WO2022242549A1 - Dispositif de réaction et dispositif d'entraînement de réaction - Google Patents

Dispositif de réaction et dispositif d'entraînement de réaction Download PDF

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Publication number
WO2022242549A1
WO2022242549A1 PCT/CN2022/092590 CN2022092590W WO2022242549A1 WO 2022242549 A1 WO2022242549 A1 WO 2022242549A1 CN 2022092590 W CN2022092590 W CN 2022092590W WO 2022242549 A1 WO2022242549 A1 WO 2022242549A1
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WO
WIPO (PCT)
Prior art keywords
capsule
reaction
pipeline
microvalve
micro
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/CN2022/092590
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English (en)
Chinese (zh)
Inventor
李大军
陈啸
朱伟杰
刘晓平
何良蒙
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Shenzhen Pinxueyou Technology Co Ltd
Original Assignee
Shenzhen Pinxueyou Technology Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from CN202110531058.9A external-priority patent/CN115418310A/zh
Priority claimed from CN202110531243.8A external-priority patent/CN115414970A/zh
Priority claimed from CN202110531062.5A external-priority patent/CN115418312A/zh
Priority claimed from CN202110650644.5A external-priority patent/CN115449474A/zh
Application filed by Shenzhen Pinxueyou Technology Co Ltd filed Critical Shenzhen Pinxueyou Technology Co Ltd
Publication of WO2022242549A1 publication Critical patent/WO2022242549A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • 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
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
    • C12M1/00—Apparatus for enzymology or microbiology
    • C12M1/36—Apparatus for enzymology or microbiology including condition or time responsive control, e.g. automatically controlled fermentors
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
    • C12M1/00—Apparatus for enzymology or microbiology
    • C12M1/36—Apparatus for enzymology or microbiology including condition or time responsive control, e.g. automatically controlled fermentors
    • C12M1/38—Temperature-responsive control

Definitions

  • the invention relates to a reaction device and its control equipment, in particular to a millimeter-scale reaction device and its control and drive equipment.
  • Microfluidics It is the integration of basic operating units such as sample preparation, reaction, separation, and detection in biological, chemical, and medical analysis processes onto micron-scale chips.
  • the micro-reaction chip at the micron level is difficult to develop; the pipeline is small, the internal resistance of the pipeline is large, and it is easy to block; it is difficult to add samples, and the current production and application costs are relatively high.
  • a reaction chip has emerged, which integrates pipes and capsules inside the plastic film as basic operating units such as sample preparation, reaction, separation, and detection, and uses external components to drive reactant flow or mixing or heating.
  • the temporary valve body is realized by melting the paraffin in the pipeline, which is very inflexible.
  • reaction device specifically refers to a biochemical reaction device.
  • PCR detection is a biochemical detection experiment widely used in the biomedical field. PCR detection requires samples to be sent to a specific PCR laboratory; in the laboratory, the samples are operated in stages and on different equipment; Measured on a real-time fluorescent quantitative PCR instrument. The operation process has high requirements for personnel, and only a dedicated PCR laboratory can be used for operation.
  • the temporary valve body is generally realized by melting the paraffin in the pipeline, or the temporary valve body is formed by temporarily extruding the plastic film, and these methods are very inflexible.
  • the application integrates the micro valve body inside the plastic or plastic film of the reaction chip, which greatly reduces the technical difficulty in the process of system design, production, control and use.
  • the reaction driving device proposed in this application solves the driving problem of microvalve and capsule; the reaction driving device can drive the flow or mixing or heating of the pipes and capsules in the reaction chip at the level of 0.1 mm to centimeters, but is not limited to The 0.1mm to centimeter-level reaction chip can also be extended to a smaller or larger system-wide reaction control system.
  • the technical solution of the present application to solve the above-mentioned technical problems is a reaction device, including a substrate, more than two microvalve bodies, more than two capsules, and pipelines; the capsules and pipelines are wrapped inside the substrate, and the force on the outer wall of the capsule can be Deformation discharges the internal liquid or air, the pipeline communicates with the capsule body, and the capsule body communicates with the capsule body or the outside through the pipeline; the micro valve body is set on the substrate, and the micro valve body can apply pressure or release pressure to the outer wall of the pipeline to drive closing or opening pipeline; or the microvalve body is wrapped inside the base material, and the internal pipeline of the microvalve body is connected to the pipeline, and the external force drives the microvalve body to close or open the internal pipeline.
  • the microvalve body includes a base A and a rotating body.
  • the rotating body includes an inner groove, and the pipe is clamped between the base A and the rotating body; the rotating body rotates to the inner groove parallel to the pipe, and the pipe opens; the rotating body rotates to the inner concave
  • the groove intersects or is perpendicular to the pipe, and the pipe is closed;
  • the microvalve body also includes a top cover A, and the top cover A includes a central opening through which a part of the rotating body is exposed;
  • the base A includes two or more cylinders, and the top cover A Including the connection groove, the substrate next to the pipe includes a connection hole, and the cylinder is snapped into the connection groove through the connection hole; or the inside of the pipe is coated with sealing paste or paraffin or oil or soft rubber coating; or a soft gasket is placed inside the pipe.
  • the microvalve body includes a base B and a spiral rotating body.
  • the base B includes a grooved stud, the spiral rotating body is connected to the stud by threads, and the pipe is clamped in the groove of the stud; the spiral rotating body rotates away from the base B, The pipe is opened; the spiral rotating body rotates close to the base B, presses the pipe, and the pipe is closed;
  • the microvalve body includes a gasket, the gasket is sleeved on the stud, and the pipe is clamped between the base B and the gasket;
  • the microvalve body includes a hose, and the hose is embedded in the pipeline; or the hose is embedded in the pipe by bonding In the pipeline; or the hose is directly embedded in the pipeline, and the outside of the hose is coated with sealing paste or paraffin.
  • the microvalve body includes a base C, a movable body C, and a cover C.
