WO2021037256A1 - 用于微流控芯片的液囊 - Google Patents

用于微流控芯片的液囊 Download PDF

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WO2021037256A1
WO2021037256A1 PCT/CN2020/112361 CN2020112361W WO2021037256A1 WO 2021037256 A1 WO2021037256 A1 WO 2021037256A1 CN 2020112361 W CN2020112361 W CN 2020112361W WO 2021037256 A1 WO2021037256 A1 WO 2021037256A1
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liquid
sac
piercing structure
membrane
microfluidic chip
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PCT/CN2020/112361
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English (en)
French (fr)
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张屹
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烟台芥子生物技术有限公司
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Publication of WO2021037256A1 publication Critical patent/WO2021037256A1/zh

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    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
    • B01L3/502—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
    • B01L3/5027—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip

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  • the invention relates to a liquid sac for a microfluidic chip, in particular to a liquid sac which can control the release of liquid in the sac by centrifugal force.
  • Microfluidic technology has been widely used in biological, chemical, and medical analysis. It can concentrate sample preparation, separation, reaction, and detection operations on a micro-scale platform, that is, a microfluidic chip.
  • the microfluidic analysis system generally includes three parts: a microfluidic chip, detection reagents and matching detection instruments.
  • the design of the microfluidic chip requires the use of micromachining technology to summarize microfluidic channels, microreaction chambers and microvalve components to achieve sample pre-processing, sample distribution, sample quantification, sample and reaction reagent mixing and reaction, and reaction on the chip.
  • the function of result detection, etc. realizes the complete process from sample entry to report result.
  • High degree of integration, automation and miniaturization are the characteristics of microfluidic technology.
  • microfluidic manipulation technology which includes the directional flow, distribution, and flow rate control of the liquid in the channel of the microfluidic chip.
  • the liquid reagents such as buffers, detection reagents
  • the liquid reagents used in the early microfluidic chips were manually injected during sample analysis, which resulted in complicated operations and large experimental errors.
  • some methods for pre-storing and releasing liquid reagents in microfluidic chips have been developed.
  • CN103272657A discloses a liquid storage method for a microfluidic chip, which includes pre-encapsulating a liquid sac containing a liquid reagent in a cavity of the microfluidic chip, and uses external mechanical forces such as squeezing, knocking, and needle Stabbing, vibration, etc. cause partial or large-area damage to the liquid sac, thereby releasing the liquid reagent stored in the liquid sac.
  • CN104884169A and US2017/0173581A1 describe methods of using external pressure to squeeze microcapsules to destroy predetermined fractured parts of the microcapsules, thereby releasing stored liquid reagents.
  • CN108525714A describes a method of using a plunger to pressurize to rupture a storage bag (ie, a microcapsule) to allow the detection reagent to flow out.
  • CN108295912A describes a microfluidic chip reagent pre-encapsulation device and its opening method, which includes forming an outwardly extending tail when encapsulating a liquid sac, and using external force to release the tail from the sealing part when the reagent is expected to be released, resulting in The reagent flows out.
  • CN104399540A describes a microfluidic chip liquid reagent release method based on centrifugation, which seals the pouch body by adopting an easy-to-tear sealing method, fixes the fixed end of the pouch body on the cavity wall, and performs centrifugation. At the same time, the relative movement of the bag body and the cavity wall tears the seal to release the liquid.
  • This method attempts to use the centrifugal force generated by the pouch itself (including the liquid reagents) during centrifugation to tear the seal, but the liquid reagents used in the microfluidic chip are often microliters or nanoscales, which are produced during centrifugation. The centrifugal force is too small to tear the seal.
  • the present invention provides a liquid capsule for storing and releasing liquid in a microfluidic chip.
  • the liquid capsule includes a liquid capsule film forming a sealed space, a liquid in the sealed space, and a puncture The structure, wherein the piercing structure can pierce the membrane of the liquid sac driven by centrifugal force, causing the liquid to be released from the liquid sac.
  • the liquid sac is a capsule, cuboid, or ellipsoid.
  • the density of the piercing structure is greater than the density of the liquid.
  • the piercing structure is spherical, cylindrical, or a shape with pointed ends (e.g., triangular pyramid, conical).
  • the piercing structure is made of a magnetic material.
  • the sac membrane includes at least one breakable part that is easily destroyed by the piercing structure.
  • the piercing structure is fixed to the inner side of the sac membrane.
  • the piercing structure is fixed to the fragile portion.
  • the liquid bladder includes a protrusion at the distal end, and the shape of the piercing structure is adapted to be received in the protrusion and pierce the protrusion when centrifuged.
  • the volume of the liquid is 10 ⁇ L to 2000 ⁇ L.
  • the present invention also provides a microfluidic chip, which includes at least one cavity and a cavity outlet channel communicating with the cavity, the cavity includes the liquid sac, and the The piercing structure in the liquid sac pierces the liquid sac membrane of the liquid sac, allowing the liquid in the liquid sac to flow out through the cavity outlet channel.
  • the shape of the liquid bladder is suitable for being contained in the cavity without rolling freely.
