use of ultrasonic, sonic or infrasonic waves; Visualisation of the interior of objects by transmitting ultrasonic or sonic waves through the object
    • G01N29/02—Analysing fluids

Definitions

  • the invention belongs to the technical field of microfluidics, and particularly relates to a surface acoustic wave microfluidic chip and a micrometer-sized acoustic focal length forming method.
  • Ultrasound can pass through thin bones and deep tissues, focusing to the area of the millimeter square, which is a very good source of stimulation for stimulating deep neuronal groups.
  • Harvey et al. first publicly and clearly described that ultrasonic stimulation of nerve fibers and muscle fibers produced a strange effect.
  • Fry et al. pointed out that ultrasound can be used to study the structure and function of the brain circuit.
  • the ultrasound stimulation effect should include both excitation and inhibition modes, and the regulation is reversible.
  • Tyler et al. demonstrated the regulation of ultrasound on the motor function area of mice by the mouse hippocampal slice test for the first time.
  • transcranial focused ultrasound directly acts on specific areas of the brain, enhancing the tactile function of the human hand.
  • This discovery proves for the first time that ultrasound can regulate human brain activity and improve awareness.
  • ultrasound may cause changes in cell membrane structure or conductivity through mechanical effects or intracavital cavitation effects; it may also rely on the electronic conductivity of microtubules in neurons.
  • Ultrasound-controlled neurological technology has become a hot research topic at home and abroad, and has recently broken through.
  • the research team of the applicant's unit, Zheng Hairong used low-frequency low-intensity transcranial ultrasound to stimulate the brain of mice, and induced the action response.
  • electrophysiological and calcium imaging techniques it was observed that glial cells produced electrical activity under the action of sound waves. And significantly increased calcium ion concentration fluorescence signal.
  • ultrasound has shown great potential to regulate neurological function in animals and humans.
  • the spatial resolution of the ultrasonic sound focal region is currently in the order of millimeters, which only stimulates the nucleus and is not sufficient to focus stimulation on a single neuron (micron diameter). This major challenge is also rarely reported in the literature. Spatial resolution is an important parameter of neuromodulation. In the above study of Legon using ultrasound to stimulate brain nerve enhancement of human hand haptic function, the spatial resolution of ultrasound is 4.9 mm ⁇ 18 mm. In this laboratory, when the researchers will use ultrasound beam When you moved a centimeter from the original position, the effect disappeared instantly. For model animal nematodes, paired neurons such as taste receptor neuron (ASE) also exhibit asymmetry in response to external NaCl stimulation. When ASEL is activated, nematodes show forward movement.
  • ASE taste receptor neuron
  • the object of the present invention is to overcome the above-mentioned deficiencies of the prior art, and to provide a surface acoustic wave microfluidic chip and a micrometer-sized acoustic focal length forming method, aiming at solving the spatial resolution of the existing ultrasonic acoustic focal region can only be millimeter.
  • An aspect of the present invention provides a surface acoustic wave microfluidic chip including a piezoelectric substrate and a first interdigital transducer, a second interdigital transducer, and the same surface disposed on the same surface of the piezoelectric substrate a microfluidic system for forming an acoustic focal region, the microfluidic system being disposed between the first interdigital transducer and the second interdigital transducer; the microfluidic system is provided with a closed Internal flow passage for holding the first fluid and the second fluid, the first interdigital transducer and the second interdigital transducer for transmitting surface acoustic waves, the first The fluid can conduct a surface acoustic wave, the second fluid does not conduct a surface acoustic wave, and the first fluid and the second fluid form a regular or irregular spacing in a microfluidic technique to produce an acoustic focal region.
  • Another aspect of the present invention provides a method for preparing the above surface acoustic wave microfluidic chip, comprising the following steps:
  • the microfluidic system is bonded to the surface of the piezoelectric substrate.
  • the invention finally provides a method for forming an acoustic focal length, comprising the following steps:
  • the surface acoustic wave microfluidic chip provided by the invention integrates the surface acoustic wave forming technology and the microfluidic technology, and the first interdigital transducer and the second interdigital transducer transmit the surface acoustic wave, and in the two In the internal flow channel in the microfluidic system, the first fluid and the piezoelectric substrate are controlled by controlling the spatial position of the first fluid that can conduct the surface acoustic wave and the second fluid that does not conduct the surface acoustic wave, and the arrangement and combination thereof.
  • the material achieves a locally selective contact in space, utilizing the great difference in acoustic impedance of the two acoustic propagation media, the large surface vibration of the bottom piezoelectric substrate material is transmitted through the conduction of the low first fluid and the non-conduction of the second fluid Clamped into a single acoustic region in the internal flow path, passing it through the top of the flow channel to the open upper surface, where a manually controlled patterned acoustic focal region is formed (two fluids: first The acoustic impedance of the fluid is small, which is good for conducting the bottom surface acoustic wave to the upper layer.
  • the second fluid has a large acoustic impedance, which is good for shielding the bottom surface acoustic wave as the peripheral boundary of the acoustic focal region.
  • the two fluids can be microfluidic. Handling a certain regular or irregular intervals, thereby simultaneously forming one or more acoustic power required field).
  • the acoustic focal region reaches the micron level, and its formation and movement technology relies on simple and mature microfluidic control technology. The adjustment mode is diversified and the control is convenient.