  • the movable body C is located in a cavity inside the base C, the cover C includes an opening, and a part of the movable body C is exposed through the opening;
  • the base C includes a first built-in pipeline, a second Two built-in pipelines, the first built-in pipeline communicates with the inlet of the microvalve body, the second built-in pipeline communicates with the outlet of the microvalve body;
  • the first built-in pipeline communicates with the opening A at the bottom of the cavity, and the second built-in pipeline communicates with the opening B at the bottom of the cavity;
  • the movable body C includes a built-in pipeline, the movable body C rotates in the cavity inside the base C, the built-in pipeline communicates with the first built-in pipeline and the second built-in pipeline of the base C, the inlet of the microvalve body communicates with the outlet of the microvalve body, and the pipeline is opened
  • the substrate includes a first substrate film and a second substrate film, and the substrate film includes prefabricated bulges or recessed capsules or pipes, and the first substrate film and the second substrate film are separated by glue or hot pressing or ultrasonic or Laser welding as one. More than two capsules or microvalves are concentrically arranged.
  • the technical solution of the present application to solve the above-mentioned technical problems may also be a reaction drive device for driving a reaction device comprising at least one microvalve body and at least one capsule body, including a microvalve body drive system and a capsule body extrusion drive system
  • the microvalve body drive system includes at least one microvalve body control subsystem
  • the microvalve body control subsystem includes: microvalve body drive motor drive module, microvalve body drive motor, microvalve body opening device, microvalve body drive motor drive
  • the module drives the microvalve drive motor to move, and the microvalve drive motor drives the microvalve opening device to open or close the microvalve on the reaction device;
  • the capsule drive system includes more than one capsule control subsystem, and each capsule control subsystem
  • the system includes: a capsule driving motor drive module, a capsule driving motor, and a capsule extruding device, the capsule driving motor driving module drives the capsule driving motor to move, and the capsule extruding device squeezes or releases the capsule on the reaction device.
  • the reaction driving device also includes a rotating device and a fixed carrying device; the rotating device is installed on the fixed carrying device and can rotate relative to the fixed carrying device;
  • the capsule on the reaction device is corresponding, the capsule driving motor is installed on the fixed bearing device, the rotating device drives the reaction device to rotate, the capsule extrusion device is aligned with the position of the capsule driving motor, and the capsule extrusion device applies pressure to the capsule or release the pressure;
  • the fixed carrying device includes the placement position of the reaction device, the capsule extrusion device is installed on the fixed carrying device, the position corresponds to the capsule on the reaction device, the capsule driving motor is installed on the rotating device, and the rotating device drives The capsule driving motor rotates, the capsule extruding device is aligned with the capsule driving motor during the rotation process, and the capsule extruding device applies or releases pressure to the capsule.
  • the driving motor of the micro valve body is installed on the fixed bearing device, the rotating device drives the reaction device to rotate, the driving motor of the micro valve body is aligned with the position of the micro valve body, and the driving motor of the micro valve body drives the micro valve body to open or close; or the micro valve body drives The motor is installed on the rotating device, and the rotating device drives the micro valve body drive motor to rotate, the position of the micro valve body drive motor and the micro valve body is aligned during the rotation process, and the micro valve body drive motor drives the micro valve body to open or close.
  • the reaction driving device also includes a reaction temperature control subsystem A, and the reaction temperature control subsystem A includes a temperature control module A, a heating module A, and a temperature coupling module A; the heating module A is attached to the temperature coupling module A, and the temperature coupling module A covers at least A temperature control capsule A; also includes a reaction temperature control subsystem B, the reaction temperature control subsystem B includes a temperature control module B, a heating module B, a temperature coupling module B, the heating module B is attached to the temperature coupling module B, and the temperature coupling Module B covers at least one temperature-controlled capsule B.
  • Beneficial effect 1 the microvalve body is integrated in the reaction device, which enhances the flexibility of the thin film reaction device; with the microvalve body and the capsule body, various reagents or powders can be pre-stored in the capsule body.
  • 2 The micro valve body directly squeezes the pipeline to seal the pipeline, which reduces the number and volume of the valve body components.
  • 3 The helical structure of the helical rotating body in the microvalve body increases the closing force.
  • the movable body C in the microvalve body uses the pipe as a part of the valve body; 5: Apply sealing paste or paraffin or oil to the inner wall of the pipe to increase the sealing ability of the microvalve body.
  • FIG. 1 is a schematic top view of an embodiment of a reaction device.
  • Fig. 2 is an exploded schematic view of an embodiment of a reaction device.
  • Fig. 3 is a three-dimensional schematic diagram of an embodiment of a microvalve body.
  • Fig. 4 is a schematic exploded view of an embodiment of a microvalve body.
  • Fig. 5 is a three-dimensional schematic diagram of an embodiment of a microvalve body.
  • Figure 6 is an exploded schematic view of an embodiment of a microvalve body.
  • Fig. 7 is a three-dimensional schematic diagram of an embodiment of a microvalve body.
  • Figure 8 is an exploded schematic view of an embodiment of a microvalve body.
  • Fig. 9 is a schematic bottom view of an embodiment of a microvalve body.
  • Fig. 9 is a schematic bottom view of an embodiment of a microvalve body.
  • FIG. 10 is a schematic perspective view of a microvalve body component.
  • Fig. 11 is a schematic front view of an embodiment of a multi-channel reaction device.
  • Fig. 12 is an exploded schematic view of a reaction driving device.
  • Fig. 14 is a schematic diagram of the electronic system framework of an embodiment of a PCR reaction driving device.
  • Fig. 15 is a three-dimensional schematic diagram of a microvalve body control integrated assembly.
  • Fig. 16 is an integrated schematic diagram of some components of a micro valve body control subsystem.
  • Fig. 17 is a schematic perspective view of an embodiment of an extrusion die set.
  • Fig. 18 is a schematic perspective view of an embodiment of the integrated control module of the microvalve body and the capsule body.
