WO2013159484A1 - 一种有导流体的微流体芯片及其应用 - Google Patents

一种有导流体的微流体芯片及其应用 Download PDF

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Publication number
WO2013159484A1
WO2013159484A1 PCT/CN2012/081673 CN2012081673W WO2013159484A1 WO 2013159484 A1 WO2013159484 A1 WO 2013159484A1 CN 2012081673 W CN2012081673 W CN 2012081673W WO 2013159484 A1 WO2013159484 A1 WO 2013159484A1
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Prior art keywords
pool
valve
sample
liquid
solution
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PCT/CN2012/081673
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English (en)
French (fr)
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杨奇
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北京博晖创新光电技术股份有限公司
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Priority to US14/396,630 priority Critical patent/US9415394B2/en
Publication of WO2013159484A1 publication Critical patent/WO2013159484A1/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
    • B01L3/502746—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 characterised by the means for controlling flow resistance, e.g. flow controllers, baffles
    • 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
    • B01L3/5025—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures for parallel transport of multiple samples
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2200/00—Solutions for specific problems relating to chemical or physical laboratory apparatus
    • B01L2200/06—Fluid handling related problems
    • B01L2200/0647—Handling flowable solids, e.g. microscopic beads, cells, particles
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2200/00—Solutions for specific problems relating to chemical or physical laboratory apparatus
    • B01L2200/10—Integrating sample preparation and analysis in single entity, e.g. lab-on-a-chip concept
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/08—Geometry, shape and general structure
    • B01L2300/0861—Configuration of multiple channels and/or chambers in a single devices
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/08—Geometry, shape and general structure
    • B01L2300/0861—Configuration of multiple channels and/or chambers in a single devices
    • B01L2300/0867—Multiple inlets and one sample wells, e.g. mixing, dilution
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2400/00—Moving or stopping fluids
    • B01L2400/04—Moving fluids with specific forces or mechanical means
    • B01L2400/0475—Moving fluids with specific forces or mechanical means specific mechanical means and fluid pressure
    • B01L2400/0487—Moving fluids with specific forces or mechanical means specific mechanical means and fluid pressure fluid pressure, pneumatics
    • B01L2400/049—Moving fluids with specific forces or mechanical means specific mechanical means and fluid pressure fluid pressure, pneumatics vacuum
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2400/00—Moving or stopping fluids
    • B01L2400/08—Regulating or influencing the flow resistance
    • B01L2400/084—Passive control of flow resistance
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2400/00—Moving or stopping fluids
    • B01L2400/08—Regulating or influencing the flow resistance
    • B01L2400/084—Passive control of flow resistance
    • B01L2400/086—Passive control of flow resistance using baffles or other fixed flow obstructions
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2400/00—Moving or stopping fluids
    • B01L2400/08—Regulating or influencing the flow resistance
    • B01L2400/084—Passive control of flow resistance
    • B01L2400/088—Passive control of flow resistance by specific surface properties
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N27/00—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means
    • G01N27/26—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means by investigating electrochemical variables; by using electrolysis or electrophoresis
    • G01N27/416—Systems
    • G01N27/447—Systems using electrophoresis
    • G01N27/44756—Apparatus specially adapted therefor
    • G01N27/44791—Microapparatus

Definitions

  • the invention belongs to the field of fluid control and detection on a microscopic scale, and is specifically a fluid-conducting polymer microfluidic chip and application thereof. Background technique
  • Fluid technology is a technique for detecting and manipulating small volumes of fluids and is a structural analysis and control method for biological and chemical fluid systems.
  • Applications and potential applications that microfluidic technology has achieved include disease diagnosis, life science research, and biological and/or chemical sensor development.
  • the polymeric microfluidic structure includes a substrate and a membrane.
  • the substrate can have a variety of structures, which can be microfluidic channels or paths, through holes, and various containers.
  • the substrate is combined with the diaphragm to form a valve structure, and the force is applied to deform the diaphragm. Therefore, the actuating valve drives the liquid to flow, forming a pump structure; and is coupled to the valve structure and the pump structure by external power as a driving device for liquid flow in the microfluidic chip.
  • "Microfluidic chip” is a microfluidic chip that uses some kind of control.
  • Polymer microfluidics are made from organic polymers, including rigid polymethyl methacrylate (PMMA), propylene-butadiene-styrene (ABS) and polystyrene (PS).
  • the polymer microfluidic structure is characterized by a "micro" structure, a microscopic overall structure, a small sample size, a small amount of reagent used, and a small fluid flow on the chip. Therefore, in order to obtain the accuracy and stability of the application target, high precision for microfluidic control is required.
  • an important problem in the application of the microfluidic chip is that when the liquid flows out of the container, residual liquid droplets are generated on the inner wall of the container and adhere to the inner wall of the container. Although the amount of this residue is small, the ratio of the relative residual amount to the microfluid is not negligible. The problem of residual liquids is an important issue affecting polymer microfluidic applications.