  • the acoustic focal length formed by the microfluidic technology can be various and can simultaneously Multiple acoustic focal zones are formed to achieve multi-focus control.
  • the method for forming an acoustic focal length is a method for forming and moving a micro-scale surface acoustic wave, and by adjusting the size of the first fluid and/or the second fluid in the surface acoustic wave microfluidic chip of the present invention, Including width, diameter, area, shape, to finely clamp the size of the acoustic focal length to the micron level, using microfluidic technology to guide one or more acoustic conduction regions to be quickly or accurately man- or programmatically addressed on a two-dimensional plane Moving, the resulting acoustic focal region can easily reach the order of a few microns that is difficult to achieve in a macroscopic system.
  • the invention realizes the movable micro-scale acoustic focal length forming technology for the first time, and has high reliability and
  • FIG. 1 is a cross-sectional view of a surface acoustic wave microfluidic chip according to an embodiment of the present invention
  • FIG. 2 is a schematic view showing the formation and movement of a sheath flow in a surface acoustic wave microfluidic chip according to an embodiment of the present invention; wherein a) is a schematic diagram of sheath flow formation; b) is a schematic diagram of sheath flow movement;
  • 1-piezoelectric substrate 2-first interdigital transducer; 3-second interdigital transducer; 4-surface acoustic wave; 5-microfluidic system; 6-internal flow channel; 61-first fluid 62-second fluid; 63-first flow channel; 64-second flow channel; 7-biological sample; 71-stimulated neuron; 72-unstimulated neuron.
  • first and second are used for descriptive purposes only and are not to be construed as indicating or implying a relative importance or implicitly indicating the number of technical features indicated.
  • features defining “first” and “second” may include one or more of the features either explicitly or implicitly.
  • the meaning of "a few” is two or more unless specifically and specifically defined otherwise.
  • an embodiment of the present invention provides a surface acoustic wave microfluidic chip, as shown in FIG. 1, comprising a piezoelectric substrate 1 and a first interdigital exchange on the same surface disposed on the piezoelectric substrate 1.
  • the second interdigital transducer 3 and the microfluidic system 5 for forming an acoustic focal region, the microfluidic system 5 being disposed at the first interdigital transducer 2 and the second Between the interdigital transducers 3; the microfluidic system 5 is provided with a closed internal flow passage 6 for containing a first fluid 61 and a second fluid 62, the first interdigitated finger
  • the transducer 2 and the second interdigital transducer 3 are for transmitting a surface acoustic wave, the first fluid 61 can conduct a surface acoustic wave, and the second fluid 62 does not conduct a surface acoustic wave, the first The fluid 61 and the second fluid 62 are formed at regular or irregular intervals by microfluidic techniques to create an acoustic focal region.
  • the surface acoustic wave microfluidic chip provided by the embodiment of the invention integrates the surface acoustic wave forming technology and the microfluidic technology, and the first interdigital transducer 2 and the second interdigital transducer 3 transmit the surface acoustic wave 4, In the internal flow channel 6 in the microfluidic system 5 between the two, the spatial position and arrangement of the first fluid 61 that can conduct the surface acoustic wave 4 and the second fluid 62 that does not conduct the surface acoustic wave are controlled.
  • the first fluid 61 and the piezoelectric substrate 1 material are spatially selectively contacted, and the large-area surface vibration of the bottom piezoelectric substrate 1 material is utilized by utilizing the great difference in acoustic impedance of the two acoustic propagation media.
  • the conduction of the first fluid 61 and the non-conduction of the second fluid 62 it is clamped in the inner flow channel 6 as a single acoustic wave region, which is conducted through the top of the flow channel to the open upper surface, on which the surface
  • the biological sample 7 (such as various biological tissues, cells, etc.) forms an artificially controlled patterned acoustic focal region, which can reach the micrometer level, thereby achieving the purpose of single cell stimulation.
  • the acoustic focal region formation and movement technology relies on simple and mature microfluidic control technology, and the adjustment mode is diversified, and the control is convenient.
  • the acoustic focal length formed by the microfluidic technology can be various, and multiple acoustic focal points can be simultaneously formed. Domain, multi-focus control; at the same time, the flexibility of the microfluidic system is also conducive to the future flexibility of the system, greatly expanding the ultrasound application space, such as wearable ultrasound control applications.
  • first fluid and the second fluid may be manipulated by microfluidic techniques such as sheath flow, multiple laminar flow, droplet array, etc. to form a regular or irregular interval, thereby simultaneously forming one or more required Sound focal length.
  • sheath flow a schematic diagram of the formation and movement of the sheath flow in the surface acoustic wave microfluidic chip shown in FIG. 2, the internal flow path 6 including the first flow path 63 for holding the first fluid 61 and In the second flow path 64 of the second fluid 62, the first flow path 63 and the second flow path 64 are perpendicular to each other and on the same plane.
  • the surface acoustic wave is conducted through the first fluid 61 and the second fluid 62 is not conducted, forming a sheath flow in the microfluidic system (Fig. 2a), and the biological sample on the surface of the microfluidic system as the sheath flow moves (Fig. 2b) A moving focal region is formed on the movement.