  • Fig. 11 is a schematic front view of an embodiment of a multi-channel reaction device.
  • Fig. 12 is an exploded schematic view of a reaction driving device.
  • Fig. 14 is a schematic diagram of the electronic system framework of an embodiment
  • FIG. 19 is a perspective view of an embodiment of a substrate of a capsule extrusion device.
  • Fig. 20 is a schematic perspective view of an embodiment of a capsule extrusion device.
  • Fig. 21 is a schematic perspective view of a partial structure embodiment of the capsule control subsystem.
  • Fig. 22 is a perspective view of a partial structure embodiment of the temperature control subsystem.
  • Fig. 23 is an exploded schematic diagram of a partial structure embodiment of the temperature control subsystem.
  • Fig. 24 is a schematic top view of an embodiment of a reaction device.
  • Fig. 25 is a schematic perspective view of an embodiment of a reaction driving device.
  • Fig. 26 is a three-dimensional schematic diagram of an embodiment of a reaction driving device without a casing.
  • FIG. 27 is a schematic perspective view of an embodiment of a control module bracket.
  • Fig. 28 is a schematic perspective view of an embodiment of a rotating device.
  • Fig. 29 is a schematic perspective view of an embodiment of a fixed carrying device.
  • Fig. 30 is a schematic perspective view of an embodiment of a temperature control unit.
  • Fig. 31 is a schematic perspective view of an embodiment of a driving motor.
  • reaction is not limited to the “reaction” in the concept of chemistry, biology and medicine, but also refers to the operation process, such as “dilution”, “dissolution”, “heating” and “cooling”, etc. Wait for the control process.
  • Different reaction devices can handle various types of biological, chemical, and medical analysis processes by setting microvalve bodies, pipes, and capsules with different numbers or connections. Because the microvalve body is integrated on the reaction device, the reaction device can be directly used as a container to accommodate various reagents and objects to be detected. With the microvalve body, various intermediate reaction products or final reaction products can be closed by the microvalve body In a capsule, this greatly expands the application range of thin-film reaction devices. With the microvalve body and the capsule body, various reagents can be pre-stored in the reaction device before leaving the factory. The reagents or powders are added into the capsule body through the pipeline communicating with the outside world to seal the pipeline. The reaction device with reagent or powder can be directly transported to the hands of the user, and with the corresponding reaction drive device, various experiments, inspections or tests can be carried out.
  • the extrusion of the capsule is driven by pneumatic components.
  • the pneumatic drive is powerful, it has a large volume and low control precision. Integrating the micro-valve body in the reaction device can manage the opening and closing of the pipeline, which greatly enhances the flexibility and application range of the thin-film reaction device. If the micro-valve body is made smaller, the integration degree of the reaction device will be higher. Integrating the valve body on the film is a major challenge. Considering the characteristics of the film, directly using the film pipe as a part of the valve body can greatly reduce the volume of the micro-valve body and reduce the number of parts, or wrap the micro-valve body part in the film. It can greatly reduce the volume of the micro valve body and facilitate integration.
  • a linear motor may be used to drive the capsule extruding device to squeeze or release the capsule.
  • the capsule extrusion device includes a sliding platform, which converts rotation into linear movement, and can also squeeze or release the capsule.
  • the sliding platform is driven by screw rotation, which can achieve high-precision translation and precisely control the amount of extrusion.
  • an embodiment of a reaction device can be used as a PCR reaction device, on which a lot of pipelines are distributed, and the pipelines connect various components, and capsules with different functions are distributed in different positions of the reaction device.
  • Capsules 13121, each capsule is connected through a pipeline, and a microvalve 13802 is arranged on the pipeline to control the opening or closing of the pipeline.
  • the reaction device includes at least one channel for adding the substance to be detected, at least one capsule 1110 and at least one channel for adding the reagent to be detected;
  • the channel for adding the substance to be detected includes an inlet 1120 for the substance to be detected, a capsule for containing the substance to be detected 1138, and a capsule for containing the substance to be detected It communicates with the capsule body through the microvalve body 1131;
  • the reagent adding channel includes a reagent adding port 2118 and a reagent capsule body 4101, and the reagent adding port communicates with the reagent capsule body through a pipeline;
  • the reagent capsule body communicates with the capsule body through the microvalve body 1131.
  • the capsules are connected in series or in parallel to form reaction channels.
  • the externally connected pipeline 2111 is connected to the heparin cap 2101, the pipeline 2118 is connected to the heparin cap 2108, the externally connected pipeline 2211 is connected to the heparin cap 2201, and the pipeline 2218 is connected to the heparin cap 2208;
  • the heparin cap can be used to inject reagents with a needle without affecting the inside of the reaction device Airtight with the outside, the reaction device can be provided to the laboratory or inspection room, and the user decides the type of reagent to be added during the reaction.
  • a plurality of positioning holes 2300 are included.
  • the injection port is closed by hot melt or ultrasonic or glue, and the reaction device can be safely transported.
  • the corresponding microvalve of the capsule is opened with the corresponding reaction driving device The body can start the reaction process.
  • the reagent capsules are closed in advance, without the need for the user to prepare reagents, which greatly reduces the difficulty of the user's operation, and at the same time ensures the consistency and scientificity of the test of the reaction device.
  • the substrate is formed by pressing and bonding the upper film, that is, the first substrate film 5100, and the lower film, that is, the second substrate film 5200, or welded by glue or heat or ultrasonic or laser.
  • the substrate film includes prefabricated raised or recessed capsules or pipes, pipes and capsules, and a large number of microvalve bodies 5300 are distributed in different positions of the film; or the external interface of the pipeline, including the injection port, which can be connected with a soft plug
  • the reagent or detection substance is added to the device; the external interface of the pipeline is connected to the heparin cap joint 5501, and the heparin cap joint 5501 is connected to the heparin cap 5511.
  • the heparin cap can also be other devices with a soft closure interface, or a joint that can be opened and closed.