  • a groove is provided under the cavity, so that the piercing structure in the liquid sac falls into the groove after piercing the liquid sac during centrifugation.
  • the bottom of the groove is provided with a groove outlet channel, and the liquid in the groove can flow into the cavity outlet channel through the groove outlet channel during centrifugation.
  • the sequential release is achieved by adjusting one or a combination of the following factors: the shape, density, mass, and combination of the piercing structure; the thickness of the vulnerable part of the sac membrane; The bonding strength of the easily breakable part of the sac membrane and the other parts of the sac membrane;
  • the liquid sac of the present invention is an independent structure and can be placed in any cavity of the microfluidic chip. Centrifugal force is used to drive the puncture structure to release the liquid. There is no need to physically weld the liquid sac and the microfluidic chip, and no additional machinery is required.
  • the structure applies mechanical force to destroy the sac structure, which is especially suitable for automated operation.
  • Fig. 1 is a schematic partial cross-sectional view of an embodiment of a microfluidic chip including a liquid capsule of the present invention.
  • Fig. 2 is a schematic partial cross-sectional view of another embodiment of a microfluidic chip including a liquid capsule of the present invention.
  • FIG. 3 is a schematic partial cross-sectional view of the microfluidic chip shown in FIG. 2 after the structure is pierced and the liquid sac is destroyed so that the liquid reagent flows out.
  • FIG. 4 is a schematic diagram showing the positional relationship of the microfluidic chip of the present invention when it is placed in a centrifuge equipped with a magnetic device for centrifugation.
  • the liquid sac provided herein uses the centrifugal force generated by the piercing structure in the liquid sac to destroy the sac membrane, thereby causing the liquid in the sac to be released.
  • liquid sac refers to a sealed container containing a liquid inside a cavity of a microfluidic chip.
  • the liquid sac may but need not be in the shape of a bladder.
  • it may be in the shape of a capsule, having an approximate cube, cuboid, sphere, cylinder, or ellipsoid shape, or an irregular shape.
  • liquid refers to liquid reagents commonly used in chemistry or medicine, such as pure water, buffers, detection solutions, and the like.
  • liquid membrane refers to the sealed container itself, which forms an internal space containing liquid.
  • the sac membrane is made of a flexible material.
  • the flexible materials used include, but are not limited to, various flexible plastic films, such as low-density polyethylene (LDPE), polypropylene (PP), polyvinyl chloride (PVC), polystyrene (PS), ABS plastic, and the like.
  • LDPE low-density polyethylene
  • PP polypropylene
  • PVC polyvinyl chloride
  • PS polystyrene
  • ABS plastic and the like.
  • the sac membrane can be a uniform material as a whole, and the puncture structure exerts pressure on a part of the flexible material during centrifugation, causing it to deform until it breaks.
  • the sac membrane may include a "fragile part".
  • the "fragile part” refers to the local sac membrane that is easily damaged by the puncture structure and releases internal liquid.
  • the "vulnerable part” may be one or more.
  • the end (distal end) of the liquid bag away from the centrifugal shaft during centrifugation may be set as a breakable part, or both the distal end and part of the side wall may be set as breakable parts.
  • the fragile part can be formed in a variety of ways, including using fragile materials, using a thinner sac membrane, or directly using the final sealing part of the sac after filling with liquid as the fragile part.
  • the vulnerable part can be combined with other parts of the sac membrane by bonding, welding, heat sealing, etc.
  • the sac membrane is mainly made of non-flexible materials.
  • the sac membrane can also be referred to as a "sac body".
  • the non-flexible materials used include, but are not limited to, high-density polyethylene (HDPE), polycarbonate (PC), glass, and metal foil (such as aluminum foil).
  • the sac membrane should include a breakable part for releasing liquid.
  • the breakable part is generally located at the distal end of the liquid sac, that is, the end away from the shaft during centrifugation.
  • the vulnerable part can be combined with other parts of the sac membrane by bonding, welding, heat sealing, etc.
  • the bonding strength with other parts itself can also be used to adjust the centrifugal speed or centrifugal force required to release the liquid.
  • piercing structure refers to a physical entity placed in a sac to destroy the integrity of the sac membrane.
  • the piercing structure applies the centrifugal force generated during centrifugation to the sac membrane, causing the sac membrane or the fragile part of the sac membrane to break, thereby releasing the stored liquid.
  • the piercing structure itself should not react with or contaminate the liquid reagents stored.
  • the piercing structure In order to pierce the sac membrane, the piercing structure should be able to generate sufficient pressure on the sac membrane or its vulnerable parts. This can be achieved in a number of ways. For example, one way is to increase the quality of the piercing structure. Due to the size of the liquid sac and its limited internal space, the piercing structure can be made of high-density materials, especially when the piercing structure is a sphere, the increase in mass will generate greater centrifugal force at the same centrifugal speed. It is also possible to provide a protruding pointed end on the piercing structure. For example, a puncture structure in the shape of a vertebral body with corners is used, or a hollow needle is used as the puncture structure.