  • a bottom surface of the inner wall of the inner flow channel is the piezoelectric substrate or covers the piezoelectric substrate. That is, the inner wall of the inner flow channel directly has a piezoelectric substrate as a bottom surface, or an acoustic conductive material is further disposed between the bottom surface of the inner wall of the inner flow channel and the piezoelectric substrate.
  • the second flow channel has a width of 1 ⁇ m to 1 cm; and the second flow channel has a height of 1 ⁇ m to 1 cm.
  • the first fluid has an acoustic impedance value of 1-100 MRayl; and the second fluid has an acoustic impedance value of 1-100 MRayl.
  • the first fluid is a gas or a liquid; the second fluid is a gas or a liquid; such as air, water, a high viscosity fluid or a low viscosity fluid or the like.
  • the material of the piezoelectric substrate comprises at least one of lithium niobate, lithium niobate, quartz and gallium arsenide; the material cutting direction of the piezoelectric substrate is X, Y, Z, X-128° At least one of Y-128°, Z-128°, 100°, and 110°; the piezoelectric substrate has a thickness of 20-1000 ⁇ m; the piezoelectric substrate shown is a transparent substrate.
  • the electrode materials of the first interdigital transducer and the second interdigital transducer are each selected from at least one of gold, platinum, copper, and aluminum; the first interdigital transducer And the shape of the second interdigital transducer is any one of a square, a circle and an ellipse; the number of electrodes in the first interdigital transducer and the second interdigital transducer It can be 1-100, that is, the interdigital transducer and the second interdigital transducer are arranged by electrode strips or vertical strip fingers, and the arrangement mode is equal or unequal spacing.
  • the material of the microfluidic system comprises at least one of plastic, rubber and hydrogel, that is, a composite material thereof may be included.
  • the plastic includes at least one of polyethylene, polyimide, polymethyl methacrylate, polydimethylsiloxane, polycarbonate, parylene, and cyclic olefin copolymer;
  • the rubber includes There is at least one of silicone rubber, fluororubber, and polyurethane;
  • the hydrogel includes at least one of polyethylene glycol, chitosan, polylactic acid, sodium alginate, and agarose.
  • the microfluidic system is a transparent system; the microfluidic system is a single layer structure or a multi-layer structure; the microfluidic system has a material molecular weight of 100 to 10 million; The material has an acoustic impedance value of 1-100 MRayl; the microfluidic system has a thickness of 1 ⁇ m to 1 cm.
  • the embodiment of the invention further provides a method for preparing the surface acoustic wave microfluidic chip, which comprises the following steps:
  • E01 fabricating a first interdigital transducer and a second interdigital transducer on a surface of the piezoelectric substrate by using a photolithography, coating, and lift-off process;
  • E02 preparing a microfluidic system by using a photolithography, casting and demolding process
  • E03 bonding the microfluidic system to the surface of the piezoelectric substrate.
  • preparing a surface acoustic wave chip preparing an interdigital electrode on a piezoelectric substrate material, the preparation process comprising one or more of electron beam evaporation, magnetron sputtering, lift-off, soft lithography, through the above process Formed and bonded to the surface of the piezoelectric base material.
  • microfluidic chips ie, microfluidic systems
  • the formation of molds used in the preparation of materials required for microfluidic systems requires the use of UV-LIGA (Ultra Deep Electroforming), Lift-off (stripping), At least one of soft photolithography, wet etching, and then molding the microfluidic material by at least one of injection molding, hot stamping, and casting.
  • the microfluidic system and its preparation method may have different materials, thicknesses and acoustic impedance values of each layer. If the multilayer materials are to be combined together, it is necessary to first perform at least one of chemical micro-etching, thermal micro-melting, corona, and plasma bonding on the respective layers of materials.
  • the above microfluidic chip is designed on the upper surface of the piezoelectric substrate material, through at least one of chemical micro-etching, thermal micro-melting, corona, plasma bonding Combine the two or more alignment methods. After the combination of the two, the contact faces together form a closed square inner flow channel, the bottom of the inner flow channel is a piezoelectric base material, and the top and the sides are microfluidic system materials.
  • an embodiment of the present invention further provides a method for forming an acoustic focal region, including the following steps:
  • S02 preparing a biological sample to be tested, and placing the biological sample on a surface of the microfluidic system opposite to the piezoelectric substrate bonding surface;
  • S03 transmitting a surface acoustic wave by the first interdigital transducer and the second interdigital transducer, the surface acoustic wave is not conducted by the first fluid conduction and the second fluid, An independent acoustic wave region is formed within the microfluidic system and passed to the biological sample placed on the surface of the microfluidic system to form an acoustic focal region.
  • the method for forming an acoustic focal length is a method for forming and moving a micro-scale surface acoustic wave, and the first fluid and/or the second is adjusted in the surface acoustic wave microfluidic chip according to the embodiment of the present invention.
  • the size of the fluid including the width, diameter, area, shape, to fine-tune the size of the acoustic focal length to the micron level, and to guide one or more acoustic conduction areas on a two-dimensional plane by microfluidic technology, fast and precise man-made or program Singularly addressing the movement, the resulting acoustic focal region can easily reach the order of a few microns that is difficult to achieve in a macroscopic system.
  • the invention realizes the movable micro-scale acoustic focal length forming technology for the first time, and has high reliability and good repeatability, and greatly improves the precision of ultrasonic regulation.
