WO2005024436A1 - カスタマイズ可能なチップおよびその製造方法 - Google Patents
カスタマイズ可能なチップおよびその製造方法 Download PDFInfo
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- WO2005024436A1 WO2005024436A1 PCT/JP2004/012753 JP2004012753W WO2005024436A1 WO 2005024436 A1 WO2005024436 A1 WO 2005024436A1 JP 2004012753 W JP2004012753 W JP 2004012753W WO 2005024436 A1 WO2005024436 A1 WO 2005024436A1
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- flow path
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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
- B01L3/502738—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 integrated valves
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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
- B01L3/502707—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 manufacture of the container or its components
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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
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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
- 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
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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
- B01L2300/00—Additional constructional details
- B01L2300/06—Auxiliary integrated devices, integrated components
- B01L2300/0627—Sensor or part of a sensor is integrated
- B01L2300/0654—Lenses; Optical fibres
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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
- B01L2300/00—Additional constructional details
- B01L2300/06—Auxiliary integrated devices, integrated components
- B01L2300/0681—Filter
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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
- B01L2300/00—Additional constructional details
- B01L2300/08—Geometry, shape and general structure
- B01L2300/0809—Geometry, shape and general structure rectangular shaped
- B01L2300/0816—Cards, e.g. flat sample carriers usually with flow in two horizontal directions
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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
- 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
- B01L2300/0864—Configuration of multiple channels and/or chambers in a single devices comprising only one inlet and multiple receiving wells, e.g. for separation, splitting
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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
- B01L3/502753—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 bulk separation arrangements on lab-on-a-chip devices, e.g. for filtration or centrifugation
Definitions
- the present invention relates to a customizable chip and a method for manufacturing the same.
- micro-mouth chemical analysis in which chemical operations such as sample pretreatment 'reaction' separation 'detection are performed on a microchip, is rapidly developing. According to microchemical analysis, only a small amount of sample needs to be used, and environmental sensitivity is small and highly sensitive analysis is possible. For this reason, if the analysis using the chip can be applied to a clinical test, etc., the test can be easily performed with a small amount of sample.
- Non-Patent Document 1 David, S. Jacobs, D wight, K. ⁇ xley, and Wayne, R. DeMott Eds., 2001, Laboratory Test Handbook with Key Word Index, 5th edition ⁇ Lexi—Comp Inc., Hudson ⁇ OH., P. 7 7-80
- the present invention has been made in view of the above circumstances, and an object of the present invention is to provide a general-purpose analyzer, an analysis chip, and a method of manufacturing the same, which can be customized according to test items.
- the term "chip” refers to a substrate provided with a function of performing a predetermined operation on an introduced sample.
- the chip according to the present invention can be configured so that, for example, a flow channel is provided on the substrate surface, and the liquid sample flows in the flow channel.
- the liquid sample may be moved in the flow channel using capillary action or the like, or may be moved by applying an external force such as an electric field or pressure.
- the liquid sample can be moved in the flow path by using the capillary phenomenon, so that an external device for applying external force is not required, and the liquid sample can be moved downstream by the configuration of the chip itself.
- the power s is acceptable.
- a substrate a plurality of flow paths provided on the substrate, and an adjusting unit provided in the plurality of flow paths and configured to be closable.
- a chip is provided in which the control section provided in one of the flow paths is closed so as to guide the sample to the other flow path.
- the term "closeable” means that it is possible to prevent a liquid from passing through the area by a physical treatment or a chemical treatment.
- the closing includes not only a mode in which the liquid is completely blocked, but also a mode in which a part of the liquid flows downstream. If you want to completely block the passage of liquid, completely close the control unit.
- control section is provided in the flow path so as to be closable, and the sample can be guided to another flow path by closing the control section provided in one flow path. It is configured as follows. For this reason, it is possible to close a desired adjustment unit according to the purpose of use of the chip or the sample and to select a flow path through which the sample moves. Therefore, it is possible to customize the chip with a simple configuration.
- a chip of a type having different measurement items can be easily obtained. For this reason, a chip suitable for an individual to be measured or a measurement item can be easily obtained in a short time.
- a customizable general-purpose chip can be stably obtained at low cost.
- a sample can be supplied only to necessary measurement items by providing an adjustment unit. Therefore, the sample can be effectively used. Therefore, necessary items can be reliably analyzed even for a small amount of sample. In addition, the amount of reagent used for analysis can be minimized.
- the adjusting portion may be a region in which the adjusting portion can be closed in post-processing.
- a desired adjustment section can be selectively closed in accordance with an analysis item in a post-processing stage. Therefore, the chip can be easily customized according to the measurement items.
- a substrate a sample introduction unit provided on the substrate, an analysis unit for analyzing a specific component in the sample introduced into the sample introduction unit, and the sample introduction unit
- the analysis unit is provided in the flow path via an adjustment unit.
- the analysis section analyzes the components in the sample.
- the sample introduced from the sample introduction unit is configured to move in the flow path and reach the analysis unit in which the adjustment unit is in the open state.
- the chip has a pretreatment unit, a separation unit, or a reaction unit, which will be described later, the chip is configured to sequentially pass through these units before reaching the analysis unit.