  • the existing polymer microfluidic chip has a container 101 as shown in FIG. 3.
  • the solution in the container is pumped out, some residual droplets remain on the inner wall of the container, even if the inner wall of the container is in the shape of a circular arc. It is also difficult to avoid. Residual liquid will affect the detection result, which will cause the error of the solution to decrease; in addition, when the container is used again, other solutions will be pumped, which will cause pollution and affect the normal reverse. Should. Summary of the invention
  • a fluid-conducting microfluidic chip has a conducting fluid in a solution pool of a microfluidic chip, and a gap between the conducting fluid and the solution cell wall is 0 to 1.5 mm.
  • the shape of the fluid guiding body is different according to the shape of the solution pool, and is one of a sphere, an elliptical sphere, a polyhedron or an irregular geometry.
  • the gap between the fluid guide and the wall of the solution tank depends on the viscosity of the solution (measured at room temperature), and when the viscosity of the solution is 0.6 to 1.2 mPa, the gap is 0. ⁇ 0.9 mm, when the solution viscosity is 1.2 to 6.0 mPa's, the void is 0.9 to 1.5 mm.
  • the surface of the fluid guiding body is subjected to silicidation treatment.
  • the silicidation treatment is carried out by a conventional method of silicidation of a plastic member, for example, using a silane solution as a silicidation solution, immersing the fluid, and then drying.
  • the surface of the fluid guide is coated with an antigen or an antibody.
  • a limiter is disposed above the fluid guiding body, and the stopper is fixed to the wall of the solution pool.
  • the microfluidic chip proposed by the invention comprises the following six solution pools: a sample pool, a dilution liquid pool, a marking liquid pool, a dissociation liquid pool, a cleaning liquid pool, a waste liquid pool, and a substrate through hole at the bottom of each pool; wherein the sample pool There is a sample pool valve and a sample through hole, and a dilution liquid pool valve and a diluent liquid through hole are arranged in the dilution liquid pool, and the marking liquid pool is provided with a marking liquid valve and a marking liquid through hole, and the dissociation liquid pool is provided with dissociation a liquid valve and a dissociation liquid through hole, the cleaning liquid pool is provided with a cleaning liquid valve and a cleaning liquid through hole, the waste liquid pool is provided with a waste liquid valve and a waste liquid through hole; each valve is respectively connected to the main valve through the passage;
  • the sample cell valve, the main valve, the diluent pool valve, and the through hole and the passage constitute a two-way sample dilution pump between the sample cell and the diluent pool;
  • the sample pool valve, the main valve, the cleaning liquid valve, and the through hole and the passage constitute a sample pool-washing liquid pool a one-way sample cleaning pump;
  • the sample pool valve, the main valve, the waste liquid valve and the through hole and the passage form a one-way sample waste liquid pump between the sample pool and the waste liquid pool;
  • the sample cell valve, the main valve, the marking liquid pool valve and the passage form a two-way sample marking pump between the sample cell and the marking liquid pool;
  • sample cell valve, main valve, dissociation reservoir valve and channel form a two-way sample dissociation enhancement pump between the sample cell-dissociation enhancement fluid pool.
  • microfluidic chip of the invention in biochemical, immunological and molecular detection.
  • the pump When each solution is discharged, when the solution is discharged from the through hole, the pump generates a negative pressure, which generates a gas flow. Due to the presence of the conductive fluid, a gap is formed between the conductive fluid and the container, and the airflow is enhanced several times. The residual droplets are pumped away; in addition, when the pump is in operation, the airflow causes the fluid to move and change position, which will remove residual droplets at different locations.
  • the stopper in the tank guides The fluid does not float out of the liquid surface, reducing the contact time between the fluid guide and the solution; the coating on the fluid guide is simpler than the coating in the container, and it is easier to control the quality of the coating.
  • the reaction efficiency can be improved: the surface of the fluid guide is coated, the antibody is coated on the fluid guide, placed in the sample container, and the antigen and antibody are bound after the sample is added.
  • the pump works, so that the solution keeps reciprocating between the two cells, and the coated conductive fluid rotates accordingly, so that the antigen in the solution is in effective contact with the coated antibody, which is far more effective than the vibration. Adequate, improve the efficiency of the reaction.
  • Figure 1 is a schematic view showing the structure of a polymer microfluidic chip of the present invention.
  • Figure 2 is a cross-sectional view of the solution cell 101 of Figure 1 taken along line A-A.
  • Figure 3 is a partial enlarged view of B in Figure 2.
  • Figure 4 is a cross-sectional view of the solution tank.
  • Figure 5 is a cross-sectional view of the solution cell with residual droplets 114 when there is no conductivity.