  • one or more acoustic conduction regions may be guided by one or more of microfluidic technologies such as sheath flow, multiple laminar flow, and droplet manipulation.
  • microfluidic technologies such as sheath flow, multiple laminar flow, and droplet manipulation.
  • the surface acoustic wave has a wavelength of 100-200 ⁇ m; the distance between the internal flow channel and the biological sample does not exceed 200 ⁇ m; the acoustic focal region
  • the plane size is (1-1000 ⁇ m) ⁇ (1-1000 ⁇ m).
  • a surface acoustic wave microfluidic chip as shown in FIGS. 1 and 2, comprising a piezoelectric substrate 1 and a first interdigital transducer 2 and a second interdigital transducer 3 disposed on the piezoelectric substrate 1.
  • the piezoelectric substrate 1 is further provided with a microfluidic system 5 for forming an acoustic focal region, the microfluidic system 5 being between the first interdigital transducer 2 and the second interdigital transducer 3;
  • the control system 5 is provided with a closed internal flow passage 6, the bottom of which is a piezoelectric substrate 1, and the internal flow passage 6 includes a first flow passage 63 and a second flow passage 64 (see Fig.
  • the second flow path 64 is on the same horizontal plane and includes mutually perpendicular portions.
  • the first flow path 63 is provided with a first fluid 61 having a low acoustic impedance
  • the second flow path 64 is provided with a second fluid 62 having a high acoustic impedance. .
  • a method for forming an acoustic focal region includes the following steps:
  • the surface acoustic wave 4 is transmitted through the first interdigital transducer 2 and the second interdigital transducer 3, and the surface acoustic wave 4 is not conducted through the first fluid 61 and the second fluid 62, and is in the microfluidic system 5
  • An independent acoustic wave region is formed and transmitted to the biological sample 7 at the top of the microfluidic system 5 to form an acoustic focal region in which the -stimulated neuron 71 and the unstimulated neuron 72 are obtained, the acoustic focal region For the micron class.

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Abstract

一种声表面波微流控芯片及微米尺寸的声焦域形成方法。该声表面波微流控芯片，包括压电基底和设置在所述压电基底上的同一表面上的第一叉指换能器、第二叉指换能器和用于形成声焦域的微流控系统，所述微流控系统设置在所述第一叉指换能器和所述第二叉指换能器之间；所述微流控系统设有封闭的内部流道，所述内部流道用于盛装第一流体和第二流体，所述第一叉指换能器和所述第二叉指换能器用于发送声表面波，所述第一流体可传导声表面波，所述第二流体不传导声表面波，所述第一流体和所述第二流体以微流控技术形成规则或不规则的间隔，从而产生声焦域。该声表面波微流控芯片可形成和移动微米级的声焦域。