- the analysis section and the separation section described below may be configured to perform their functions by applying an external force, but the separation and separation of a predetermined component are automatically performed according to the flow of the liquid sample. It is preferable that the analysis of the separated components is performed sequentially.
- Such a configuration can be realized by using a capillary phenomenon, a water level difference, and the like as a driving force for moving the liquid sample.
- the capillary phenomenon for the movement of the liquid sample, the sample introduced into the sample introduction section can be moved in the flow path without applying an external force, and can be used for analysis in the analysis section.
- the chip of the present invention has a plurality of flow paths, and an adjustment unit is provided on each flow path. For this reason, it is possible to select only a desired flow path from among the plurality of flow paths and open the selected flow path, and close the adjustment units on the other flow paths. Therefore, the sample introduced into the sample It is possible to move to the analysis unit along a desired route.
- the substrate a sample introduction unit provided on the substrate, an analysis unit for analyzing a specific component in the sample introduced into the sample introduction unit, and a sample introduction unit
- a flow path that branches the introduced sample to the plurality of analysis sections; and a control section that is provided in the flow path and that can be closed.
- a chip is provided in which the control section on the branched channel is closed to guide the sample to another analysis section.
- the chip of the present invention has a plurality of analysis units, and an adjustment unit is provided in a flow path communicating with each analysis unit. For this reason, the sample introduced into the sample introduction unit can be selectively moved only to a desired analysis unit. For this reason, a sample can be supplied only to the analysis unit corresponding to a required item from the analysis units corresponding to a plurality of analysis items. Therefore, even if the amount of the sample is very small, only the necessary analysis can be reliably selected and performed.
- the adjustment section may be configured to be able to be closed by providing a part of the flow path. Further, in the chip of the present invention, the adjusting section may be configured to be able to be closed by making the surface of the flow path hydrophobic. By doing so, the adjusting section can be securely closed.
- the chip of the present invention may have a separation unit that includes a part of the flow channel and separates components contained in the sample introduced into the sample introduction unit and guides the components to the analysis unit. By doing so, it is possible to surely separate the predetermined components in the sample and to provide the selected predetermined analysis. Therefore, the analysis sensitivity can be improved.
- the chip of the present invention may be configured to have a pre-processing unit that performs predetermined pre-processing on the sample introduced into the sample introduction unit, upstream of the separation unit. By doing so, the sample can be pretreated on the chip. Therefore, the sample can be analyzed in a state more suitable for measurement.
- the pre-processing unit may include the adjusting unit. By doing so, it is possible to prepare a configuration corresponding to a plurality of pre-processes, and customize the pre-process by closing the adjusting unit at the time of post-processing. Therefore, it is possible to select and execute the pretreatment according to the sample.
- the pretreatment unit is provided in a liquid reservoir and downstream of the liquid reservoir.
- a liquid switch unit for controlling the supply of the liquid sample from the pretreatment unit to the separation unit, wherein the liquid switch unit includes a damming unit for damping the liquid in the liquid reservoir;
- a trigger flow passage communicating with the flow passage near the damming portion and guiding the liquid to the damming portion, and the adjusting portion may be provided in the trigger flow passage.
- the chip of the present invention may have a reaction section for causing a predetermined reaction to the components separated in the separation section. By doing so, the sample can be analyzed in a state more suitable for measurement. Further, in the present invention, the reaction section may have the adjustment section. By doing so, it is possible to prepare a configuration corresponding to a plurality of reactions, and to customize the reaction in the reaction unit by closing the adjustment unit during post-processing. Therefore, it is possible to select and execute a reaction according to the sample.
- the reaction section includes a liquid reservoir and a liquid switch portion provided downstream of the liquid reservoir, and the liquid switch portion dams the liquid in the liquid reservoir.
- the adjusting section may be wider than the flow path and configured to be closable. By doing so, the adjusting section can be selectively closed.
- the adjustment section may have a configuration in which a part thereof is open to the outside.
- the chip of the present invention may have a configuration in which a lid is provided to cover the upper surface of the flow channel, and the control section has an opening in the lid.
- a configuration including a substrate and a plurality of flow paths provided on the substrate, wherein a part of the plurality of flow paths is closed.
- a featured chip is provided.
- a chip manufacturing method including a step of preparing a substrate having a plurality of flow paths formed therein and a step of closing a part of the flow paths. You.
- the method for manufacturing a chip of the present invention includes a step of closing a part of the flow path, a chip in which the sample does not move downstream from the closed area can be stably manufactured. Therefore, a movement path according to the sample can be stably formed on the substrate.
- the step of closing the flow path may include a step of making a part of the flow path hydrophobic. By doing so, a part of the flow path can be more reliably closed. Therefore, a customized chip can be manufactured more stably.
- the step of closing the flow path may include a step of deforming a part of the flow path and blocking the flow path. By doing so, the flow path can be more reliably closed.
- the step of closing the flow path may include a step of sealing a part of the flow path.
- sealing a part of the flow path the flow path can be reliably shut off so that the liquid does not move in the sealed area. For this reason, a part of the flow path can be closed more reliably.
- sealing the flow channel means closing a cross section of the flow channel with a sealing member.
- the vicinity of the damming portion may be the damming portion or downstream of the damming portion. By doing so, the liquid can be more reliably blocked.
- control section provided in one flow path is closed to guide the sample to another flow path.