  • the base material composed of film material has a small thickness and can be stored in curls, which is very suitable for production, storage and preservation.
  • a reaction temperature control subsystem can be installed in the corresponding equipment of the capsule 1210, or a reaction temperature control subsystem can be installed in the corresponding positions of other capsules.
  • one primer reagent can detect one object to be detected, and different primers are placed in 8 capsules to detect 8 types of objects to be detected.
  • the temperature conditions required for the PCR reaction are the same, and 8 capsules can be tested at the same time. Perform temperature cycling operations required for PCR reactions.
  • the second-level reaction zone is located between the first-level reaction zone 1221 and the third-level reaction zone 1223; the second-level reaction zone includes at least one set of secondary reaction integrated units; the secondary reaction integrated unit Including the reagent inlet, the reagent capsule, and the second-stage capsule; the reagent inlet and the reagent capsule are connected through pipelines; the reagent capsule and the second-stage capsule are connected through a microvalve body; two or more secondary reactions
  • the second-stage capsules of the integrated unit are connected in cascade or parallel through the micro-valve body; the first-stage reaction zone and the second-stage reaction zone are connected through the micro-valve body; Communication through the microvalve body.
  • the first-stage reaction area includes a substance to be detected adding port 1120, a substance to be detected containing capsule 1138, and a capsule 1110 in the first stage reaction zone; the substance to be detected adding port 1120 is connected to the substance to be detected containing capsule 1138 through a pipeline;
  • the object containing capsule body 1138 is communicated with the capsule body 1110 of the first-stage reaction zone through the microvalve body 1131;
  • the second-stage reaction zone comprises a reagent inlet 2118, a reagent capsule body 1230, and a second-stage capsule body 1210; the reagent inlet port 2118 and the reagent
  • the capsule body 1230 communicates with the pipeline; the reagent capsule body 1230 communicates with the second-stage capsule body 1210 through the microvalve body 1250; 13802 can open or close the communication between the third-stage reaction zone capsule and the second-stage reaction zone.
  • the capsule in the third-stage reaction zone includes a first temperature capsule 13111 and a second temperature capsule 13121, and the first temperature capsule and the second temperature capsule are communicated through pipelines.
  • a fluorescence detection capsule 13131 is also included between the first and second temperature capsules, the base material of the fluorescence detection capsule is made of transparent material; the arrangement of the first and second temperature capsules and the fluorescence detection capsules is not limited in order , the fluorescence detection capsule can be arranged on the outermost side.
  • the primer inlet is communicated with the primer containing capsule through a pipeline, and the primer containing capsule is connected with the third-stage reaction zone capsule through a microvalve 13801;
  • the first and second temperature capsules can be two constant temperature regions
  • the external reaction driving device can control the first or second temperature capsule to maintain the set temperature through the temperature control module, let the reaction reagent go through the first temperature capsule, and then go through the second temperature capsule, by allowing the PCR reaction liquid to
  • the movement of capsules in different temperature regions can speed up the temperature cycle of PCR, and can also control the temperature change more precisely.
  • the real-time fluorescence quantitative PCR reaction device needs to perform fluorescence detection in each temperature cycle, by setting the fluorescence detection capsule 13131 between the first temperature capsule 13111 and the second temperature capsule 13121, and setting excitation on both sides of the fluorescence detection capsule.
  • the light emission tube and the fluorescence detection tube can allow the maximum luminous flux to pass through the object to be detected, and also have a short optical path.
  • the first-level reaction zone also includes a first-level reagent inlet 1520 and a first-level reagent capsule 1530; the first-level reagent inlet is connected to the first-level reagent capsule through a pipeline; the first-level reagent capsule 1530 is connected to the first
  • the capsules 1110 in the reaction zones of the first stage are communicated with each other through the microvalve 1531 .
  • One or more channels for adding reagents are set in the first-stage reaction area, which is convenient for adding reagents into the capsules of the first-stage reaction area, and facilitates the storage and addition control of different kinds of reagents. Reaction devices with different needs have different pipelines and capsules.
  • Two or more layers of plastic are used for crimping and bonding, which greatly reduces production and processing costs.
  • the second plastic layer is preformed into capsules or pipes by pressing or blistering, and the flat plastic can ensure the positional accuracy of each component.
  • Some embodiments also include an independently arranged digestion agent injection channel, including a digestion agent injection port, a digestion agent holding capsule, and a digestion agent releasing microvalve body;
  • the capsule body is connected to the pipeline system of the PCR reaction device through the digestion agent releasing micro-valve body.
  • the digestion agent injection channel can be set at any position that communicates with the pipeline. After the experiment or test is over, the reaction drive device drives the micro-valve body inside the equipment to open, allowing the digestion agent to flow through each capsule or internal pipeline, and the reaction product or added Various substances are digested.
  • the first-stage reaction zone 120101 includes two or more channels for adding substances to be detected; the channels for adding substances to be detected in the first-level reaction zone and the PCR reaction of the third-level reaction zone 120103
  • the channels are paired one-to-one, and the capsules in the first-stage reaction zone communicate with the capsules in the third-stage reaction zone through paired microvalves.
  • the first-stage reaction area includes 8 channels for adding substances to be detected, wherein one channel for adding substances to be detected includes an inlet for adding substances to be detected 18110, a capsule for containing substances to be detected 18120, and a capsule for the first-stage reaction area 18150; Port 18110 communicates with the substance-to-be-tested capsule 18120 through pipelines; the substance-to-be-tested capsule 18120 communicates with the capsule 18150 in the first-stage reaction zone through a microvalve 18130; the third-stage reaction zone includes 8 PCR reaction channels, of which One PCR reaction channel includes a reagent inlet 2320, a reagent capsule 2330, and a third-stage reaction zone capsule 2310; the reagent inlet 2320 is connected to the reagent capsule 2330 through a pipeline; the reagent capsule 2330 is connected to the third-stage reaction zone capsule 2310 The first-stage reaction zone capsule 18150 communicates with the third-stage reaction zone capsule 2310 through the microvalve body 23802 .