Description

声表面波微流控芯片及微米尺寸的声焦域形成方法 技术领域
本发明属于微流控技术领域，具体涉及一种声表面波微流控芯片及微米尺寸的声焦域形成方法。
 背景技术
超声波能穿过薄的骨和深层组织，聚焦到毫米见方的区域，是一种非常适合用于刺激深层神经元类群的刺激源。早在1929年，Harvey等人就首次公开清晰描述了超声刺激神经纤维与肌肉纤维产生了异样效果。1955年Fry等人研究指出超声可以用来研究大脑回路的结构和功能，超声刺激效应应该包括兴奋与抑制两种模式，且调控作用是可逆的。2008年，Tyler等人第一次通过小鼠脑海马切片实验证明了超声对小鼠脑运动功能区的调控作用。2014年，Legon等人发现将经颅聚焦超声波直接作用于脑部特定区域，能增强人手的触觉功能。这项发现第一次证明了超声波能调节人类脑活动、提高觉察能力。在超声产生调控效应的物理及生物机制的研究上，目前公认的是超声可能通过力学效应作用或膜内空化效应导致细胞膜结构或导电系数变化；也可能借助神经元内微管的电子导电性，实现对神经元调控。超声调控神经技术已成为当前国内外研究热点，近期突破不断。申请人所在单位的郑海荣研究员课题组使用低频低强度经颅超声刺激小鼠大脑，并诱发动作响应，并利用电生理及钙成像技术，观察到了神经胶质细胞在声波的作用下产生电活动，且显著提升的钙离子浓度荧光信号。由此可见，超声已表现出能够调控动物及人类神经功能的巨大潜力。
但是，超声声焦域空间分辨率目前为毫米级，只能够刺激神经核团，不足以聚焦刺激到单个神经元（微米级直径），这一大挑战也是此领域鲜见文献报导的原因。空间分辨率是神经调控的重要参数，在上述Legon使用超声刺激脑部神经增强人手触觉功能的研究中，超声的空间分辨率为4.9mm×18mm，在该实验室中，当研究人员将超声波束从原来位置移动了一厘米时，这种影响即刻消失了。对于模式动物线虫来说，成对的神经元如味觉神经元ASE（taste receptor neuron）在响应外界NaCl刺激上也会表现出不对称性，只激活ASEL时，线虫则表现向前运动，反之，激活紧邻其右的ASER则会表现转弯，由此可见空间分辨率的重要性。由于目前的超声刺激装置大多使用压电陶瓷换能器件，压电陶瓷产生的体声波频率低、能量发散，并且作用范围较大，不能够做到精确刺激。
近年来，随着超声调控神经功能的仪器开发及其应用在世界范围内广受关注，伴随着广大医生和患者对超声调控精准度提高的迫切需求，研制高分辨率声焦域技术势在必行。
 技术问题
本发明的目的在于克服现有技术的上述不足，提供一种声表面波微流控芯片及微米尺寸的声焦域形成方法，旨在解决现有超声声焦域空间分辨率只能为毫米级的技术问题。
 技术解决方案
为实现上述发明目的，本发明采用的技术方案如下：
本发明一方面提供一种声表面波微流控芯片，包括压电基底和设置在所述压电基底上的同一表面上的第一叉指换能器、第二叉指换能器和用于形成声焦域的微流控系统，所述微流控系统设置在所述第一叉指换能器和所述第二叉指换能器之间；所述微流控系统设有封闭的内部流道，所述内部流道用于盛装第一流体和第二流体，所述第一叉指换能器和所述第二叉指换能器用于发送声表面波，所述第一流体可传导声表面波，所述第二流体不传导声表面波，所述第一流体和所述第二流体以微流控技术形成规则或不规则的间隔，从而产生声焦域。
本发明另一方面提供一种上述声表面波微流控芯片的制备方法，包括如下步骤：
利用光刻、镀膜和剥离工艺在压电基底表面制作第一叉指换能器和第二叉指换能器；
利用光刻、浇铸和脱模工艺制备微流控系统；
将所述微流控系统键合在所述压电基底表面。
本发明最后提供一种声焦域形成方法，包括如下步骤：
提供本发明的上述声表面波微流控芯片；
制备待测生物样品，将所述生物样品置于所述微流控系统的与所述压电基底结合面相对的表面上；
通过所述第一叉指换能器和所述第二叉指换能器传送声表面波，所述声表面波通过所述第一流体传导和所述第二流体不传导，在所述微流控系统内形成独立声波区域并传至置于所述微流控系统表面的所述生物样品上，形成声焦域。
 有益效果
本发明提供的声表面波微流控芯片集声表面波形成技术和微流控技术于一体，第一叉指换能器和第二叉指换能器发送声表面波，而在两者之间的微流控系统中的内部流道内，通过控制可传导声表面波的第一流体和不传导声表面波的第二流体的空间位置及其排列、组合，使第一流体与压电基底材料在空间上达到局部选择性的接触，利用这两种声传播介质声阻抗的巨大差异性，将底部压电基底材料的大面积表面振动通过低第一流体的传导和第二流体的不传导，在内部流道里钳制为一个个单独的声波区域，穿过流道顶部将其传导至开放的上表面，在该平面上形成可人为控制的图案化声焦域（两种流体即：第一流体声阻抗小，有利于将底部声表面波传导至上层，第二流体声阻抗大，有利于屏蔽底部声表面波，作为声焦域外围边界。两种流体可以以微流控技术操控形成一定规则或不规则的间隔，从而同时形成需要的一个或多个声焦域）。该声焦域达到微米级，其形成及移动技术依赖于简单、成熟的微流体控制技术，调节方式多样化，操控便利，借助微流控技术形成的声焦域可以多种多样，并可以同时形成多个声焦域，做到多焦点调控；同时，微流控体系的柔性化，也利于该系统未来实现柔性化，极大拓展了超声应用空间，如可穿戴式超声调控应用等。本发明提供的声焦域形成方法，是一种形成和移动微米级声表面波的方法，通过在本发明声表面波微流控芯片中，调节第一流体和/或第二流体的尺寸，包括宽度、直径、面积、形状，以精细钳制声焦域的尺寸至微米级，通过微流控技术引导一个、多个声传导区域在二维平面上快速、精准的人为或程序性地寻址移动，该形成的声焦域可以轻易达到宏观体系难以实现的数个微米的量级。本发明首次实现了可移动的微米级声焦域形成技术，而且可靠性高、重复性好，极大提高了超声调控的精准度。