- a plurality of control sections that can be opened to the flow path are provided. It is also possible to provide a structure in which a sample is guided to the flow channel by opening some of the control sections. According to such a configuration, it is possible to select a flow path in the post-processing according to the type of the sample, and to open only the adjustment unit for guiding the sample to the selected flow path. For this reason, the chip can be customized according to the sample type and analysis item.
- a main flow path a liquid reservoir, a flow path connecting the main flow path and the liquid reservoir, and a damming portion provided in the flow path to block liquid in the flow path.
- a trigger flow path communicating with the flow path at or near the damming section and guiding the liquid to the damming section; a liquid switch section including the damming section and the trigger flow path; It is characterized by having a closing switch for closing a path, a delay channel provided in the trigger channel or the channel, and an adjusting unit for setting opening and closing of the channel or the trigger channel.
- a general-purpose analyzer is provided.
- the sample reaches the liquid reservoir from the main flow path through the flow path, and is subjected to a predetermined analysis.
- the components of the general-purpose analyzer according to the present invention can be standardized according to the analysis items to be assumed, and can be suitably used as a general-purpose analyzer.
- the controller is provided for the purpose of setting the flow path or the trigger flow path to the open state or the closed state. If at least a part of the control part is open, the liquid can pass through the control part, but if the control part is blocked, the liquid cannot pass through the control part. Therefore, by setting the opening and closing of the adjustment unit, it is possible to set the movement path of the liquid. Therefore, the general-purpose analyzer of the present invention has a configuration that can be customized according to the type of sample to be analyzed and the type of reaction by adjusting the open / close state of the controller.
- the liquid switch section has a switch structure for controlling the flow of a liquid such as a sample or a buffer in the flow path.
- a liquid such as a sample or a buffer in the flow path.
- the damming portion may be configured to absorb liquid and retain the liquid, or the damming portion itself may be lyophobic to the flowing liquid, and the liquid may be dammed at its upstream end. It may be.
- the liquid switch section includes a trigger channel, and the liquid blocked by the blocking section flows out downstream of the blocking section when coming into contact with the liquid flowing through the trigger channel.
- the liquid switch is provided in the channel, the sample can be introduced from the channel into the liquid reservoir with good controllability. Therefore, in a general-purpose analyzer, a predetermined reaction required for analysis can be stably generated under desired conditions, and thus a desired analysis result can be obtained. In addition, by providing a liquid switch, multiple steps in the general-purpose analyzer can be triggered at appropriate timing by capillary force, triggered by one sample injection without the aid of an external controller. .
- the delay channel is a channel that is provided at a predetermined position of the channel or the trigger channel, and delays the time for which the liquid flows to one area force to another area.
- the conditions such as a predetermined reaction required for the analysis can be set more suitably.
- the closing switch is a valve configured to close the flow path or the trigger flow path when a predetermined amount of liquid is introduced into the flow path or the trigger flow path provided with the closing switch. It has a structure. With this structure, the general-purpose analyzer of the present invention can guide only a predetermined amount of liquid to the liquid reservoir via the flow path or the trigger flow path, and can further prevent the liquid from flowing backward.
- a reagent may be held in the liquid reservoir. This makes it possible to more efficiently perform the analysis requiring a reagent in the general-purpose analyzer.
- two of the liquid reservoirs In the general-purpose analyzer of the present invention, two of the liquid reservoirs, one of the liquid switches, one of the closure switches, one of the delay channels, and one of the adjusters are provided. It can be configured to have one or two. Further, in the general-purpose analyzer of the present invention, the liquid reservoir may have five reservoirs, and each of the liquid switch, the closing switch, the delay channel, and the regulator may have two or more reservoirs. Can be.
- the general-purpose analyzer can take various modes, for example, as described in (I) below.
- the first general-purpose analyzer described in (II) or the third general-purpose analyzer described in (III) can be employed.
- the general-purpose analyzer of the following (I) and the following (III) has the main flow path and the flow path, and further has the following configuration.
- it may be configured to further include one closing switch.
- a configuration including at least two liquid reservoirs, at least one adjustment unit, at least one closure switch, at least one liquid switch, and at least one delay channel.
- a chip comprising a substrate and the general-purpose analyzer provided on the substrate. Since the chip of the present invention has the above-described general-purpose analysis unit, the configuration and the number of the analysis units can be standardized according to the analysis items to be assumed, and the chip can be suitably used as a general-purpose chip. Further, in the chip of the present invention, in a later step, the open / close state of the adjustment unit provided in the general-purpose analysis unit can be set according to the analysis item, and the configuration suitable for the item can be customized. For this reason, the components in the sample can be analyzed simply and reliably with a minimum number of samples.
- the chip of the present invention may be configured to include a plurality of the general-purpose analyzers.
- the chip configuration can be standardized so that it can be used for multiple analyses. Therefore, the convenience can be further improved as a general-purpose chip.
- the chip can be made to be a chip that allows a tester to perform a desired analysis.
- the chip of the present invention can be customized for individual users.
- the chip of the present invention can take various modes. For example, the following configuration can be adopted and can be customized for each disease.