  • Figure 6 is a cross-sectional view of the solution cell with a flow of fluid to create a gas stream 115.
  • Figure 7 is a top plan view of a polymer microfluidic chip solution cell of the present invention.
  • Figure 8 is a bottom plan view of the polymer microfluidic chip of the present invention.
  • Figure 9 is a structural view of the sample dilution pump 302.
  • Figure 10 is a structural view of the sample cleaning pump 305 and the sample waste pump 306.
  • Figure 11 is a connection diagram between the diluent pool, the sample tank, and the cleaning solution tank.
  • Figure 12 is a structural view of the sample marking pump 303.
  • Figure 13 is a block diagram of the sample dissociation enhancement pump 304.
  • Figure 14 is a schematic view of a polymer microfluidic detection device of the present invention.
  • the fluid may be made of a polymer or a composite of organic or inorganic materials such as polyethylene, polystyrene, polytetrafluoroethylene, wood, silica gel or a composite thereof.
  • the crucible used was purchased from Continent Plymer Co. under the designation CP-51, and the ABS used was purchased from Dow Chemical Co. under the designation 340.
  • the automatic sample loading device was purchased from Tecan Group Ltd.
  • Example 1 Preparation of a coated flow guiding sphere
  • the coating is finished, washed twice with washing solution, calculated by 300 ⁇ 1/packaged ball, and the composition of the washing liquid is 10mM pH 7.4 PBS (phosphate buffer) containing 5% Tween-20;
  • the coated diversion sphere is placed on the absorbent filter paper to absorb the remaining solution, and then placed in a beaker.
  • a certain amount of blocking solution is added in an amount of 150 ⁇ /coated spheroid, and sealed at room temperature. 2 hours, PBS containing 1 OmM pH 7.4 containing 1% BSA;
  • the blocking solution was poured out, and the coated diversion sphere was placed on a water-absorbent filter paper to absorb the remaining solution, and then dried in a 28 ° C incubator for 20 hours.
  • the fluid is made of polyethylene.
  • 1% APES (aminopropyltriethoxysilane) ethanol solution as the silicidation solution, pour 500 mL of silicidation solution into a 1000 mL beaker, place the fluid into the beaker and completely immerse it; after silicidation for 1 minute, remove it, in the air.
  • the microfluidic chip is fabricated using PMMA and includes six solution cells, see Figure 7: sample cell 201, diluent cell 202, labeling cell 203, dissociation cell 204, cleaning solution cell 205, and waste cell 206.
  • sample cell 201 sample cell 201
  • diluent cell 202 labeling cell 203
  • dissociation cell 204 dissociation cell 204
  • cleaning solution cell 205 waste cell 206.
  • waste cell 206 waste cell 206.
  • the fluid guiding body placed in the waste liquid tank is made of silica gel, and its shape is the same as that of the waste liquid pool, and the surface is not coated.
  • Example 4 Polymer microfluidic chip with a diverting sphere
  • sample tank 201 sample tank 201, diluent pool 202, labeling tank 203, dissociation tank 204, washing tank 205, waste tank 206, and tank wall 105 of the tank, at the bottom of the tank Substrate via 104;
  • sample cell valve 211 + main valve 217 + diluent cell valve 212 and substrate via 104 and channel 106 form a bidirectional pump between sample cell 201 and diluent cell 202, sample dilution pump 302.
  • the sample pool valve 211 + the main valve 217 + the cleaning liquid valve 215 and the through holes and passages constitute a one-way pump between the sample pool 201 and the cleaning liquid pool 205, the sample cleaning pump 305;
  • the sample pool valve 211 + Main valve 217 + waste liquid valve 216 and through holes and passages constitute a one-way pump between sample pool 201 and waste liquid pool 206, sample waste liquid pump 306.
  • the sample cell valve 211 + main valve 217 + mark liquid pool valve 213 and the passage constitute a two-way pump between the sample cell 201 and the marking liquid pool 203, the sample marking pump 303;
  • the sample pool valve 211 + the main valve 217 + the dissociation liquid pool valve 214 and the passage constitute a two-way pump between the sample pool 201 and the dissociation enhancement liquid pool 204, and the sample dissociation enhancement pump 304; 4, 5, 6, wherein a coated flow guiding body 111 is placed in the sample cell 201; the sample cell diameter is 6.4 mm, the diameter of the coated flow guiding sphere is 5.5 mm, the spherical material is polystyrene; There is a ring-shaped stopper 112, and the stopper is fixed on the sample pool.
  • the cylindrical container has a diameter of 6.4 mm, a depth of 10 mm, a circular guide diameter of 5.5 mm (Fig. 6), a material of polystyrene, a solution of 200 ⁇ l, and a pump volume of the pump.
  • the maximum is ⁇ /time, and the number of pumping times is 30.