  • piercing structures In practical applications, high-density physical entities with pointed ends can be used as piercing structures.
  • a piercing structure made of magnetic materials for example, Fe, Co, Ni elements and their alloys
  • the use of magnetic force is also conducive to placing the piercing structure near the distal end of the sac membrane before centrifugation, which facilitates the positioning and piercing of the distal end of the sac membrane.
  • the piercing structure should destroy the sac membrane during centrifugation, but not during the storage and transportation of the sac.
  • the piercing structure is a sphere, this purpose is easier to achieve.
  • the piercing structure has a pointed end, it can be considered to limit the piercing structure to a specific location in the sac, for example, in the protruding end of the sac.
  • the puncture structure can be fixed on the sac membrane or its easily broken part to prevent accidental movement of the puncture structure during transportation and puncture the sac membrane.
  • the puncture structure can also be fixed on the side wall of the liquid sac, and the sac membrane can be torn during centrifugation, which facilitates the destruction of the sac membrane and release of liquid.
  • the piercing structure can be made of a metal material with a higher density.
  • the piercing structure can be coated with an inert material to prevent it from reacting with liquid reagents.
  • the puncture structure may be covered with a liquid sac membrane material, which facilitates the fixation of the puncture structure on the inner wall of the liquid sac by means of welding, bonding, or the like.
  • distal refers to the part that is relatively far away from the centrifugal shaft when the microfluidic chip is placed on a centrifuge for centrifugation.
  • the liquid sac of the present invention can be placed in the cavity of the microfluidic chip.
  • the cavity has an outlet channel through which the liquid is released from the liquid capsule and enters other structures of the microfluidic chip to participate in the reaction. If necessary, the cavity can also have inlets or vents.
  • the sequential or sequential release of multiple liquid sacs can be conveniently realized in the microfluidic chip.
  • materials of different densities can be selected to make spheres of the same volume, and they can exert different pressures on the liquid sac membrane at the same rotation speed.
  • the centrifugal speed gradually increases, the densest sphere breaks the sac membrane first and releases liquid.
  • any method capable of changing the pressure applied by the puncture structure to the sac membrane can be used for this purpose. It can also be considered to realize the sequential release of liquid from multiple sacs by adjusting the bonding strength of the easily breakable part and other parts of the sac membrane.
  • the sac of the present invention does not rely on the weight of the liquid reagent to destroy the sac membrane. Therefore, the liquid sac of the present invention is suitable for storing as little as microliters or even nanoliters of liquid reagents.
  • the liquid sac 1 is placed in the cavity 21 of the microfluidic chip 2.
  • the liquid sac 1 is approximately capsule-shaped, and includes a sac membrane 11, a liquid reagent 12 encapsulated by the sac membrane 11, and a piercing structure 13 freely existing in the liquid reagent 12.
  • the liquid sac 1 occupies most of the space of the cavity 21 and cannot be freely turned inside the cavity 21.
  • the cavity 21 communicates with the inlet channel 23 and the outlet channel 24 in the microfluidic chip 2.
  • the piercing structure 13 is a sphere, made of steel.
  • the sac membrane 11 is made of plastic film.
  • the piercing structure 13 contacts the distal end 111 of the sac membrane 11 and applies pressure, which causes the distal end 111 to deform and eventually break, so that the liquid reagent 12 is released and enters the outflow channel 24 and subsequent channels or reaction chambers.
  • the thickness of the distal end 111 is made smaller than other parts of the sac membrane 11.
  • a groove 25 can be provided in the microfluidic chip 2 close to the distal end 111 of the capsule membrane 11, so that the piercing structure 13 will fall into the groove 25 after damaging the capsule membrane 11 during centrifugation, so as to prevent The piercing structure 13 enters or blocks the outlet channel 24 after destroying the sac membrane 11.
  • a groove outlet channel 26 can be provided at the bottom of the groove 25 to communicate with the outlet channel 24 to ensure that the liquid reagent 12 in the liquid capsule 1 can all flow into the outlet channel 24.
  • the inner diameter of the groove outlet channel 26 is smaller than the diameter of the piercing structure 13.
  • FIG. 2 shows another embodiment of the sac of the present invention.
  • the liquid bladder 1 is approximately capsule-shaped, but has a protruding portion 14 formed at its distal end.
  • the protruding part includes a side wall 141 and a bottom 142.
  • the piercing structure 13 is approximately conical, and its tip is suitable for piercing the bottom 142 during centrifugation.
  • the size of the piercing structure 13 is consistent with the inner space of the protruding part 14 so that the piercing structure 13 can be held in the protruding part 14 during transportation or storage, and the bottom 142 can be pierced directionally during centrifugation.
  • a groove 25 and a groove outlet channel 26 are provided below the protruding portion 14 of the liquid capsule 1 in the microfluidic chip 2 (relative to the direction of the liquid capsule away from the centrifugal axis during centrifugation). After centrifugation, the piercing structure 13 pierces the bottom 142 and falls into the groove 25, and the liquid reagent 12 flows out (see FIG. 3).