- An analysis unit including at least one third general-purpose analysis unit and at least three first or second general-purpose analysis units, at least one of which is a liquid holding a reagent;
- the reagent is a reagent necessary for measuring an anti-glutamate decarboxylase antibody
- the first or second general-purpose analyzer When the part has the reagent, the reagent holds a reagent necessary for measuring one or more items selected from the group consisting of hemoglobin Alc, 1,5-anhydro_D_glucitol, and glycoalbumin. .
- An analyzer that includes at least eight first or second general-purpose analyzers; at least one of the eight second general-purpose analyzers includes the liquid reservoir holding a reagent;
- the reagent is selected from the group consisting of aspartate aminotransferase activity, alanine aminotransferase activity, ⁇ -glutamyl transpeptidase, total cholesterol, triglyceride, HDL cholesterol, fasting blood glucose (Gnorecose), and hemoglobin Ale Configuration that is the reagent needed to measure one or more items to be measured.
- An analysis unit including at least nine first or second general-purpose analysis units; and at least one of the nine first or second general-purpose analysis units includes the liquid reservoir holding a reagent.
- the reagents include remnant lipoprotein cholesterol, LDL-cholesterol, lipoprotein a, apoprotein AI, apoprotein A-II, apoprotein B, apoprotein C_II, apoprotein C_III, apoprotein E, creatine. Holds reagents necessary to measure one or more items selected from the group consisting of phosphokinase, aspartate aminotransferase activity, alanine aminotransferase activity, and ⁇ -glutamyl transpeptidase Constitution.
- At least one of the nine second general-purpose analyzers contains reagents.
- the reagents include remnant lipoprotein cholesterol, LDL-cholesterol, lipoprotein a, apoprotein AI, apoprotein A-II, apoprotein B, apoprotein C_II, and apoprotein C.
- -III and apoprotein E may be configured to hold reagents necessary for measuring one or more items selected from the group consisting of apoprotein E.
- the analysis unit may include at least 13 first or second general-purpose analysis units.
- the analyzer has an analyzer that includes at least two third general-purpose analyzers and at least eight first or second general-purpose analyzers, at least one of which has the above-mentioned liquid reservoir holding reagents.
- the reagent is a reagent necessary for measuring one or two items selected from the group consisting of HBs antibody and HCV antibody.
- the reagent may be alkaline phosphatase, ratate dehydrogenase, total protein, albumin, zinc sulfate turbidity test, thymol turbidity test, cholinesterase, or total A reagent that is necessary for measuring one or more items selected from the group consisting of bilirubin.
- An analysis unit including at least seven first or second general-purpose analysis units, at least one of the first or second general-purpose analysis units includes the liquid reservoir holding a reagent,
- the above-mentioned reagent is a reagent necessary for measuring one or more items selected from the group consisting of total protein, albumin, urea nitrogen, creatine, sodium ion, potassium ion, and chlor ion.
- At least two third general-purpose analyzers and fewer first or second general-purpose analyzers When the third general-purpose analyzer has the reagent, the reagent has a renin activity and a renin activity, wherein at least one of the analyzers has the reagent reservoir.
- An analysis unit including at least two third general-purpose analysis units and at least two first or second general-purpose analysis units, at least one of which is a liquid holding a reagent. If there is a reservoir and the two third general-purpose analyzers have the reagents, the reagents are necessary for measuring one or two items selected from the group consisting of vitamin B12 and folic acid. When the first or second general-purpose analyzer has the reagent, the reagent is a reagent necessary for measuring one or two items selected from the powerful group. Configuration.
- An analysis unit including at least three third general-purpose analysis units, at least one of the three third general-purpose analysis units includes the liquid reservoir holding a reagent, and the reagent includes: A composition that is a reagent necessary for measuring one or two items selected from the group consisting of triothyronine, thyroxine, and thyroid stimulating hormone.
- the chip of the present invention further includes the same number of the general-purpose analyzers as the number for the sample, and the same number of the general-purpose analyzers uses the same measurement as the sample using the standard solution. May be implemented. In this way, the measurement result of the sample can be calibrated using the measurement result of the standard solution. Therefore, it is possible to perform a more accurate measurement using the tip.
- an analysis chip and a general-purpose analyzer that can be customized according to an analysis item, and a method of manufacturing the same are realized.
- FIG. 1 is a diagram showing functional blocks of a chip according to an embodiment.
- FIG. 2 is a diagram showing a configuration of a chip having the function of FIG. 1.
- FIG. 3 is a sectional view taken along line AA ′ of FIG. 2.
- FIG. 4 is a sectional view taken along line BB ′ of FIG. 2.
- FIG. 5 is a sectional view taken along line BB ′ of FIG. 2.
- FIG. 6 is a sectional view taken along the line C-C ′ of FIG. 2.
- FIG. 7 is a diagram for explaining a method of closing a tip adjustment unit according to the embodiment.
- FIG. 8 is a diagram for explaining a method of closing a tip adjustment unit according to the embodiment.
- FIG. 9 is a diagram for explaining a method of closing a tip adjustment unit according to the embodiment.
- FIG. 10 is a diagram showing functional blocks of a chip according to an embodiment.
- FIG. 11 is a diagram showing a configuration of a chip having the functions of FIG.
- FIG. 12 is a diagram showing a configuration of a measurement unit of the chip in FIG. 11.
- FIG. 13 is a diagram illustrating a configuration of a measurement unit of the chip in FIG. 11.