  • Table 2 Results of microfluidic chip drainage experiments
  • Example 6 Detection of anti-carcinoembryonic antigen by microfluidic chip
  • the automatic sample loading device adds 300 ⁇ l of the dilution solution to the dilution liquid pool 202, 2.0 ml of the cleaning liquid is added to the cleaning liquid pool 205, 200 ⁇ l of the hydrazine labeling liquid is added to the labeling liquid pool 203, and 150 ⁇ l of the fluorescent enhancement liquid is added to the dissociation liquid.
  • the sample dilution pump 302 works in both directions, so that the sample in the sample pool 201 and the diluent pool 202 is mixed with the diluent for 30 to 60 minutes; when the mixture is stopped, the mixture is all stored in the sample pool 201. ;
  • the sample waste liquid pump 306 works in one direction, and discharges the mixed liquid in the sample pool 201 into the waste liquid pool 206;
  • sample cleaning pump 305 works in one direction, sucking the cleaning liquid into the sample cell 201; then performing step d) discharging the waste liquid; repeating steps e) and d), performing 4 times of cleaning;
  • the sample mark pump 303 works in both directions, the ⁇ mark liquid flows between the sample cell 201 and the mark cell 203, and the ⁇ mark liquid and the "antigen antibody (coating) reaction combination" obtained in the step c) are mixed. Continuing for about 30 minutes; stopping the marking solution in the sample cell 201, and then performing step d) to remove the waste liquid into the waste liquid pool 206;
  • the sample dissociation enhancement pump 304 works in both directions, so that the dissociation enhancement fluid flows between the sample cell 201 and the dissociation liquid pool 204, dissociates for 5 min, and dissociates the dissolving fluid in the dissociation liquid pool at the stop.
  • detection unit 402 moves to the detection position of microfluidic detection chip 100 for detection, see FIG.
  • the above embodiments are merely illustrative of the preferred embodiments of the present invention, and are not intended to limit the scope of the present invention, and various modifications made by those skilled in the art to the technical solutions of the present invention without departing from the spirit of the invention. And improvements are intended to fall within the scope of protection defined by the claims of the invention.