  • the piercing structure 13 can be fixed to the side wall 141 by welding or bonding. In this way, on the one hand, the piercing structure 13 can be prevented from being displaced during transportation or storage. On the other hand, the piercing structure 13 can not only damage the bottom 142 through its tip during centrifugation, but also tear the side wall 141 combined with it by tearing.
  • magnetic force may be used to facilitate the piercing structure 13 to destroy the sac membrane 11.
  • the microfluidic chip 2 including the liquid capsule 1 shown in Fig. 1 is placed in a centrifuge provided with a magnetic device 3 (such as a magnet or an electromagnet) on the outer periphery.
  • the magnetic device 3 can position the piercing structure 13 at the distal end 111 of the sac membrane 11 by magnetic force.
  • the pressure exerted by the piercing structure 13 on the distal end 111 of the sac membrane 11 during centrifugation can be influenced by changing the magnitude of the magnetic force exerted by the magnetic device 3 on the piercing structure 13.
  • Polypropylene (PP) is used to make multiple identical liquid sacs, and the sealing part (distal) is sealed with a heat sealer.
  • the aluminum foil film has a double-layer structure, one layer is a PP film, and the other layer is a supporting aluminum foil. When heated, the PP film melts and bonds with other liquid sac films. By controlling the heat sealing temperature, pressure and time, a consistent heat sealing tightness on the sealing plane can be achieved. Different volumes of liquid are enclosed in these sacs. Divided into 2 groups, the liquid sac group 1 only includes liquid, and the liquid sac group 2 is added with a steel ball to assist in the release of liquid. Place the liquid sacs in the cavity of the microfluidic chip, and centrifuge on the centrifuge. The results are shown in Table 1.
  • the liquid sac A includes steel balls with a diameter of 1 mm and 400 microliters of liquid
  • the liquid sac B includes a steel column of 1 mm ⁇ 1 mm ⁇ 4 mm and 400 microliters of liquid.
  • the liquid sac of the present invention is an independent structure and can be placed in any cavity of the microfluidic chip. Centrifugal force is used to drive the puncture structure to release the liquid. There is no need to physically weld the liquid sac and the microfluidic chip, thereby avoiding the complexity of micro-processing Process, there is no need to use additional mechanical structure to apply mechanical force to destroy the liquid sac structure.