- FIG. 14 is a diagram showing a configuration of a measuring device according to an embodiment.
- FIG. 15 is a view showing a state in which a chip is inserted into the measuring device of FIG. 14.
- FIG. 16 is a diagram showing a configuration of a measuring device according to an embodiment.
- FIG. 17 is a diagram showing a configuration of a chip according to an embodiment.
- FIG. 18 is a sectional view taken along the line DD ′ of FIG. 17.
- FIG. 19 is a diagram showing functional blocks of a chip according to an embodiment.
- FIG. 20 is a diagram showing functional blocks of a chip according to an embodiment.
- FIG. 21 is a diagram showing a configuration of a chip having a separation unit according to the embodiment.
- FIG. 22 is a diagram showing a configuration of a separation region of the chip of FIG. 21.
- FIG. 23 illustrates a separation method using the separation region in FIG. 22.
- FIG. 24 is a diagram showing a configuration of a chip according to an embodiment.
- 25 is a diagram showing a configuration of a mixing section of the chip in FIG. 24.
- FIG. 26 is a diagram showing a configuration of a mixing section of the chip of FIG. 24.
- FIG. 27 is an enlarged view of a liquid switch part of FIG. 26.
- FIG. 28 is a view showing a damming portion of the liquid switch portion of FIG. 26.
- FIG. 29 A diagram showing the configuration of a trigger channel of a chip according to an embodiment.
- FIG. 30 A diagram showing functional blocks of a chip according to an embodiment.
- FIG. 31 is a diagram showing functional blocks of a chip according to an embodiment.
- FIG. 32 is a diagram showing a configuration of a chip according to an embodiment.
- FIG. 33 is a diagram showing a pre-processing unit of the chip in FIG. 32.
- FIG. 34 is a diagram showing functional blocks of a chip according to an embodiment.
- FIG. 35 is a diagram showing functional blocks of a chip according to an embodiment.
- FIG. 36 is a diagram showing a configuration of a chip according to an embodiment.
- FIG. 37 shows a configuration of a reaction section of the chip of FIG. 36.
- FIG. 38 is a diagram showing a configuration of a chip detection unit according to the embodiment.
- FIG. 39 A conceptual diagram showing a configuration of a chip manufacturing apparatus according to an embodiment.
- FIG. 40 is a conceptual diagram showing the configuration of a chip manufacturing apparatus according to an embodiment.
- FIG. 41 is a diagram illustrating a method of closing the tip adjustment section according to the embodiment.
- FIG. 42 is a diagram illustrating a method of closing a tip adjusting section according to the embodiment.
- FIG. 43 is a view showing a configuration of a chip manufacturing apparatus according to an embodiment.
- FIG. 44 is a diagram showing a chip manufacturing procedure according to the embodiment.
- FIG. 45 is a diagram showing a configuration of an isolation region of the chip in FIG. 21.
- FIG. 46 is a diagram showing a configuration of an isolation region of the chip in FIG. 21.
- FIG. 47 is a plan view showing the configuration of the trigger channel of the chip according to the embodiment.
- FIG. 48 is a plan view showing the configuration of the trigger channel of the chip according to the embodiment.
- FIG. 49 is a plan view showing the configuration of the chip detection unit according to the embodiment.
- FIG. 50 is a plan view showing the configuration of the chip detection unit according to the embodiment.
- FIG. 51 is a cross-sectional view showing a configuration of a chip having the detection unit in FIG. 50.
- FIG. 52 is a plan view showing a configuration of a closing switch of the detection unit of the chip according to the embodiment.
- FIG. 53 is a plan view showing the structure of a liquid switch section of the chip having the detection section of FIG. 50.
- FIG. 54 is a diagram showing a set of main inspection items measured at the re-examination, a measurement method, and a class of a reaction part capable of realizing the set.
- FIG. 55 is a diagram showing a set of main inspection items measured at the re-examination, a measurement method, and a class of a reaction part capable of realizing the method.
- FIG. 56 is a diagram showing a set of main test items measured at the re-examination, a measurement method, and a class of a reaction part capable of realizing the set.
- FIG. 57 is a diagram showing a set of main test items measured at the re-examination, a measurement method, and a class of a reaction part capable of realizing the set.
- FIG. 58 is a plan view showing the configuration of the chip detection unit according to the embodiment.
- the chip includes a sample introduction unit, a control unit, and an analysis unit as a basic configuration.
- the analysis section the components in the separated sample are analyzed.
- the analysis unit may be a detection unit that can be visually detected as a result of, for example, a detection reaction of a predetermined component. Further, the analysis unit may be a measurement unit in which sample components to be subjected to measurement using an external device are stored.
- the first embodiment has a configuration in which the analysis unit is a detection unit
- the second embodiment has a configuration in which the analysis unit is a measurement unit. The specific configuration of the adjustment unit will be described later in the following embodiments.
- a required item can be selected from a plurality of detected items and detected.
- a capable chip This chip has a plurality of detection units corresponding to each detection item as an analysis unit.
- Each of the dispensing channels communicating with each of the detecting units is provided with an adjusting unit for setting whether or not to advance the liquid downstream of the dispensing channel. By setting the opening and closing of each control unit, the sample is guided only to the detection unit corresponding to the required items.