  • the microfluidic chip disclosed by the invention can reduce the residual liquid residue, form a gap between the fluid guiding body and the container, enhance the airflow, and remove the residual liquid droplets; the set stopper prevents the fluid guiding fluid from floating out of the liquid surface, reducing the guiding
  • the fluid has no contact time with the solution; the coating is simpler and easier to control the quality of the coating than the coating in the container; the sputtering can be controlled when the solution is pumped, and the quality of the coating can be controlled;
  • the rotation of the fluid in the pool causes the antigen in the solution to be in effective contact with the antibody coated on the surface of the fluid guide, which is more effective than the vibration and improves the reaction efficiency.

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Abstract

一种有导流体（111）的微流体芯片（100）及其在生化、免疫和分子检测中的应用，在微流体芯片（100）的溶液池（101）内有导流体（111），导流体（111）表面包被有抗原或抗体，该导流体（111）与溶液池壁（105）之间的空隙为0〜1.5mm。

Description

一种有导流体的微流体芯片及其应用 技术领域
本发明属于微观尺度下流体控制和检测领域， 具体为一种有导流体的聚 合物微流体芯片及其应用。 背景技术
流体技术是检测和操控微小体积流体的技术， 是应用于生物和化学流体 ***的结构分析和控制方法。 微流体技术已经实现的应用和潜在的应用包括 疾病诊断、 生命科学研究、 以及生物和 /或化学传感器研制。
聚合物微流体结构包括基板和隔膜。 在聚合微流体结构中， 基板上可以 有各种结构， 可以是微流体通道或路径， 通孔， 及各种容器。 基板与隔膜结 合， 可构成阀结构， 施加力使隔膜变形， 因此致动阀驱使液体流动， 构成泵 结构； 通过外部动力与阀结构、 泵结构耦合， 作为微流体芯片内液体流动的 驱动装置。 根据应用要求， 对微流体芯片进行个性化设计， 实现高效率样本 检测。 "微流控芯片"是釆用某种控制方式的微流体芯片。 聚合物微流体用有 机聚合物制造， 包括刚性的聚甲基丙烯酸甲酯（PMMA ), 丙烯-丁二烯 -苯乙 烯 （ABS ) 和聚苯乙烯 （PS ) 等。
聚合物微流体结构的特点是在 "微" 上， 整体结构微， 使用样本量微， 使用试剂量微， 芯片上流体流量微。 因此， 为得到应用目标的准确性、 稳定 性， 要求对微流体控制的高精度。
目前， 微流体芯片在应用中存在的重要问题是液体在从容器中流动流出 时会在容器内壁上产生残留液滴， 附着在容器内壁上。 这种残留， 其量虽然 微小， 但其对微流体产生的相对残留量比率是不能忽略的。 残留液的问题是 影响聚合物微流体应用的重要问题。
现有的聚合物微流体芯片， 其容器 101如图 3所示， 当将容器内溶液泵 出后， 在容器内壁上会留有一些附着的残留液滴， 即使容器内壁釆用圆弧角 形状也难以避免。 残留液体会影响检测结果， 它会使溶液量减少产生误差； 另外， 当此容器再次使用时， 有其它溶液泵入， 会造成污染， 影响正常的反 应。 发明内容
为解决现有微流体芯片存在的不足， 本发明的目的是提出一种有导流体 的微流体芯片。
为实现本发明目的技术方案为：
一种有导流体的微流体芯片， 在微流体芯片的溶液池内有导流体， 该导 流体与溶液池壁之间的空隙为 0〜1.5mm。
其中， 所述导流体的形状根据溶液池形状不同而不同， 是圆球体、 椭圆 球体、 多面体或不规则几何体中的一种。 当溶液池是不规则形状时， 导流体 其中，所述导流体与溶液池壁之间的空隙取决于溶液的粘度（常温测定）, 当溶液粘度为 0.6〜1.2mPa 时， 所述空隙为 0〜0.9mm , 当溶液粘度为 1.2〜6.0mPa's时， 所述空隙为 0.9〜1.5mm。