  • the release conditions of the liquid mainly depend on the weight and structure of the high-density material that assists in breaking the closed structure. When the closed structure is stable, adjusting the weight and structure of the broken ring structure can provide a variety of ways to release the liquid, so as to realize the orderly release of the liquid in the microfluidic control.
  • the release of liquid depends on the structure of the broken ring, which is also suitable for the storage and release of small amounts of liquid. Since the destruction of the liquid sac of the present invention does not depend on the volume of the liquid in the sac, the liquid sac of the present invention can be used for the storage and release of other liquids as little as nanometers, and can be used to control the density and/or shape of the puncture structure.
  • the orderly release of liquid reagents in the same microfluidic chip is particularly suitable for automated operations.

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Abstract

本发明提供了用于在微流控芯片内储存和释放液体的液囊。本发明还提供了包括一个或更多个所述液囊的微流控芯片。本发明的液囊为独立结构，可以放置在微流控芯片的任何腔体中，尤其适合于微流控芯片的自动化操作。

Description

用于微流控芯片的液囊
本申请要求于2019年8月30日提交至中国专利局、申请号为201910815800.1、发明名称为“用于微流控的液囊”的中国专利申请的优先权。
技术领域
本发明涉及微流控芯片用液囊，尤其是可通过离心力控制液囊内液体释放的液囊。
背景技术
微流控技术目前已广泛应用于生物、化学以及医学分析中，其可将样品的制备、分离、反应、检测等操作集中于微米尺度的平台即微流控芯片上。微流控分析系统一般包括微流控芯片、检测试剂和配套的检测仪器三部分。微流控芯片的设计需要利用微加工技术汇总微流道、微反应腔和微阀组件，以实现在芯片上完成样品前处理、样品分配、样品定量、样品和反应试剂的混合和反应、反应结果的检测等功能，实现从样品进入到报告结果的完整流程。高度集成化、自动化和微量化是微流控技术的特点。
微流控技术主要内容之一是微流体操控技术，其包括液体在微流控芯片的通道内定向流动、分配、流速控制等。早期的微流控芯片所用的液体试剂(如缓冲液，检测试剂)是在进行样品分析时手动进样，这导致操作复杂并且实验误差较大。近几年，已开发出一些在微流控芯片中预存储和释放液体试剂的方法。
CN103272657A公开了一种微流控芯片的液体存储方法，其包括将容纳有液体试剂的液囊预封装在微流控芯片的腔体内，在使用时借助外部机械力如挤压、敲击、针刺、震动等使液囊局部或大面积破损，从而将液囊内部存储的液体试剂释放出来。CN104884169A和US2017/0173581A1描述了使用外部压力挤压微囊，使微囊的预定断裂部分破坏，从而将存储的液体试剂释放的方法。CN108525714A描述了使用柱塞加压使储液袋(即微囊)破裂以让检测试剂流出的方法。CN108295912A描述了微流控芯片试剂的预封装装置及其开启方法，其包括在封装液囊时形成一个向外延伸的尾部，并且在希望试剂释放时使用外力让该尾部从封接部位脱离，导致试剂流出。这些方法虽然实现了将液体试剂预先保存在微流控芯片的腔体内，但液体试剂的释放仍然需要另外的手动或机械操作，不利于自动化检测。
CN104399540A描述了一种基于离心作用的微流控芯片液体试剂释放方法，其通过采用易撕裂的封接方式密封袋囊体、将袋囊体的固定端固定于腔体壁上、以及在离心时通过袋囊体与腔体壁的相对移动撕开密封处而释放液体。该方法试图利用离心时袋囊体 自身(包括其中的液体试剂)产生的离心力撕开密封处，但微流控芯片中所用的液体试剂常常都是微升或纳升级别，离心时所产生的离心力太小而难以撕开密封处。在袋囊体和腔体都极其微小时，将袋囊体固定于腔体壁在工艺上并不容易实现。另外，为了离心时袋囊体和腔体壁能够相对移动，需要腔体有足够大的空间，这显然对于微流控芯片的微型化是不利的。