  • the channel for adding the substance to be detected in the first-stage reaction zone includes the channel for adding the pre-reaction reagent. 18220 is communicated through a pipeline; the pre-reaction reagent capsule 18220 is communicated with the first-stage reaction zone capsule 18150 through a microvalve 18230 .
  • One or more reagent addition channels are set in the channel for adding the substance to be detected in the first-stage reaction zone, which is convenient for adding the reagents into the capsule of the first-stage reaction zone, and is convenient for storage and addition control of different kinds of reagents.
  • an embodiment of a microvalve body includes a base A7100 and a rotating body 7300 .
  • the rotating body 7300 includes an inner groove 7310 , and the pipe is clamped between the base A7100 and the rotating body 7300 .
  • the pipe formed by the upper and lower films has a certain deformation ability.
  • the rotating body rotates to the inner groove parallel to the pipe, the pipe opens and the liquid can pass through the pipe, especially when pressure is applied to the connected capsule. Liquid or gas is then able to pass through the microvalve body.
  • the rotating body rotates until the inner groove intersects or is perpendicular to the pipe.
  • the pipe is pressed by the part of the rotating body that does not have an inner concave, and the pipe is in a closed state.
  • sealing paste or paraffin or oil or soft rubber coating on the inner wall of the pipeline, the sealing ability when the micro valve body is closed can be increased, and the closing pressure when the micro valve body is closed can also be reduced.
  • a soft gasket can be placed in the pipeline. When it is closed, due to the pressure, the soft gasket will deform to a certain extent and play the role of a sealing gasket.
  • the microvalve body also includes a top cover A7200, the top cover A includes a central opening 7210, and a part 7320 of the rotating body is exposed through the central opening; the base A includes two or more columns 7121, and the top cover A includes The connection groove 7221, the base material next to the pipe includes a connection hole, and the column 7121 is snapped into the connection groove 7221 through the connection hole.
  • One side of the top cover A and the base A includes an arc-shaped protrusion 7110, and the rotating body includes an indicating portion 7330, and the indicating portion overlaps with the arc-shaped protrusion to indicate that the microvalve body is opened.
  • One side of the top cover A and the base A includes an arc-shaped protrusion 7110, and the rotating body includes an indicating portion 7330, and the indicating portion overlaps with the arc-shaped protrusion to indicate that the microvalve body is opened.
  • the microvalve body includes a base B12100, a spiral rotating body 12200, the base B includes a grooved stud 12110, the spiral rotating body is threaded to the stud, and the pipe clamp Hold in the groove 12111 of the stud; the helical rotating body turns away from the base B, and the pipe opens; the helical rotating body turns close to the base B, presses the pipe, and the pipe closes.
  • the pipeline of the substrate there is a hole for the stud 12110 to pass through.
  • the pipeline can pass through the groove 12111 of the stud, and the screw rotating body 12200 can rotate up and down on the stud 12110, that is, the stud 12110 is Slotted studs; the slotted studs can be centered or eccentric, or cut off a portion of the stud body.
  • the force exerted on the pipeline by the helical rotating body 12200 during the rotation process is variable, increasing the rotation force can increase the pressure and make the pipeline more tightly closed.
  • the micro-valve body includes a gasket 12300, the gasket is sleeved on the stud, and the pipe is clamped between the base B and the gasket; the micro-valve body includes a hose 12500, and the hose is pre-buried in the pipe; or the hose is pre-buried in the pipe by bonding In the pipeline; or the hose is directly embedded in the pipeline, and the outside of the hose is coated with sealing paste or paraffin.
  • Adding an annular gasket 12300 or a non-annular gasket between the base B and the spiral rotating body 12200 can reduce the friction on the substrate during the spiral rotation and prevent the deformation of the substrate. At the same time, the periphery of the gasket can better provide the pipeline Apply closing pressure.
  • the pre-embedded hose 12500 can deform and close the internal passage when it encounters pressure. When the pressure disappears, it has a certain recovery ability and can open the pipeline by itself. Applying sealing paste or paraffin to the outside of the hose can reduce the difficulty of installation and reduce the possibility of air leakage and liquid leakage outside the pipe and hose.
  • Using the pre-embedded hose can greatly reduce the rotational driving force of the helical rotating body 12200, and the hose can be a hose with a certain degree of elasticity.
  • the microvalve body includes a base C15100, a movable body C15200, and a cover C15300, the movable body C is located in the cavity 15110 inside the base C, and the cover C includes an opening 15310, A part 15210 of the movable body C is exposed through the opening;
  • the base C includes a first built-in pipeline 16100 and a second built-in pipeline 16200, the first built-in pipeline communicates with the microvalve body inlet 16110, and the second built-in pipeline communicates with the microvalve body outlet 16210;
  • One built-in pipeline communicates with the opening A15510 at the bottom of the cavity, and the second built-in pipeline communicates with the opening B15520 at the bottom of the cavity;
  • the movable body C includes a built-in pipeline 17100, the movable body C rotates in the cavity inside the base C, and the built-in pipeline 17100 communicates with the bottom of the base C
  • the micro-valve body and the pipeline are relatively independent, the micro-valve body is independently produced, and the precision can be very high.
  • the contact surface between the base C and the movable body C is a plane, and the movable body C includes the built-in pipeline 17100 and the external pipeline is parallel, which is different from the traditional
  • the unique ball valve structure is also different from the traditional valve body. This valve body structure is small in size and low in height, which greatly facilitates integration inside the membrane.
  • the microvalve body includes a gasket covering the openings of the first built-in pipe and the second built-in pipe inside the base C. Gasket 15810 covers cavity bottom opening A15510 and gasket 15820 covers cavity bottom opening B15520.