其中， 所述导流体表面经过硅化处理。 硅化处理釆用对塑料部件硅化处 理的常规方法， 例如， 以硅烷溶液作为硅化液， 浸没导流体， 然后干燥。
其中， 所述导流体表面包被有抗原或抗体。
其中， 所述导流体上方安置有限位器， 限位器与溶液池壁固定在一起， 当球体比重低于液体时， 限定导流体浮动和运动范围， 使导流体完全浸入溶 液。
本发明提出的微流体芯片包括以下 6个溶液池： 样本池、 稀释液池、 标 记液池、 解离液池、 清洗液池、 废液池， 每个池底部有基板通孔； 其中样本 池中设有样本池阀和样本通孔， 稀释液池中设有稀释液池阀和稀释液通孔， 标记液池设有标记液阀和标记液通孔， 解离液池中设有解离液阀和解离液通 孔， 清洗液池设有清洗液阀和清洗液通孔， 废液池设有废液阀和废液通孔； 各阀通过通道分别与主阀相连；
所述样本池阀、 主阀、 稀释液池阀及通孔和通道构成样本池 -稀释液池之 间的双向的样本稀释泵；
所述样本池阀、 主阀、 清洗液阀及通孔、 通道， 构成样本池 -清洗液池之 间的单向的样本清洗泵；
所述样本池阀、 主阀、 废液阀及通孔、 通道， 构成样本池-废液池之间的 单向的样本废液泵；
所述样本池阀、 主阀、 标记液池阀及通道， 构成样本池-标记液池之间的 双向的样本标记泵；
所述样本池阀、 主阀、 解离液池阀及通道， 构成样本池-解离增强液池之 间的双向的样本解离增强泵。
本发明所述的微流体芯片在生化、 免疫和分子检测中的应用。
本发明的有益效果在于：
可减少排液残留： 在每次溶液排出时， 当溶液从通孔排出时， 泵产生负 压， 产生气流， 由于导流体的存在， 使导流体与容器之间形成间隙， 气流增 强数倍， 将残留液滴抽走； 另外， 泵在工作时， 气流会使导流体运动， 变换 位置， 这样会将不同位置上的残留液滴抽走。
可控制溶液泵入时的溅射： 当溶液从基板的通孔泵入时， 流速很大， 会 产生溅射， 导流体可以阻止溶液泵入的溅射； 本池内的限位器， 使导流体不 会浮出液面， 减少导流体与溶液无接触时间； 在导流体上包被与在容器中包 被相比较， 工艺简单， 更便于控制包被质量。
可提高反应效率： 将导流体表面进行包被， 抗体包被在导流体上， 放置 在样本容器中， 加入样本后， 抗原抗体结合。 在样本池中， 泵工作， 使溶液 在两个池间不停地往复流动， 包被的导流体随之转动， 使溶液中的抗原与包 被表面的抗体有效接触， 远比振动的效果更加充分， 提高反应效率。 附图说明
图 1为本发明聚合物微流体芯片结构示意图。
图 2为图 1沿 A-A向的溶液池 101剖面图。
图 3为图 2中的 B处的局部放大图。
图 4为溶液池剖面图。
图 5为溶液池剖面图， 无导流体时， 有残留液滴 114。
图 6为溶液池剖面图， 有导流体排液产生气流 115。 图 7为本发明聚合物微流体芯片溶液池俯视图。
图 8为本发明聚合物微流体芯片底部仰视图。
图 9为样本稀释泵 302结构图。
图 10为样本清洗泵 305、 样本废液泵 306结构图。
图 11为稀释液池、 样本池、 清洗液池之间的连接图。
图 12为样本标记泵 303结构图。
图 13为样本解离增强泵 304结构图。
图 14 为本发明聚合物微流体检测装置简图。
图 1〜14中， 各序号代表的部件如表 1。
表 1 : 各序号代表的部件
Figure imgf000005_0001
具体实施方式
以下实施例用于说明本发明， 但不用来限制本发明的范围。 液池的形状时不规则形状时， 可釆用不规则形状的导流体。 导流体可以釆用 聚合物制造，也可以釆用有机物或无机物结合的复合材料制造，例如聚乙烯、 聚苯乙烯、 聚四氟乙烯、 木材、 硅胶中的一种或其复合物。 实施例中，所用 ΡΜΜΑ购自美国大陆聚合物公司（ Continent Plymer Co. ) 牌号 CP-51 , 所用 ABS购自美国道化学公司（ Dow Chemical Co. ) ,牌号 340。 自动加样装置购自 Tecan Group Ltd.。
实施例中所使用药品， 如无特殊说明， 均为分析纯。 实施例中， 若无特 别说明， 所使用的方法均为本领域常规方法。
实施例 1: 制备有包被的导流球体
1 )用 50mM pH9.6的碳酸钠 -碳酸氢钠缓冲液将用于包被的癌胚抗体 1 : 6000倍稀释， 备用；
2 )将导流球体放置于烧杯中， 按照 ΙΟΟμΙ/个球体的量计算， 加入上述稀 释的癌胚抗体溶液；
3 )上述烧杯密封， 置于 4°C环境， 放到震动台上， 震荡包被 20小时；
4 )包被结束， 用洗液洗涤 2次， 按 300μ1/个包被球计算， 洗液成分为 10mM pH7.4的 PBS (磷酸缓冲液 )含 5%吐温 -20;
5 )洗涤结束， 将包被后的导流球体置于吸水滤纸上吸干剩佘溶液， 之后 置于烧杯中， 按 150 μΐ/个包被球体的量加入一定量的封闭液， 室温下封闭 2 小时， 封闭液成分为 1 OmM pH7.4的 PBS含 1 %BSA;
6 )封闭结束， 将封闭液倒出， 将包被的导流球体置于吸水滤纸上吸干剩 佘溶液， 然后置于 28°C恒温培养箱内干燥 20小时。
实施例 2: 导流体硅化