 附图说明
为了更清楚地说明本发明实施例中的技术方案，下面将对实施例或现有技术描述中所需要使用的附图作简单地介绍，显而易见地，下面描述中的附图仅仅是本实用新型的一些实施例，对于本领域普通技术人员来讲，在不付出创造性劳动性的前提下，还可以根据这些附图获得其他的附图。
图1为本发明实施例的声表面波微流控芯片的剖视图；
图2为本发明实施例的声表面波微流控芯片中鞘流形成和移动示意图；其中，a）为鞘流形成示意图；b）为鞘流移动示意图；
其中，图中各附图标记：
1-压电基底；2-第一叉指换能器；3-第二叉指换能器；4-声表面波；5-微流控系统；6-内部流道；61-第一流体；62-第二流体；63-第一流道；64-第二流道；7-生物样品；71-刺激的神经元；72-未刺激的神经元。
 本发明的实施方式
为了使本发明要解决的技术问题、技术方案及有益效果更加清楚明白，以下结合实施例，对本发明进行进一步详细说明。应当理解，此处所描述的具体实施例仅仅用以解释本发明，并不用于限定本发明。
需要说明的是，当元件被称为“固定于”或“设置于”另一个元件，它可以直接在另一个元件上或者间接在该另一个元件上。当一个元件被称为是“连接于”另一个元件，它可以是直接连接到另一个元件或间接连接至该另一个元件上。
需要理解的是，术语“长度”、“宽度”、“上”、“下”、“前”、“后”、“左”、“右”、“竖直”、“水平”、“顶”、“底”“内”、“外”等指示的方位或位置关系为基于附图所示的方位或位置关系，仅是为了便于描述本发明和简化描述，而不是指示或暗示所指的装置或元件必须具有特定的方位、以特定的方位构造和操作，因此不能理解为对本发明的限制。
此外，术语“第一”、“第二”仅用于描述目的，而不能理解为指示或暗示相对重要性或者隐含指明所指示的技术特征的数量。由此，限定有“第一”、“第二”的特征可以明示或者隐含地包括一个或者更多个该特征。在本发明的描述中，“若干”的含义是两个或两个以上，除非另有明确具体的限定。
一方面，本发明实施例提供了一种声表面波微流控芯片，如图1所示，包括压电基底1和设置在所述压电基底1上的同一表面上的第一叉指换能器2、第二叉指换能器3和用于形成声焦域的微流控系统5，所述微流控系统5设置在所述第一叉指换能器2和所述第二叉指换能器3之间；所述微流控系统5设有封闭的内部流道6，所述内部流道6用于盛装第一流体61和第二流体62，所述第一叉指换能器2和所述第二叉指换能器3用于发送声表面波，所述第一流体61可传导声表面波，所述第二流体62不传导声表面波，所述第一流体61和所述第二流体62以微流控技术形成规则或不规则的间隔，从而产生声焦域。
本发明实施例提供的声表面波微流控芯片集声表面波形成技术和微流控技术于一体，第一叉指换能器2和第二叉指换能器3发送声表面波4，而在两者之间的微流控系统5中的内部流道6内，通过控制可传导声表面波4的第一流体61和不传导声表面波的第二流体62的空间位置及其排列、组合，使第一流体61与压电基底1材料在空间上达到局部选择性的接触，利用这两种声传播介质声阻抗的巨大差异性，将底部压电基底1材料的大面积表面振动通过第一流体61的传导和第二流体62的不传导，在内部流道6里钳制为一个个单独的声波区域，穿过流道顶部将其传导至开放的上表面，在该平面上的生物样品7（如各种生物组织、细胞等）中形成可人为控制的图案化声焦域，该声焦域可达微米级，从而达到单细胞刺激的目的。该声焦域形成及移动技术依赖于简单、成熟的微流体控制技术，调节方式多样化，操控便利，借助微流控技术形成的声焦域可以多种多样，并可以同时形成多个声焦域，做到多焦点调控；同时，微流控体系的柔性化，也利于该系统未来实现柔性化，极大拓展了超声应用空间，如可穿戴式超声调控应用等。
进一步地，所述第一流体和第二流体可以以微流控技术如鞘流、多路层流、液滴阵列等操控形成一定规则或不规则的间隔，从而同时形成需要的一个或多个声焦域。以鞘流为例，如图2所示的声表面波微流控芯片中鞘流形成和移动示意图，所述内部流道6包括用于盛装所述第一流体61的第一流道63和用于盛装所述第二流体62的第二流道64，所述第一流道63和所述第二流道64相互垂直、且处在同一平面上。声表面波通过第一流体61传导和第二流体62不传导，在微流控系统内形成鞘流（图2a），随着鞘流移动（图2b）可在微流控系统表面的生物样品上形成移动的声焦域。
进一步地，所述内部流道的内壁的底面为所述压电基底，或覆盖于所述压电基底之上。即所述内部流道的内壁直接以压电基底为底面，或所述内部流道的内壁底面与压电基底之间还设置有声传导材料。
进一步地，所述第二流道的宽度为1μm-1cm；所述第二流道的高度为1μm-1cm。
进一步地，所述第一流体的声阻抗值为1-100MRayl；所述第二流体的声阻抗值为1-100MRayl。更进一步地，所述第一流体为气体或液体；所述第二流体为气体或液体；如空气，水，高粘度流体或低粘度流体等。
进一步地，所述压电基底的材料包括铌酸锂、钽酸锂、石英和砷化镓中的至少一种；所述压电基底的材料切割方向为X、Y、Z、X-128°、Y-128°、Z-128°、100°和110°中的至少一种；所述压电基底的厚度为20-1000μm；所示述压电基底为透明基底。