  • the spherical rotating body has an arc-shaped contact surface with the valve body wall, so it is difficult to install gaskets, and it is difficult to make small volume and height.
  • the device for opening the microvalve or capsule can be installed on a structure similar to a 3D printer, and can move on the X-axis and Y-axis to find and drive the microvalve or capsule that needs to be opened.
  • the reaction driving device clamps the reaction device 19100 in the middle of the equipment.
  • the front frame 19200 of the equipment and the rear frame 19300 of the equipment are the bearing structures of internal components.
  • the reaction driving device includes a large number of drive motors and various functional components inside the equipment.
  • the front frame 19200 can be turned upside down, exposing the installation position of the reaction chip 19100.
  • the compression of the capsule can be driven by pneumatic components or by an electric motor.
  • the motor drive module of the micro valve body control subsystem includes a motor control system, the motor control system includes a network control bus interface, the micro valve body control subsystem is connected to a control network through the network control bus interface, and the network control bus interface is an rs-485 bus interface Or Powerbus bus interface or Ethernet interface.
  • the reaction drive device also has electronic systems, which can be divided into different units according to different functions.
  • the electronic system includes main control unit, display unit, control input unit, excitation light source control and fluorescence detection unit, micro valve control unit, capsule control unit, reaction temperature control unit, ambient temperature control unit, magnetic bead control unit, pretreatment control unit. Due to the large number of capsules and motors that need to be controlled, general computer chips or microprocessor chips do not have so many I/O interfaces. It is an effective method to connect many microprocessors through the network to form a network. RS485 serial communication interface is used. As a communication network, it can greatly reduce the internal network connection.
  • the WIFI unit can communicate with external devices wirelessly, and the debugging serial port is convenient for device development and device maintenance.
  • equipment part 4000 integrates many microvalve body control subsystems, and each microvalve body motor drive module Integrated on the circuit board 4100, the opening device of the microvalve body in one microvalve body control subsystem includes a rotating shaft 4210, and the front end of the rotating shaft 4210 includes a Phillips screwdriver joint, which can rotate the rotating parts in the microvalve body of the reaction device,
  • the output shaft of the micro valve body motor 4230 passes through the hole of the circuit board 4100 and is connected with the rotating shaft 4210 of the opening device.
  • an angle sensor 4220 is installed, and a capsule driving motor 4120 is also included in FIG. 15 .
  • the microvalve body motor drive module is integrated on the circuit board
  • the microvalve body opening device includes a rotating shaft 5210
  • the front end of the rotating shaft 5210 includes a Phillips screwdriver joint 5211, which can rotate the rotating parts in the microvalve body of the reaction device
  • the angle sensor 5220 is sleeved on the connecting shaft of the rotating shaft 5210
  • the output shaft of the microvalve body motor 5230 is connected to the rotating shaft 5210, and there is a gap 5223 for installing a circuit board at the connection.
  • a telescoping device can be installed inside the rotating shaft 5210. When the rotating shaft 5210 is in contact with the microvalve body of the rotating reaction device, it can be properly deformed and squeezed to buffer the contact impact force. Or when the bolt is turned, the turning shaft 5210 can be contracted or extended according to the height of the bolt turning.
  • the capsule extrusion devices of multiple capsule control subsystems are integrated and installed together to form an extrusion module 6000, and each capsule extrusion device can operate independently.
  • Different shapes of the body correspond to different shapes.
  • the volume of the corresponding pretreatment capsule extruding device 6120 is the largest, and the capsule extruding device 6110 corresponding to the capsule 1110 is relatively smaller.
  • the position of each capsule extrusion device corresponds to the distribution of capsules on the reaction device.
  • the extrusion module 6000 also includes a plurality of holes through which the rotation shaft of the microvalve body opening device passes.
  • Extrusion module 6000 can decompose the substrate of the capsule extrusion device, on which microvalve holes 9200 and capsule holes 9100 are distributed.
  • the capsule hole 9100 prevents the capsule from being deformed in the X-axis and Y-axis directions during extrusion.
  • a set of capsule extruding device includes a capsule driving frame 11000, a movable head 11010, and a rotating screw 11020.
  • One end of the rotating screw is rotatably fixed on the capsule driving frame 11000, and the other end of the rotating screw is fixed on the capsule driving frame 11000.
  • One end is threadedly connected with the movable head.
  • the output shaft of the capsule motor 12010 drives the rotating rod 12020 to rotate, the rotating rod 12020 drives the rotating screw rod 11020 to rotate, and the rotating screw rod 11020 drives the movable head 11010 to move up and down.
  • the capsule driving frame 11000 has a first support rod 11001 and a second support rod 11002 , and two collars of the movable head 11010 .
  • the capsule motor 12010 is connected to the rotating rod 12020 through the motor shaft, and the end of the rotating rod 12020 includes a bolt interface 12021, which can be coupled to the rotating screw rod 11020.
  • the temperature control subsystem includes a temperature control module, a heating module 14010, and a temperature coupling module 14020.
  • the heating module is attached to the temperature coupling module, and the temperature sensor 14030 is attached to the temperature coupling module.
  • the temperature coupling module is placed in the temperature control tank 14050 , and the temperature coupling module 14020 is fixed in the temperature control tank 14050 by the temperature control tank cover 14060 .
  • It also includes a fluorescence detection subsystem.
  • the fluorescence detection subsystem includes a fluorescence excitation module and a fluorescence detection module. The fluorescence excitation module emits excitation light into the capsule, and the fluorescence detection module receives the fluorescence emitted by the capsule.
  • the maximum luminous flux can pass through the object to be detected, and at the same time, there is a short optical path.
  • Circuits such as excitation light-emitting tubes and fluorescent detection tubes are more sensitive to temperature.
  • the temperature inside the device can be controlled at a suitable temperature.
  • the reaction device is placed on a supporting part, and the reaction device is driven to the set capsule or microvalve driving device, so that the number of driving devices can be greatly reduced.