导流体使用聚乙烯制造。 以 1%APES (氨丙基三乙氧基硅烷） 乙醇溶液 作为硅化液， 将硅化液 500mL倒入 lOOOmL烧杯中， 将导流体放入烧杯中， 完全浸没； 硅化 1分钟后， 取出， 空气中静止 0〜5s; 5s后将导流体放入装 超纯水烧杯中， 浸没， 晃动两下， 沥去水； 然后放入装乙醇烧杯中， 浸没， 搅动两下， 沥去乙醇， 平放于干净且干燥的纱布或滤纸上； 待乙醇溶液部分 挥发后， 将导流体平放于 40°C烘箱中干燥 30分钟。
实施例 3: 不规则的导流体
微流体芯片用 PMMA制造，包括有 6个溶液池， 参见图 7: 样本池 201 , 稀释液池 202, 标记液池 203 , 解离液池 204, 清洗液池 205, 废液池 206。 放置于废液池内的导流体使用硅胶制造， 其形状和废液池的形状一样， 表面 没有包被。
实施例 4: 有导流球体的聚合物微流体芯片
6个溶液池， 参见图 7: 样本池 201 , 稀释液池 202, 标记液池 203 , 解 离液池 204, 清洗液池 205 , 废液池 206, 以及溶液池的池壁 105 , 池底有基 板通孔 104;
7个阀， 参见图 8: 样本池阀 211 , 稀释液池阀 212, 标记液池阀 213 , 解离液池阀 214, 清洗液阀 215 , 废液阀 216, 主阀 217, 以及主阀与各分阀 间的通道 106。
参见图 9, 其中， 样本池阀 211+主阀 217+稀释液池阀 212及基板通孔 104和通道 106,构成样本池 201与稀释液池 202之间的双向泵，样本稀释泵 302。
参见图 10, 其中， 样本池阀 211+主阀 217+清洗液阀 215及通孔、 通道， 构成样本池 201与清洗液池 205之间的单向泵， 样本清洗泵 305; 样本池阀 211+主阀 217+废液阀 216及通孔、 通道， 构成样本池 201与废液池 206之间 的单向泵， 样本废液泵 306。
参见图 12, 其中， 样本池阀 211+主阀 217+标记液池阀 213及通道， 构 成样本池 201与标记液池 203之间的双向泵， 样本标记泵 303;
参见图 13 , 其中， 样本池阀 211+主阀 217+解离液池阀 214及通道， 构 成样本池 201与解离增强液池 204之间的双向泵， 样本解离增强泵 304; 参见图 4、 5、 6, 其中， 在样本池 201内放置有包被的导流球体 111 ; 样 本池直径为 6.4mm, 包被导流球体直径为 5.5mm, 球体材料为聚苯乙烯； 样 本池上方有圆环状的限位器 112, 限位器固定在样本池上。
实施例 5: 有导流体的聚合物微流体芯片排液实验
釆用实施例 4 的聚合物微流体芯片， 圆柱形容器直径为 6.4mm, 深度 10mm, 圆形导流体直径为 5.5mm (图 6 ), 材料为聚苯乙烯， 溶液 200μ1, 泵 的泵液量最大为 ΙΟμΙ/次， 泵出次数 30次， 实验结果如表 2。 表 2: 微流体芯片排液实验结果
Figure imgf000008_0001
实施例 6: 微流体芯片检测抗癌胚抗原
1 ) Eu3+-DTPA的制备： 用纯化水（含 Eu3+ 10 "6mol/L )稀释 1- ( 4-异硫 氰酸苄基） 二乙烯三胺五乙酸（简称 DTPA ), 将该溶液置于 37°C恒温水浴 中加热反应 2小时， 得铕螯合剂液；
2 ) Eu3+-DTPA标记抗癌胚抗原单克隆抗体： 将 lmg抗癌胚抗原单克隆 抗体对 0.1M碳酸盐缓冲液（pH 9.3 ) 4°C透析 16小时， 透析后抗体溶液转移 至 EP管 （塑料离心管）， 取 Eu3+-DTPA 0.2mg, 加入抗体溶液中， 室温避光 搅拌 14小时；
3 ) 纯化： 将8 6^6 200填料混匀装入1 30(^层析柱中， 待填料下 沉后， 用纯化水进行压柱， 流速控制在 2.5 ml/min, 流 2个柱体积即可。 柱 子压好后， 用 O.lmmol/L NaOH对柱子进行处理， 流速控制在 2.5 ml/min, 2 个柱体积即可。 然后用水洗平， 再用柱平衡液（0.1%高纯度 BSA牛血清蛋 白水溶液）对纯化柱平衡 1小时。 用移液器吸取步骤 2)标记好的抗体缓慢 加入到柱子内， 用洗脱液（50mMTris-HCl三羟甲基氨基甲烷盐酸盐缓冲液， 含 0.9%NaCl和 0.05%叠氮钠 pH7.8 )对样品进行洗脱，流速控制在 lml/min。
4 ) 收集： 收集样品 lml/管， 根据蛋白检测仪 280nm蛋白的吸光度值选 择吸光度高的 5管合并， 并将目的产物经过 0.22μηι滤膜过滤除菌， 置于 4°C 环境保存， 得到铕标记的癌胚抗原抗体溶液， 简称铕标记液。
5 )制备荧光增强液： 6ml冰醋酸用 0.1M的邻苯二甲酸氢钾调 pH值 3.2, 加入 15ιπηο1 β-ΝΤΑ ( β-萘甲酰三氟丙酮）， 50μηιο1 ΤΟΡΟ (三正辛基氧化膦）， lml Triton X-100 (聚乙二醇辛基苯基醚）， 纯化水定容至 1L, 搅拌混匀。 6 )制备样本稀释液： 含 1%牛血清白蛋白、 含 0.02%乙二胺四乙酸二钠 的 Tris-HCl缓冲液；
7 )制备清洗液： 含 5% Tween20(吐温 20)的 0.2MTris-HCl缓冲液； a)加样加试剂， 将 ΙΟΟμΙ步骤 4 ) 制备的样本铕标记的癌胚抗原抗体溶 液加入到实施例 4制备的微流体检测芯片 100样本池 201内， 将微流体检测 芯片 100安置在微流体控制单元 403上， 放置好稀释液、 清洗液、 荧光增强 液；