- FIG. 1 is a functional block diagram showing functions of the chip according to the present embodiment.
- the chip shown in FIG. 1 is a chip capable of analyzing components in a sample, and includes a sample introduction unit 212, a control unit 312, and a detection unit 214.
- the chip 311 can be formed on the surface of a substrate made of an elastic material such as silicon, glass, quartz, various plastic materials, or rubber. For example, it is possible to form a groove on the surface of the substrate, seal the groove with a surface member, and form a member that performs the function shown in FIG. 1 in a space surrounded by these and a flow path that connects them. .
- FIG. 2 is a diagram showing an example of a configuration of a chip 311 having the functions of FIG.
- an inlet 217, a main flow path 221, a dispensing flow path 222, a controller 314, a detection tank 223, and a liquid reservoir 224 are provided on a substrate 216.
- FIG. 3 is a sectional view taken along line AA ′ of FIG.
- constituent members such as the main flow path 221 and the like are omitted, and only a laminated structure of the substrate 216, the lid 226, and the seal 227 is shown.
- a lid 226 is provided above the substrate 216.
- the lid 226 is provided with an air hole 225 communicating with the liquid reservoir 224 and each detection tank 223. Further, the upper surface of the lid 226 may be sealed with a seal 227 for the purpose of avoiding entry of dust.
- FIG. 3 is a cross-sectional view with a seal.
- the size of the substrate 216 can be, for example, about 3-10 cm X 2-7 cm. Further, the thickness of the substrate 216 can be, for example, about 0.5 mm lcm.
- the material of the lid 226 can be, for example, the material used for the substrate 216.
- the surface of the substrate 216 and the bottom surface of the lid 226, that is, the surface bonded to the substrate 216 are preferably hydrophilic. By making the surface hydrophilic, the force for introducing and moving the sample into the chip 313 using the capillary action can be obtained. In this case, the sample can be introduced or moved without providing an external driving device such as a pump or an electrode, so that a simple device configuration can be achieved.
- the main channel 221 and the dispensing channel 222 have, for example, a width of about 100 ⁇ m and a depth of about 20 ⁇ m.
- the detection tank 223 can be, for example, a cylindrical liquid reservoir having a diameter of about 2 mm or a rectangular parallelepiped liquid reservoir having a diameter of about 2 mm.
- the depth of the detection tank 223 can be approximately the same as the dispensing flow channel 222, or can be slightly shallower than the thickness of the substrate.
- the depth of the detection tank 223 is almost the same as that of the dispensing channel 222. Or by making it slightly shallower than the thickness of the substrate, the optical path length can be increased and the detection sensitivity can be improved.
- the air hole 225 need not be provided directly above the detection tank 223 as long as the air hole 225 communicates with the detection tank 223 in the vicinity of the detection tank 223.
- the air hole 225 can have a size S of, for example, about ⁇ 50 ⁇ m lmm. This makes it possible to reliably guide the liquid to the detection tank 223. Further, it is preferable that the surface around the air hole 225 is made hydrophobic. By making the surface of the air hole 225 hydrophobic, it is possible to prevent the liquid dispensed into the detection tank 223 from leaking from the air hole 225. Therefore, a certain amount of liquid can be collected in the detection tank 223. Further, loss of the sample can be prevented.
- the scenery 227 may be formed so as to be peelable when the tip 313 is used.
- an emulsion adhesive such as butyl acetate may be applied to the surface of a thin film of various plastic materials.
- an epoxy or silicone adhesive can be used.
- the inlet 217 corresponding to the sample inlet 212 is a part into which a predetermined sample is introduced, and the tip 313 has a shape of a liquid reservoir.
- Such an inlet 217 is a cylindrical liquid reservoir having a diameter of about 3 mm, and can be formed by penetrating a hole of the same size in the lid 226.
- the liquid reservoir 224 used as a waste liquid reservoir is obtained by forming a cylindrical liquid reservoir having a diameter of about 5 mm and forming an air hole 225 at a position corresponding to the lid 226.
- the surface around the air hole 225 is hydrophobic, like the air hole 225 near the detection tank 223.
- the air hole 225 does not have to be provided immediately above the waste liquid reservoir 219 as long as the air hole 225 is in communication with the liquid reservoir 224 in the vicinity of the liquid reservoir 224.
- the air hole 225 can have a size of, for example, about ⁇ 50 zm 2 mm.
- the air hole 2 near the detection tank 223 May be larger than 25.
- the seal 227 is first removed. By peeling off the seal 227, the inlet 217 and the air hole 225 are opened and come into contact with the outside air. Next, the sample is introduced into the opened inlet 217. The introduced sample is guided to the main channel 221 by a capillary phenomenon.
- the sample components in the main flow path 221 are guided from the dispensing flow path 222 communicating with the main flow path 221 to a plurality of detection tanks 223, and are dispensed.
- the detection tank 223 is a detection unit in FIG.
- a predetermined number of dispensing channels 222 and detection tanks 223 can be provided on the substrate 216.
- FIGS. 4A and 4B are cross-sectional views taken along the line BB ′ of FIG. 2, and are diagrams illustrating a configuration example of the detection unit 214 having the detection tank 223 as a main component.
- the detection tank 223 has a detection reagent 231 on the bottom surface.