  • the driving device can be placed on a carrier part, and the driving device can be moved to the capsule body or microvalve body to be operated, which can also reduce the number of driving devices.
  • the capsule includes a substance to be tested containing capsule 2015, a reagent capsule 2011, a PCR primer containing capsule 2031, and a capsule 2021; Sealed with a rubber stopper or an openable cap; the reagent capsule is connected to the reagent inlet through a pipeline, and the reagent inlet is closed with a soft rubber plug or an openable cap; or the reagent inlet is ultrasonically welded or heat-pressed or sealed after the reagent is added Glue plugging; the PCR primer holding capsule is connected to the PCR primer inlet through a pipeline, and the PCR primer inlet is closed by a soft rubber plug or an openable cap, or sealed by ultrasonic welding or heat pressing or sealant after adding PCR primers; The object holding capsule communicates with the capsule through the micro valve body; the capsule communicates with the PCR primer containing capsule through the micro valve body; the PCR primer containing capsule is made of light-transmitting material.
  • the reaction device is fan-shaped.
  • the PCR primer holding capsule can be designed to a fan-shaped edge with a large radius, and the structure of the object-to-be-tested capsule 2015 and the reagent capsule 2011 can be designed to a fan-shaped inner ring with a small radius.
  • One object to be detected needs to detect multiple results, and multiple PCR primers can be set. If a plurality of microvalves are provided on the pipeline 2050, different sample holding capsules, reagent capsules and PCR primer containing capsules can be divided into multiple groups, and multiple input and multiple detection tests or applications can be performed.
  • the rotating device 3010 can rotate inside the reaction driving device
  • the fixed carrying device includes a fixed chassis 3020, a control module bracket 3030; the upper casing 3040 carries a display screen 3051 and an input keyboard 3052.
  • the reaction device is placed on the rotating device 3010 and can rotate with the rotating device.
  • the capsule extrusion device is installed on the rotating device, and its position corresponds to the capsule on the reaction device; the capsule extrusion device corresponds to the capsule and can maintain the state of the capsule.
  • the capsule needs to be output by half
  • the liquid can be driven by a screw rod to squeeze out half of the liquid from the capsule body, and the position and state of the screw rod remain unchanged, and half of the state can be maintained.
  • the capsule driving motor is installed on the fixed bearing device, and different capsule capsule extrusion devices can be driven by one or several capsule driving motors, which greatly reduces the number of capsule driving motors.
  • the driving motor of the micro valve body Including the driving motor of the micro valve body; the driving motor of the micro valve body is installed on the fixed bearing device, the rotating device drives the reaction device to rotate, the driving motor of the micro valve body is aligned with the position of the micro valve body during the rotation process, and the driving motor of the micro valve body drives the micro valve body On or off.
  • the reaction device is fixed and the control module bracket drives the drive motor, temperature control unit and other modules to rotate, various detection functions can also be realized. After the control module bracket rotates, each module needs to be powered by a brush or a battery.
  • the control module bracket 3030 includes two groups of micro valve body driving motors, micro valve body driving motor 5010 and micro valve body driving motor 5011, the two groups of micro valve body driving motors are symmetrical in structure, if two groups of reaction devices are placed, because of the symmetrical structure, the two A group of micro valve body drive motors can simultaneously control the operation of two groups of reaction devices. If the microvalve body drive motor is placed on the slide module driven by the screw, microvalve bodies with different radius settings can also be driven, which can be more flexible, and a reaction drive device can drive reaction devices with different radius settings. It includes at least one temperature control unit.
  • the temperature control unit includes a heating module and a temperature coupling module.
  • the heating module is installed on the temperature coupling module; the temperature control unit is installed on a fixed bearing device, and the rotating device drives the reaction device to rotate.
  • the control module bracket 3030 includes two sets of temperature control units, the temperature control unit 5021 and the temperature control unit 5022.
  • the two sets of temperature control units are symmetrical in structure. If two sets of reaction devices are placed, because of the symmetrical structure, the two sets of temperature control units can simultaneously control two The temperature control operation of the group reaction device.
  • the PCR test requires temperature cycle control of two temperature ranges for the liquid in the capsule.
  • the reaction device is placed in the rotating device 3010, which can quickly switch between the two temperature ranges, speeding up the test process and reducing the difficulty of temperature control. It includes at least one vibration unit; the vibration unit is installed on the fixed bearing device, the rotating device drives the reaction device to rotate, the vibration unit is aligned with the capsule body during the rotation process, and the vibration unit contacts the capsule body.
  • the control module bracket 3030 includes two sets of vibration units, the vibration unit 5031 and the vibration unit 5032, and the structures of the two groups of vibration units are symmetrical.
  • At least one fluorescence detection subsystem is also included.
  • the fluorescence detection subsystem includes a fluorescence excitation module and a fluorescence detection module.
  • the fluorescence excitation module and the fluorescence detection module are installed on a fixed carrier, and the rotating device drives the reaction device to rotate.
  • the module and the fluorescence detection module are aligned with the capsule during the rotation process; after alignment, the light sent by the fluorescence excitation module illuminates the capsule, and the fluorescence detection module detects the excited fluorescence of the capsule;
  • the capsule drive motor or microvalve body drive motor includes a shaft telescopic control
  • the shaft telescopic control device includes an electromagnet, and the electromagnet is powered on or off to drive the shaft to extend or shorten;
  • the temperature control unit includes a lifting control device, and the lifting control device includes an electromagnet, and the electromagnet is powered on or off to drive the temperature control unit to rise or lower.
  • the control module bracket 3030 includes a fluorescence detection module 5051 , and the fluorescence excitation module can also be placed on the fixed chassis 3020 .
  • fluorescence detection different reaction systems correspond to different excitation light bands.
  • excitation modules and fluorescence detection modules of different bands can be set to inspect different capsules.
  • the control module bracket 3030 includes a support column 7010 , and the control module bracket 3030 is connected to the fixed chassis 3020 through the support column 7010 .