b)启动检测， 自动加样装置将 300μ1稀释液加入稀释液池 202, 将 2.0ml 清洗液加入清洗液池 205 , 将 200μ1铕标记液加入标记液池 203 , 将 150μ1荧 光增强液加入解离液池 204;
c)抗原抗体（包被）反应结合；样本稀释泵 302双向工作，使样本池 201、 稀释液池 202中的样本与稀释液混合， 持续 30〜60min; 停止时混合液全部贮 存在样本池 201 ;
d)排出废液， 样本废液泵 306单向工作， 将样本池 201内混合液排入废 液池 206;
e)清洗， 样本清洗泵 305单向工作， 将清洗液吸入样本池 201 ; 然后执 行步骤 d )排出废液； 重复步骤 e ) 和步骤 d ), 进行 4次清洗；
f)铕标记， 样本标记泵 303双向工作， 使铕标记液在样本池 201和标记 池 203间流动， 铕标记液和步骤 c )得到的 "抗原抗体（包被）反应结合体"， 混合， 持续约 30min; 停止时标记液在样品池 201 内， 然后执行步骤 d )排 除废液到废液池 206内；
g)再次清洗， 执行步骤 e), 进行 5次；
h)解离增强，样本解离增强泵 304双向工作，使解离增强液在样本池 201 和解离液池 204间流动， 进行解离， 持续 5min, 停止时解离增强液在解离液 池 204内；
i)检测，检测单元 402移动到微流体检测芯片 100的检测位置进行检测， 参见图 14。 以上的实施例仅仅是对本发明的优选实施方式进行描述，并非对本发明 的范围进行限定， 在不脱离本发明设计精神的前提下， 本领域普通工程技术 人员对本发明的技术方案作出的各种变型和改进， 均应落入本发明的权利要 求书确定的保护范围内。 工业实用性
本发明公开的微流体芯片可减少排液残留， 使导流体与容器之间形成间 隙， 气流增强， 将残留液滴抽走； 设置的限位器使导流体不会浮出液面， 减 少导流体与溶液无接触时间； 在导流体上包被与在容器中包被相比较， 工艺 简单， 更便于控制包被质量； 可控制溶液泵入时的溅射， 便于控制包被质量； 在溶液池中的导流体的转动， 使溶液中的抗原与包被导流体表面的抗体有效 接触， 比振动的效果更加充分， 提高反应效率。

Claims

权 利 要 求 书
1、 一种有导流体的微流体芯片， 其特征在于， 在所述微流体芯片的溶 液池内有导流体， 该导流体与溶液池壁之间的空隙为 0〜1.5mm。
2、 如权利要求 1所述的微流体芯片， 其特征在于， 所述导流体的形状 根据溶液池形状不同而不同， 是圆球体、 椭圆球体、 多面体或不规则几何体 中的一种。
3、 如权利要求 1所述的微流体芯片， 其特征在于， 所述导流体与溶液池 壁 （105) 之间的空隙取决于溶液的粘度， 当溶液粘度为 0.6〜1.2 mPa-s时， 所述空隙为 0〜0.9mm,当溶液粘度为 1.2〜6.0 mPa's时，所述空隙为 0.9〜1.5mm。
4、 如权利要求 1所述的微流体芯片， 其特征在于， 所述导流体表面经过 硅化处理。
5、 如权利要求 1所述的微流体芯片， 其特征在于， 所述导流体表面包被 有抗原或抗体。
6、 如权利要求 1所述的微流体芯片， 其特征在于， 所述导流体上方安置 有限位器（112), 限位器与溶液池壁 （105) 固定在一起。
7、 如权利要求 1 所述的微流体芯片， 其特征在于， 该芯片包括以下 6 个溶液池：样本池（ 201 )、稀释液池（ 202 )、标记液池（ 203 )、解离液池（ 204 )、 清洗液池（205 )、废液池（206),每个池底部有通孔（ 104);其中样本池（201 ) 中设有样本池阀（211 )和样本通孔， 稀释液池 202中设有稀释液池阀（212) 和稀释液通孔， 标记液池 （203 )设有标记液阀 （213) 和标记液通孔， 解离 液池（204) 中设有解离液阀 （214)和解离液通孔， 清洗液池（205 )设有清 洗液阀（215)和清洗液通孔， 废液池（206)设有废液阀（216)和废液通孔； 各阀通过通道（106)分别与主阀 （217)相连；
所述样本池阀 （211)、 主阀 （217)、 稀释液池阀 （212)及通孔和通道构 成样本池 （201 ) -稀释液池 （202) 之间的双向的样本稀释泵（302);
所述样本池阀 （211)、 主阀 （217)、 清洗液阀 （215)及通孔、 通道， 构 成样本池 （201 ) -清洗液池 （205 ) 之间的单向的样本清洗泵（ 305 ); 所述样本池阀 （211)、 主阀 （217)、 废液阀 （216)及通孔、 通道， 构成 样本池 （201 ) -废液池 （206)之间的单向的样本废液泵（306);
所述样本池阀 （211)、 主阀 （217)、 标记液池阀 （213)及通道， 构成样 本池 （201 ) -标记液池 （203 )之间的双向的样本标记泵（ 303 );
所述样本池阀 （211)、 主阀 （217)、 解离液池阀 （214)及通道， 构成样 本池 （201 ) -解离增强液池 （204) 之间的双向的样本解离增强泵（304)。
8、 权利要求 1〜7任一所述的微流体芯片在生化、 免疫和分子检测中的应 用。
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