进一步地，所述第一叉指换能器和所述第二叉指换能器的电极材料均选自金、铂、铜和铝中的至少一种；所述第一叉指换能器和所述第二叉指换能器的形状为方形、圆形和椭圆形中的任意一种；所述第一叉指换能器中和所述第二叉指换能器的电极个数可以为1-100个，即通过电极横条或竖条状叉指排列形成叉指换能器和第二叉指换能器，排列模式为等或不等间距。
进一步地，所述微流控系统的材料包括塑料、橡胶和水凝胶中的至少一种，即可以包括其复合材料。所述塑料包括聚乙烯、聚酰亚胺、聚甲基丙烯酸甲酯、聚二甲基硅氧烷、聚碳酸酯、聚对二甲苯和环烯烃共聚物中的至少一种；所述橡胶包括有硅橡胶、氟橡胶和聚氨酯中的至少一种；所述水凝胶包括聚乙二醇、壳聚糖、聚乳酸、海藻酸钠和琼脂糖中的至少一种。
进一步地，所述微流控系统为透明系统；所述微流控系统为单层结构或多层结构；所述微流控系统的材料分子量为100-1000万；所述微流控系统的材料的声阻抗值为1-100MRayl；所述微流控系统的厚度为1μm-1cm。
本发明实施例还提供一种上述声表面波微流控芯片的制备方法，包括如下步骤：
E01：利用光刻、镀膜和剥离工艺在压电基底表面制作第一叉指换能器和第二叉指换能器；
E02：利用光刻、浇铸和脱模工艺制备微流控系统；
E03：将所述微流控系统键合在所述压电基底表面。
进一步地，上述声表面波微流控芯片的制备方法的具体步骤如下：
1）制备声表面波芯片：在压电基底材料上制备叉指电极，制备工艺包括电子束蒸镀、磁控溅射、lift-off、软光刻中的一种或几种，通过上述工艺形成并结合在所述压电基底材料的表面。
2）制备微流控芯片（即微流控系统）：制备微流控系统所需的材料中使用的模具的形成，需要使用UV-LIGA（紫外深电铸）、Lift-off（剥离）、soft photolithography（软光刻）、湿法刻蚀中的至少一种，然后通过注塑、热压印、浇铸中的至少一种使微流控材料成型。所述微流控系统及其制备方法，每层的材料、厚度及其声阻抗值都可以是不同的。如需将所述的多层材料组合在一起，需要先对各层材料进行化学微腐蚀、热微融、电晕、等离子键合中的至少一种。
3）声表面波芯片和微流控芯片键合：将上述微流控芯片设计到压电基底材料的上表面，通过化学微腐蚀、热微融、电晕、等离子键合中的至少一种将两者以上下对准方式结合在一起。两者结合后，接触面共同形成封闭的方形的内部流道，内部流道底部为压电基底材料，顶部和两侧为微流控系统材料。
另一方面，本发明实施例还提供一种声焦域形成方法，包括如下步骤：
S01：提供本发明的上述声表面波微流控芯片；
S02：制备待测生物样品，将所述生物样品置于所述微流控系统的与所述压电基底结合面相对的表面上；
S03：通过所述第一叉指换能器和所述第二叉指换能器传送声表面波，所述声表面波通过所述第一流体传导和所述第二流体不传导，在所述微流控系统内形成独立声波区域并传至置于所述微流控系统表面的所述生物样品上，形成声焦域。
本发明实施例提供的声焦域形成方法，是一种形成和移动微米级声表面波的方法，通过在本发明实施例声表面波微流控芯片中，调节第一流体和/或第二流体的尺寸，包括宽度、直径、面积、形状，以精细钳制声焦域的尺寸至微米级，通过微流控技术引导一个、多个声传导区域在二维平面上快速、精准的人为或程序性地寻址移动，该形成的声焦域可以轻易达到宏观体系难以实现的数个微米的量级。本发明首次实现了可移动的微米级声焦域形成技术，而且可靠性高、重复性好，极大提高了超声调控的精准度。
具体地，本发明实施例的声焦域形成方法中，可通过鞘流、多路层流、液滴操控等微流控技术中的一种或多种，引导一个、多个声传导区域在二维平面上快速、精准的人为或程序性地寻址移动；其中，鞘流技术的形成和移动示意图如图2所示。
进一步地，本发明实施例的声焦域形成方法中，所述声表面波的波长为100-200μm；所述内部流道到所述生物样品之间的距离不超过200μm；所述声焦域的平面尺寸为（1-1000μm）×（1-1000μm）。
本发明先后进行过多次试验，现举一部分试验结果作为参考对发明进行进一步详细描述，下面结合具体实施例进行详细说明。
实施例1
一种声表面波微流控芯片，如图1和图2所示，包括压电基底1和设置在压电基底1上的第一叉指换能器2和第二叉指换能器3，压电基底1上还设置有用于形成声焦域的微流控系统5，该微流控系统5在第一叉指换能器2和第二叉指换能器3之间；微流控系统5设有封闭的内部流道6，内部流道6的底部为压电基底1，且内部流道6包括第一流道63和第二流道64（见图2），第一流道63和第二流道64在同一水平面上、且含有相互垂直的部分，第一流道63内设有低声阻抗的第一流体61，第二流道64内设有高声阻抗的第二流体62。
实施例2
一种声焦域形成方法，如图1和图2所示，包括如下步骤：
S11：提供本发明实施例1的上述声表面波微流控芯片；
S12：制备待测生物样品7，将生物样品7置于声表面波微流控芯片上的微流控系统5顶端、并与第二流体62重叠；
S13：通过第一叉指换能器2和第二叉指换能器3传送声表面波4，声表面波4通过第一流体61和第二流体62不传导，在微流控系统5内形成独立声波区域并传至微流控系统5顶端的生物样品7上，形成声焦域，该生物样品7中即可得到-刺激的神经元71和未刺激的神经元72，该声焦域为微米级。
以上所述仅为本发明的较佳实施例而已，并不用以限制本发明，凡在本发明的精神和原则之内所作的任何修改、等同替换和改进等，均应包含在本发明的保护范围之内。

Claims (15)

  1. 一种声表面波微流控芯片，其特征在于，包括压电基底和设置在所述压电基底上的同一表面上的第一叉指换能器、第二叉指换能器和用于形成声焦域的微流控系统，所述微流控系统设置在所述第一叉指换能器和所述第二叉指换能器之间；