发明内容
在一方面，本发明提供了一种用于在微流控芯片内储存和释放液体的液囊，所述液囊包括形成密封空间的液囊膜、处于所述密封空间内的液体和刺破结构，其中所述刺破结构能够在离心力驱动下刺破所述液囊膜，导致所述液体从所述液囊释放。
在一些实施方案中，所述液囊为胶囊形、长方体或椭圆体。
在一些实施方案中，所述刺破结构的密度大于所述液体的密度。
在一些实施方案中，所述刺破结构为球形、柱形或带有尖末端的形状(例如三角锥形，圆锥形)。
在一些实施方案中，所述刺破结构由磁性材料制成。
在一些实施方案中，所述液囊膜包括至少一个易于被所述刺破结构破坏的易破坏部分。
在一些实施方案中，所述刺破结构被固定于所述液囊膜的内侧。
在一些实施方案中，所述刺破结构被固定于所述易破坏部分。
在一些实施方案中，所述液囊在远端包括突出部分，所述刺破结构的形状适合于容纳在所述突出部分内并在离心时刺破所述突出部分。
在一些实施方案中，所述液体的体积为10μL至2000μL。
另一方面，本发明还提供了一种微流控芯片，其包括至少一个腔体和与所述腔体相通的腔体出口通道，所述腔体内包括所述液囊，在离心时所述液囊内的刺破结构刺破所述液囊的液囊膜，让所述液囊内的液体通过所述腔体出口通道流出。
在一些实施方案中，所述液囊的形状适合于容纳在所述腔体内而不会自由翻滚。
在一些实施方案中，所述腔体的下方设置有凹槽，以便离心时所述液囊内的刺破结构在刺破所述液囊后落入所述凹槽内。
在一些实施方案中，所述凹槽底部设置有凹槽出口通道，所述凹槽内的液体能够在离心时通过所述凹槽出口通道流入所述腔体出口通道中。
在一些实施方案中，容纳有所述液囊的腔体为两个或两个以上，并且至少一个所述液囊内的刺破结构刺破其所在的液囊所需的离心力不同于其他液囊，以便在离心时实现所述液囊内所述液体的顺序释放。
在一些实施方案中，通过调整以下因素之一或它们的组合来实现所述顺序释放：所 述刺破结构的形状、密度、质量及其组合；所述液囊膜的易破坏部分的厚度；所述液囊膜的易破坏部分与所述液囊膜的其他部分的结合强度；
所述液囊处于所述微流控芯片中的位置；以及在所述刺破结构为磁性材料时，是否对所述刺破结构施加磁力和施加磁力的大小。
本发明的液囊为独立结构，可以放置在微流控芯片的任何腔体中，利用离心力驱动穿刺结构来释放液体，无需将液囊和微流控芯片进行物理焊接，也无需利用额外的机械结构施加机械力来破坏液囊结构，尤其适合于自动化操作。
附图说明
图1为包括本发明液囊的微流控芯片的一个实施方案的部分截面示意图。
图2为包括本发明液囊的微流控芯片的另一实施方案的部分截面示意图。
图3为图2所示微流控芯片在刺破结构破坏液囊使得液体试剂流出后的部分截面示意图。
图4为显示本发明的微流控芯片置于设置有磁力装置的离心机内离心时的位置关系示意图。
具体实施方式
除非另有说明，本文使用的所有技术和科学术语具有本领域普通技术人员所通常理解的含义。
本文提供的液囊利用离心状态下液囊内刺破结构产生的离心力破坏液囊膜，从而导致液囊内的液体释放。
本文中所用的术语“液囊”指用于预置于微流控芯片的腔体内的内部容纳有液体的密封容器。液囊可以但不必是囊状物的形状，其例如可以为胶囊形状，具有近似正方体、长方体、球体、圆柱体或椭圆体的外形，或者为不规则形状。这里所用的术语“液体”指化学或医学上常用的液体试剂，例如纯水、缓冲液、检测溶液等。
本文中所用的术语“液囊膜”，指该密封容器自身，其形成了容纳液体的内部空间。
在一些情形下，液囊膜由柔性材料制成。所用的柔性材料包括但不限于各种柔性塑料薄膜，例如低密度聚乙烯(LDPE)、聚丙烯(PP)、聚氯乙烯(PVC)、聚苯乙烯(PS)、ABS塑料等。液囊膜可以整体上为均一材料，离心时刺破结构对该柔性材料的一部分施加压力，导致其变形，直至破碎。或者，希望液囊在离心时被定位破坏时，液囊膜可以包括“易破坏部分”。这里“易破坏部分”指容易被刺破结构破坏而释放内部液体的局部液囊膜。“易破坏部分”可以为一个或多个，例如可以将离心时液囊远离离心轴的端部(远端)设置成易破坏部分，或者将远端和部分侧壁都设置成易破坏部分。易破坏部分可以通过多种方式形成，包括使用易破碎的材料，使用更薄的液囊膜，或者直接将液囊在填 充液体后的最后封接部位作为易破坏部分。易破坏部分可以通过粘接、焊接、热封等方式与液囊膜的其它部分结合。
在另一些情形下，液囊膜主要由非柔性材料制成，这种情况下液囊膜也可称为“液囊体”。所用的非柔性材料包括但不限于高密度聚乙烯(HDPE)、聚碳酸酯(PC)、玻璃、金属箔(如铝箔)。在使用非柔性材料时，液囊膜应包括易破坏部分用于释放液体。该易破坏部分一般位于液囊的远端，即离心时远离轴心的端部。易破坏部分可以通过粘接、焊接、热封等方式与液囊膜的其它部分结合。与其它部分的结合强度本身也可以用于调节释放液体所需的离心转速或离心力。
本文中所用的术语“刺破结构”指被置于液囊内用于破坏液囊膜的完整性的物理实体。刺破结构将离心时产生的离心力施加于液囊膜上，导致液囊膜或液囊膜的易破坏部分破碎，从而释放存储的液体。刺破结构本身应不与存储的液体试剂反应或污染液体试剂。