- the detection reagent 231 can be, for example, a substance or a reagent that interacts with a specific component contained in the sample to develop, emit, discolor, decolor, or quench, for example.
- the detection reagent 231 is dissolved or dispersed in the mobile phase, and a predetermined detection reaction is performed in the detection tank 223.
- the detection reagent 231 is not introduced into one of the detection tanks 223, but is used as a reference liquid reservoir. You can also.
- a color or the like due to the detection reaction is visually observed through the lid 226.
- FIG. 4B since the microlenses 228 are formed on the lid 226, the state inside the detection tank 223 can be observed in an enlarged manner. Therefore, for example, color development, light emission, discoloration, bleaching or extinction in the detection tank 223 can be visually recognized in more detail. Further, even when the detection tank 223 is extremely small, the color development, light emission, discoloration, decolorization or extinction can be visually recognized. Therefore, a small amount of the sample to be analyzed can be removed.
- FIG. 5 and FIG. 6 are diagrams showing still another configuration of the detection unit 214.
- FIG. 5 is a sectional view taken along the line BB ′ of FIG. 2
- FIG. 6 is a sectional view taken along the line CC ′ of FIG.
- the microlenses 228 may be formed between the plurality of detection tanks 223.
- the microlens 228 may be, for example, a kamaboko type. In this way, the structure of lid 226 Configuration can be further simplified.
- the detection reagent 231 can be different.
- a plurality of dispensing channels 222 are sequentially branched from the main channel 221. Since the dispensing channel 222 is a channel narrower than the main channel 221, the capillary phenomenon occurs. As a result, sample components are sequentially introduced from the detection tank 223 communicating with the upstream dispensing channel 222.
- an adjusting section 314 is provided in each dispensing channel 222.
- the adjusting unit 314 is configured so as to close the dispensing flow channel 222 as necessary and to stop the dispensing channel 222 so that the sample does not proceed downstream.
- the sample is guided only to the dispensing channel 222 with the control unit 314 opened, and a predetermined detection reaction is performed in the corresponding detection tank 223.
- no detection reaction is performed in the corresponding detection tank 223.
- the force of the tip 313 can be customized according to the analysis item.
- the chip 313 is provided with a detection tank 223 corresponding to the analysis item assumed in advance, and is unnecessary if only the dispensing flow path 222 communicating with the detection tank 223 corresponding to the detection reaction necessary for the sample is opened. Since no sample is introduced into the detection tank 223, it is possible to use the minimum necessary sample for the necessary and sufficient detection reaction.
- the production of the chip 313 in FIGS. 2 and 3 is performed, for example, as follows.
- a groove is formed in the substrate 216 to form a main channel 221 and a dispensing channel 222. Further, an inlet 217 communicating with the main flow path 221, a detection tank 223, and a liquid reservoir 224 are formed.
- a method suitable for the type of the material of the substrate 216 such as press molding using a mold such as etching or embossing, injection molding, or photo-curing, is used. Can be done.
- the width of the main channel 221 is appropriately set according to the properties of the sample. For example For samples containing high molecular weight components (DNA, RNA, proteins, sugar chains), use 5 ⁇ 5 ⁇ -about 1000 ⁇ m.
- An adjusting section 314 is formed on the dispensing channel 222.
- the adjusting unit 314 may be configured to prevent the liquid from flowing downstream of the dispensing channel 222.
- the adjusting unit 314 may be formed by performing a hydrophobic treatment on a part of the dispensing channel 222.
- Can be. 7 to 9 are cross-sectional views illustrating a method for selectively hydrophobizing and closing a specific dispensing channel 222.
- the substrate 216 is mounted on the mounting table 322.
- three adjusting units 314a-adjusting unit 314c are illustrated as adjusting units 314.
- the adjusting unit 314a is closed and the adjusting unit 314b and the adjusting unit 314c are opened.
- the adjusting section forming device 317 includes a press substrate 318 having a concave portion 321 corresponding to the shape of the substrate 216, a printing rod 319, and a PDMS (polydimethylmethylsiloxane) stamp 320.
- the printing rod 319 is formed corresponding to each position of the adjustment unit 314 on the substrate 216, and in FIG. 7, the adjustment unit 314a-adjustment unit 314c.
- the printing rod 319 has a PDMS stamp 320 at the tip, and is inserted into the press substrate 318 so as to be movable in the vertical direction in the figure.
- the printing rod 319 corresponding to the adjustment section 314 to be closed is projected toward the recess 321 side.
- the printing rod 319 provided at a position corresponding to the adjustment section 314a is projected to the concave section 321 side.
- FIG. 8 shows a state in which the adjusting section forming device 317 is pressed onto the mounting table 322 so that the concave portion 321 is fitted to the substrate 216.
- the PDMS stamp 320 provided at the tip of the protruding printing rod 319 is deformed and is provided in the adjusting section 314a.
- FIG. 9 shows a state in which the adjusting section forming device 317 has been removed from the mounting table 322.
- the PDMS layer 323 is formed on the surface of the adjustment unit 314a pressed against the PDMS stamp 320. Since the PD MS layer 323 is hydrophobic, the sample introduced into the dispensing channel 222 having the control section 314a cannot move downstream from the control section 314a, and is blocked by the control section 314a. In this case, the width of the hydrophobic PDMS layer 323 shall be 100 ⁇ m 1000 ⁇ m. You can.