    所述微流控系统设有封闭的内部流道，所述内部流道用于盛装第一流体和第二流体，所述第一叉指换能器和所述第二叉指换能器用于发送声表面波，所述第一流体可传导声表面波，所述第二流体不传导声表面波，所述第一流体和所述第二流体以微流控技术形成规则或不规则的间隔，从而产生声焦域。
  2. 如权利要求1所述的声表面波微流控芯片，其特征在于，所述内部流道包括用于盛装所述第一流体的第一流道和用于盛装所述第二流体的第二流道，所述第一流道和所述第二流道相互垂直、且处在同一平面上。
  3. 如权利要求1所述的声表面波微流控芯片，其特征在于，所述内部流道的内壁的底面为所述压电基底，或所述内部流道的内壁的底面覆盖于所述压电基底之上。
  4. 如权利要求2所述的声表面波微流控芯片，其特征在于，所述第二流道的宽度为1μm-1cm；和/或
    所述第二流道的高度为1μm-1cm。
  5. 如权利要求1所述的声表面波微流控芯片，其特征在于，所述第一流体的声阻抗值为1-100MRayl；和/或
    所述第二流体的声阻抗值为1-100MRayl。
  6. 如权利要求1所述的声表面波微流控芯片，其特征在于，所述压电基底的材料切割方向为X、Y、Z、X-128°、Y-128°、Z-128°、100°和110°中的至少一种；和/或
    所述压电基底的厚度为20-1000μm；和/或
    所述压电基底为透明基底。
  7. 如权利要求1所述的声表面波微流控芯片，其特征在于，所述第一叉指换能器和所述第二叉指换能器的形状为方形、圆形和椭圆形中的任意一种；和/或
    所述第一叉指换能器中和所述第二叉指换能器的电极个数为1-10个。
  8. 如权利要求1所述的声表面波微流控芯片，其特征在于，所述微流控系统的材料包括塑料、橡胶和水凝胶中的至少一种；其中，
    所述塑料包括聚乙烯、聚酰亚胺、聚甲基丙烯酸甲酯、聚二甲基硅氧烷、聚碳酸酯、聚对二甲苯和环烯烃共聚物中的至少一种；和/或
    所述橡胶包括有硅橡胶、氟橡胶和聚氨酯中的至少一种；和/或
    所述水凝胶包括聚乙二醇、壳聚糖、聚乳酸、海藻酸钠和琼脂糖中的至少一种。
  9. 如权利要求1所述的声表面波微流控芯片，其特征在于，所述微流控系统为透明系统；和/或
    所述微流控系统为单层结构或多层结构；和/或
    所述微流控系统的材料分子量为100万-1000万Da；和/或
    所述微流控系统的材料的声阻抗值为1-100MRayl；和/或
    所述微流控系统的厚度为1μm-1cm。
  10. 如权利要求1所述的声表面波微流控芯片，其特征在于，所述第一流体为气体或液体；和/或
    所述第二流体为气体或液体。
  11. 如权利要求1-10任一项所述的声表面波微流控芯片的制备方法，其特征在于，包括如下步骤：
    利用光刻、镀膜和剥离工艺在压电基底表面制作第一叉指换能器和第二叉指换能器；
    利用光刻、浇铸和脱模工艺制备微流控系统；
    将所述微流控系统键合在所述压电基底表面。
  12. 一种声焦域形成方法，其特征在于，包括如下步骤：
    提供权利要求1-10任一项所述的声表面波微流控芯片；
    制备待测生物样品，将所述生物样品置于所述微流控系统的与所述压电基底结合面相对的表面上；
    通过所述第一叉指换能器和所述第二叉指换能器传送声表面波，所述声表面波通过所述第一流体传导和所述第二流体不传导，在所述微流控系统内形成独立声波区域并传至置于所述微流控系统表面的所述生物样品上，形成声焦域。
  13. 如权利要求12所述的声焦域形成方法，其特征在于，所述微流控系统可通过鞘流、多路层流和液滴中的至少一种，形成所述独立声波区域。
  14. 如权利要求12所述的声焦域形成方法，其特征在于，所述声表面波的波长为100-200μm；和/或
    所述内部流道到所述生物样品之间的距离不超过100μm。
  15. 如权利要求12所述的声焦域形成方法，其特征在于，所述声焦域的平面尺寸为（1-1000μm）×（1-1000μm）。
PCT/CN2018/078252 2018-03-07 2018-03-07 声表面波微流控芯片及微米尺寸的声焦域形成方法 WO2019169573A1 (zh)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101301990A (zh) * 2008-01-17 2008-11-12 上海交通大学 用于芯片实验室的声表面波微流体驱动器及其制造方法
US20150325775A1 (en) * 2014-05-12 2015-11-12 Taiyo Yuden Co., Ltd. Acoustic wave device and method for manufacturing the same

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101301990A (zh) * 2008-01-17 2008-11-12 上海交通大学 用于芯片实验室的声表面波微流体驱动器及其制造方法
US20150325775A1 (en) * 2014-05-12 2015-11-12 Taiyo Yuden Co., Ltd. Acoustic wave device and method for manufacturing the same

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