为了刺破液囊膜，刺破结构应能够对液囊膜或其易破坏部分产生足够的压力。这可以通过多个途径实现。例如，一种方式是增加刺破结构的质量。由于液囊本身的大小及其内部空间有限，可以使用高密度材质制作该刺破结构，尤其是刺破结构为球体时，质量增加会在相同的离心转速时产生更大的离心力。还可以在在刺破结构上设置突出的尖末端。例如，使用带角部的椎体形状的刺破结构，或者使用空心针作为刺破结构。实际应用时，可以使用高密度的带尖末端的物理实体作为刺破结构。另外，可以使用磁性材料(例如，Fe、Co、Ni元素及其合金)制成的刺破结构，通过对其施加定向磁力而促进其破坏液囊膜。使用磁力还有利于在离心前将刺破结构置于液囊膜的远端附近，方便实现对液囊膜远端的定位刺破。
刺破结构应该在离心时破坏液囊膜，但在液囊的保存和运输过程中不破坏液囊膜。在刺破结构为球体时，该目的较容易实现。在刺破结构具有尖末端时，可以考虑将刺破结构限于液囊内的特定部位，例如位于液囊的突出末端内。在一些情形下，可以将穿刺结构固定在液囊膜或其易破坏部分上，以防止运输过程中穿刺结构的意外移动而刺破液囊膜。在液囊为柔性材料制成的胶囊形状时，也可以将穿刺结构固定于液囊侧壁上，离心时可以撕扯液囊膜，方便破坏液囊膜而释放液体。
穿刺结构可以采用密度较高的金属材料制作。在一些情形下，可以用惰性材料包覆穿刺结构以防止其与液体试剂反应。在另一些情形下，可以采用液囊膜材料包覆穿刺结构，这有利于穿刺结构例如通过焊接、粘结等方式固定在液囊内壁。
在表示位置关系时，本文所用的“远端”或“下方”指当将微流控芯片置于离心机上离心时，相对远离离心轴的部分。
本发明的液囊可放置在微流控芯片的腔体中。该腔体具有出口通道，液体从液囊中释放后通过出口通道进入到微流控芯片的其它结构中参与反应。如果有必要，该腔体也可以有进口或者通气孔。
采用本发明的液囊，通过控制刺破结构的密度、大小和/或结构，可以方便地在微流控芯片内实现多个液囊的依次或顺序释放。例如，当采用球体破坏液囊时，可以选择不同密度的材料制作同样体积的球体，它们在同样的转速下可以对液囊膜施加不同的压力。在离心转速逐渐增加时，密度最大的球体最先破坏液囊膜而释放液体。显然，能够改变刺破结构施加于液囊膜的压力的方式均可用于本目的。还可以考虑通过调整易破坏部分与液囊膜的其它部分的结合强度来实现多个液囊液体的依次释放。
如上文所描述的，本发明的液囊并不依赖于液体试剂的自身重量来破坏液囊膜。因此，本发明的液囊适合存储少至微升或者甚至纳升量的液体试剂。
以下结合附图进一步详细说明本发明。
参见图1，液囊1被置于微流控芯片2的腔体21中。液囊1为近似胶囊状，包括液囊膜11、液囊膜11包封的液体试剂12、以及自由存在于液体试剂12中的刺穿结构13。液囊1占据腔体21的大部分空间，不能在腔体21内自由翻转。该腔体21与微流控芯片2内的进口通道23和出口通道24相通。刺穿结构13为球体，由钢材质制成。液囊膜11采用塑料薄膜制成。离心时，穿刺结构13与液囊膜11的远端111接触并施加压力，导致远端111变形并最终破碎，从而让液体试剂12释放，进入流出通道24以及后续通道或反应腔体内。为了方便穿刺结构13破坏远端111，将该远端111的厚度制作成小于液囊膜11的其他部分。另外，可在微流控芯片2中靠近液囊膜11的远端111处设置一凹槽25，使得离心时刺穿结构13在破坏液囊膜11后落入该凹槽25内，以防止刺穿结构13在破坏液囊膜11后进入或堵塞出口通道24。考虑到该凹槽25也可能存留部分液体，可以在该凹槽25的底部设置凹槽出口通道26，与出口通道24相通，以保证液囊1内的液体试剂12能够全部流入出口通道24。凹槽出口通道26的内径小于刺穿结构13的直径。
图2显示了本发明液囊的另一种实施方案。液囊1为近似胶囊状，但在其远端形成有突出部分14。突出部分包括侧壁141和底部142。刺穿结构13近似圆锥形，其尖端适合于在离心时刺破底部142。刺穿结构13的大小与突出部分14的内部空间吻合，使得运输或储存时刺穿结构13能够保持在该突出部分14内，并且在离心时定向刺破底部142。类似地，在微流控芯片2中液囊1的突出部分14的下方(离心时相对于液囊远离离心轴的方向)设置有凹槽25和凹槽出口通道26。离心后，刺穿结构13刺破底部142落入凹槽25内，液体试剂12流出(见图3)。
在一些情形下，例如液囊膜11为塑料薄膜时，可以将刺穿结构13通过焊接或粘合方式与侧壁141固定。这样，一方面可以防止运输或保存时刺穿结构13发生位移，另 一方面，离心时刺穿结构13不仅可通过其尖端破坏底部142，还可通过撕扯破毁与其结合的侧壁141。
在一些实施方案中，可通过磁力来促进刺破结构13破坏液囊膜11。参见图4，将图1中显示的包括液囊1的微流控芯片2置于外周设置有磁力装置3(如磁铁或电磁铁)的离心机中。在刺穿结构13为钢珠时，磁力装置3可以通过磁力将刺穿结构13定位于液囊膜11的远端111处。另外，可通过改变磁力装置3施加在刺穿结构13上的磁力大小影响离心时刺穿结构13施加在液囊膜11的远端111上的压力。
在微流控芯片2中放置有多个液囊时，可通过离心转速、刺穿结构的形状和/或质量、液囊膜在微流控芯片上的相对位置、液囊膜本身的厚度和/或易破坏程度、是否使用磁力装置和/或磁力大小等多方面的灵活调整来保证多个液囊内液体的按顺序释放。
实施例1
使用聚丙烯(PP)制成多个相同液囊，封口处(远端)用热封机封闭铝箔膜。铝箔膜为双层结构，一层为PP薄膜，另外一层为支持用的铝箔，加热的条件下，PP薄膜熔解，与其他液囊膜部分发生粘合。通过控制热封温度、压力和时间以取得在密封平面上一致性的热封紧密度。在这些液囊中分别封闭不同体积的液体。分为2组，其中液囊组1中仅包括液体，液囊组2加入1个钢珠用于辅助液体释放。将液囊分别置于微流控芯片的腔体内，于离心机上离心。结果如表1所示，在1200rpm下离心30秒，液囊组2中液体释放，液囊组1结构仍然完整。在1500rpm条件下离心30秒，液囊组1中的液体仍未释放，直至2200rpm时才释放。