  • the rotating device 3010 includes two positions 8010 and 8011 for placing the reaction device, and the position 8011 in the figure places the reaction device; of course, it is also possible to set 4 positions for placing the reaction device, and place 4 reactions at a time device, for reaction actuation.
  • a lot of capsule extruding devices are placed at the bottom of the rotating device, such as capsule extruding devices and capsule extruding devices.
  • the capsule extruding device is arranged on the rotating device 3010, and the capsule to be extruded corresponds to a capsule extruding device, which can maintain the pressure applied to the capsule during the rotation process.
  • the capsule driving motor 10010 is installed on the fixed carrying device, and the capsule driving motor can also be arranged above the microvalve driving motor.
  • the temperature control unit includes a lifting control device.
  • the lifting control device includes an electromagnet 13010.
  • the electromagnet is powered on or off to drive the temperature control unit to rise or fall.
  • the temperature control unit includes a heating module 13020, a temperature coupling module 13030, and a temperature detection module 13050.
  • the heating module is installed on the temperature coupling module. In the figure, multiple heating modules are located at different positions of the temperature coupling module.
  • the temperature coupling modules can be controlled in series or in parallel.
  • the temperature coupling module may be an integrated cooling module.
  • the capsule drive motor or the microvalve body drive motor includes a shaft telescopic control device 34010, and the shaft telescopic control device includes an electromagnet, which drives the shaft to extend or shorten when the electromagnet is powered on or off; The head of the screwdriver needs to be retracted to facilitate the operation of the rotating device, and the electromagnet is used to push the screwdriver out, or pull the screwdriver back, so that the rotating device 3010 can be easily avoided.

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Abstract

L'invention concerne un dispositif de réaction (19100). Le dispositif de réaction comprend un matériau de base, au moins deux corps de micro-vanne (13802, 1131, 5300, 1250, 13801, 1531, 18130, 23801, 23802, 18230) et des capsules (1110, 13121, 4201, 1210, 13131, 2021) enveloppées dans le matériau de base, et des conduites (2111, 2118, 2211, 2218); les capsules (1110, 13121, 4201, 1210, 13131, 2021) sont en communication avec les capsules (1110, 13121, 4201, 1210, 13131, 2021) ou l'extérieur au moyen des conduites (2111, 2118, 2211, 2218); les corps de micro-vanne (13802, 1131, 5300, 1250, 13801, 1531, 18130, 23801, 23802, 18230) sont agencés sur le matériau de base et peuvent appliquer une pression sur les parois externes des conduites (2111, 2118, 2211, 2218) ou relâcher la pression de manière à entraîner les conduites (2111, 2118, 2211, 2218) à se fermer ou à s'ouvrir; et, en variante, les corps de micro-vanne (13802, 1131, 5300, 1250, 13801, 1531, 18130, 23801, 23802, 18230) sont enveloppés dans le matériau de base, des conduites internes des corps de micro-vanne (13802, 1131, 5300, 1250, 13801, 1531, 18130, 23801, 23802, 18230) sont raccordées aux conduites (2111, 2118, 2211, 2218), et les corps de micro-vanne (13802, 1131, 5300, 1250, 13801, 1531, 18130, 23801, 23802, 18230) peuvent être entraînés pour fermer ou ouvrir les conduites internes sous l'action d'une force externe. Un système d'entraînement de corps de micro-vanne d'un dispositif d'entraînement de réaction comprend au moins un trajet de corps de micro-vanne (13802, 1131, 5300, 1250, 13801, 1531, 18130, 23801, 23802, 18230) et un sous-système de commande de corps de capsule, et des moteurs électriques d'entraînement de corps de micro-vanne (5010, 5011) entraînent un dispositif d'ouverture de corps de micro-vanne à ouvrir ou à fermer les corps de micro-vanne (13802, 1131, 5300, 1250, 13801, 1531, 18130, 23801, 23802, 18230) sur le dispositif de réaction; et des dispositifs de pression de capsule (6120, 6110) pressent ou relâchent les capsules (1110, 13121, 4201, 1210, 13131, 2021) sur le dispositif de réaction. Les corps de micro-vanne (13802, 1131, 5300, 1250, 13801, 1531, 18130, 23801, 23802, 18230) sont intégrés dans le dispositif de réaction, une gestion d'ouverture et de fermeture est réalisée sur les conduites (2111, 2118, 2211, 2218), et la flexibilité et la plage d'application du dispositif de réaction de type film sont améliorées.
PCT/CN2022/092590 2021-05-16 2022-05-13 Dispositif de réaction et dispositif d'entraînement de réaction Ceased WO2022242549A1 (fr)

Applications Claiming Priority (8)

Application Number Priority Date Filing Date Title
CN202110531058.9A CN115418310A (zh) 2021-05-16 2021-05-16 一种生化反应驱动装置
CN202110531243.8 2021-05-16
CN202110531243.8A CN115414970A (zh) 2021-05-16 2021-05-16 一种生化反应装置
CN202110531062.5A CN115418312A (zh) 2021-05-16 2021-05-16 一种pcr反应装置
CN202110531062.5 2021-05-16
CN202110531058.9 2021-05-16
CN202110650644.5 2021-06-11
CN202110650644.5A CN115449474A (zh) 2021-06-09 2021-06-11 一种生化反应与驱动装置

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CN1208464A (zh) * 1995-12-05 1999-02-17 盖默拉生物科学公司 利用向心加速度以激发具有自有资讯微型流态系统之中的液体运动的装置和方法
JP2007248218A (ja) * 2006-03-15 2007-09-27 Pentax Corp マイクロチップ
CN102679039A (zh) * 2012-05-07 2012-09-19 博奥生物有限公司 一种集成于微流控芯片内的气动微阀
CN105032512A (zh) * 2015-08-25 2015-11-11 辽宁中医药大学 用于药物配伍筛选的集成化微流控芯片、制备方法及应用
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