表1.包括或不包括刺破结构的离心结果
Figure PCTCN2020112361-appb-000001
实施例2
使用聚丙烯(PP)制成两个相同液囊，封口处(远端)用热封机封闭铝箔膜。均封闭500微升液体。其中液囊A中仅包括液体，液囊B中还加入了锥形钢刺破结构。液囊和刺破结构的形状如图2所示。将液囊A和B分别置于微流控芯片的腔体内，于离心机上离心。在1000rpm下离心30秒，液囊B中液体释放，液囊A结构仍然完整。直至2000rpm条件下离心30秒，液囊A中的液体才能够释放。
实施例3
使用聚丙烯(PP)制成两个相同液囊，封口处(远端)用热封机封闭铝箔膜。封闭400微升液体。其中液囊A中包括1mm粒径的钢珠和400微升液体，液囊B中包括1mm×1mm×4mm的钢柱和400微升液体。将液囊A和B分别置于同一微流控芯片的平行腔体内，于离心机上离心。在600rpm下离心30秒，液囊B中液体释放，液囊A结构仍然完整。接着增加转速，在1200rpm下继续离心30秒，液囊A中的液体释放。
实施例4
使用聚丙烯(PP)制成四个相同液囊，封口处(远端)用铝箔热封，分别封闭50微升、100微升、200微升液体、400微升和0.65g三角锥形的金属结构。将液囊分别置于微流控芯片的腔体内，于离心机上离心。离心结果显示在表2中。在700rpm下离心30秒，液囊结构都仍然完整。在900rpm条件下离心30秒，所有液囊都打开，液体完全释放。在此离心条件下，液体的释放基本上不依赖于液体的体积。
表2包含不同体积液体的液囊的离心结果
Figure PCTCN2020112361-appb-000002
本发明的液囊为独立结构，可以放置在微流控芯片的任何腔体中，利用离心力驱动穿刺结构来释放液体，无需将液囊和微流控芯片进行物理焊接，避免了微加工的复杂工艺，也无需利用额外的机械结构施加机械力来破坏液囊结构。液体的释放条件主要依赖于辅助破环封闭结构的高密度材料的重量和结构。在封闭结构稳定的情况下，调整破环结构的重量和结构可以提供多种释放液体的方式，从而实现微流控中的液体有序释放。特别是在离心微流控中，通过离心转速和液囊放置的位置(相对于离心轴的距离)就可以有多种的手段控制液体的释放。液体的释放取决于破环结构，这样也适合微量液体的储 存和释放。由于本发明液囊的破坏不依赖于液囊内液体体积，因此本发明液囊可以用于少至纳升级别的液体的存储和释放，并且能够通过控制刺破结构的密度和/或形状在同一微流控芯片中实现液体试剂的有序释放，这尤其适合于自动化操作。

Claims (16)

  1. 用于在微流控芯片内储存和释放液体的液囊，所述液囊包括形成密封空间的液囊膜、处于所述密封空间内的液体和刺破结构，其中所述刺破结构能够在离心力驱动下刺破所述液囊膜，导致所述液体从所述液囊释放。
  2. 如权利要求1所述的液囊，其为胶囊形、长方体或椭圆体。
  3. 如权利要求1或2所述的液囊，其中所述刺破结构的密度大于所述液体的密度。
  4. 如权利要求1至3任一项所述的液囊，其中所述刺破结构为球形、柱形或带有尖末端的形状。
  5. 如权利要求1至4任一项所述的液囊，其中所述刺破结构由磁性材料制成。
  6. 如权利要求1至5任一项所述的液囊，其中所述液囊膜包括至少一个易于被所述刺破结构破坏的易破坏部分。
  7. 如权利要求1至6任一项所述的液囊，其中所述刺破结构被固定于所述液囊膜的内侧。
  8. 如权利要求1至7任一项所述的液囊，其中所述刺破结构被固定于所述易破坏部分。
  9. 如权利要求1至8任一项所述的液囊，其中所述液囊在远端包括突出部分，所述刺破结构的形状适合于容纳在所述突出部分内并在离心时刺破所述突出部分。
  10. 如权利要求1至9任一项所述的液囊，其中所述液体的体积为10μL至2000μL。
  11. 一种微流控芯片，包括至少一个腔体和与所述腔体相通的腔体出口通道，所述腔体内包括前述权利要求任一项所述的液囊，在离心时所述液囊内的刺破结构刺破所述液囊的液囊膜，让所述液囊内的液体通过所述腔体出口通道流出。
  12. 如权利要求11所述的微流控芯片，其中所述液囊的形状适合于容纳在所述腔体内而不会自由翻滚。
  13. 如权利要求11或12所述的微流控芯片，其中所述腔体的下方设置有凹槽，以便离心时所述液囊内的刺破结构在刺破所述液囊后落入所述凹槽内。
  14. 如权利要求13所述的微流控芯片，其中所述凹槽底部设置有凹槽出口通道，所述凹槽内的液体能够在离心时通过所述凹槽出口通道流入所述腔体出口通道中。
  15. 如权利要求11至14任一项所述的微流控芯片，其中容纳有所述液囊的腔体为两个或两个以上，并且至少一个所述液囊内的刺破结构刺破其所在的液囊所需的离心力不同于其他液囊，以便在离心时实现两个或两个以上所述液囊内的液体的顺序释放。
  16. 如权利要求15所述的微流控芯片，其中通过调整以下因素之一或它们的组合来实现所述顺序释放：
    所述刺破结构的形状、密度、质量及其组合；
    所述液囊膜的易破坏部分的厚度；
    所述液囊膜的易破坏部分与所述液囊膜的其他部分的结合强度；
    所述液囊处于所述微流控芯片中的位置；以及
    在所述刺破结构为磁性材料时，是否对所述刺破结构施加磁力和施加磁力的大小。
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