- the PDMS stamp 320 is brought into contact with the part to be closed of the adjustment part 314 on the substrate 216, so that the channel surface of the adjustment part 314 to be closed can be made hydrophobic.
- the adjustment section 314 can be selectively closed simply and reliably.
- the position of the print bar 319 can be controlled manually, for example.
- a control unit for controlling the position of the print bar 319 in the adjustment unit forming device 317 the position of the print bar 319 can be more easily controlled.
- a driving mechanism using a solenoid coil and a magnet can be applied as the driving force for moving the position of the printing bar 319.
- FIG. 41 and FIG. 42 are diagrams illustrating a method of closing the adjustment unit 314 by heating.
- the stamp 320a provided at the end of the printing rod 319 is heated to a temperature equal to or higher than the glass transition temperature of the constituent material of the substrate 216, and is pressed against the adjusting portion 314 from the upper surface of the substrate 216.
- a wedge-shaped metal piece protruding toward the end can be used as the stamp 320a.
- the heating of the stamp 320a can be performed, for example, by providing a heater unit in the printing stick 319.
- the substrate 216 near the adjusting portion 314 is softened, and the resin displaced when the stamp 320a enters the substrate 216 rises on the dispensing flow path 222 and is deformed. .
- the substrate 216 is cured again, so that a partition wall that seals and blocks the dispensing channel 222 is formed. Is done.
- the force of the recured resin projecting above the upper surface of the substrate 216 This configuration is suitably used when the lid 226 is not provided on the upper part of the chip. Further, if the recured resin is prevented from protruding above the upper surface of the chip, the chip can be efficiently customized without having to remove the protruding portion before joining with the lid 226.
- the opening and closing of the adjusting section 314 can be performed by a simple operation, the chip can be easily customized in a short time.
- an inlet 217 and an air hole 225 are formed in the lid 226.
- the obtained substrate 216 and lid 226 are joined. Further, if necessary, the upper surface of the lid 226 is sealed with a sheath 227. Thus, 313 chips are obtained.
- a method in which a small amount of a solvent capable of dissolving the substrate 216 is applied to the surface of the substrate 216, and then the lid 226 is pressed against the surface and bonded for example, a method in which a small amount of a solvent capable of dissolving the substrate 216 is applied to the surface of the substrate 216, and then the lid 226 is pressed against the surface and bonded.
- a method of bonding by applying ultrasonic waves in a state where the substrate 216 and the lid 226 are in contact with each other, or a method of applying and bonding a predetermined adhesive may be used.
- a heat fusion method may be used.
- the chip 313 can exhibit good separation ability.
- the coating material include a substance having a structure similar to a phospholipid constituting a cell membrane.
- a water-repellent resin such as a fluororesin or a hydrophilic substance such as bovine serum albumin, it is possible to prevent molecules such as DNA from adhering to the channel wall.
- the surface of the substrate 216 may be coated with a hydrophilic polymer material such as an MPC (2-methacryloyloxystyl phosphorylcholine) polymer or a hydrophilic silane coupling agent.
- the surface of the substrate 216 is hydrophilized using an MPC polymer, specifically, Lipidua (registered trademark, manufactured by NOF CORPORATION) or the like can be used.
- Lipidure registered trademark
- a buffer solution such as TBE (trisborate + EDTA) buffer to a concentration of 0.5 wt%, and this solution is dissolved in the main channel 221 or the dispensing channel 222. By filling the inside and letting it stand for several minutes, the channel wall can be coated.
- a hydrophilic film such as a silicon oxide film on the surface of the channel 230. Due to the formation of the hydrophilic film, the buffer solution is smoothly introduced without applying any external force. Further, by forming at least the surface of the substrate 216 with a hydrophilic polymer material such as PHEMA (polyhydroxyethyl methacrylate), non-specific adsorption of sample components to the surface of the substrate 216 can be suppressed. Can be. For this reason, even if the amount of the sample is very small, the fractionation and detection can be reliably performed.
- PHEMA polyhydroxyethyl methacrylate
- detection of a predetermined component in the sample is selected according to the sample, and the detection is performed using one chip 311. It can be carried out. Therefore, it is possible to analyze only necessary items using the minimum necessary samples.
- the color reaction is performed to determine the presence or absence of a specific component in the sample or to measure the concentration. S can do it.
- the substrate 216 is formed of a transparent material. By doing so, more accurate detection can be performed.
- the transparent material specifically, for example, quartz, cyclic polyolefin, PMMA (polymethyl methacrylate), PET (polyethylene terephthalate) and the like can be used.
- the detection using the chip 313 can be suitably used when the detection is performed by directly using the sample introduced from the inlet 217.
- Such detection which is preferably detected by a single-step detection reaction in the detection tank 223 includes, for example, detection of one type of liver enzyme, araninaminotransferase (ALT), in plasma.
- ALT araninaminotransferase
- the detection tank 223 that is not used for detection that is, the detection tank 223 that communicates with the dispensing channel 222 in which the adjustment unit 314 is closed may not have the detection reagent 231.
- a liquid reservoir communicating with the main flow path 221 is further provided, and a buffer for diluting a sample is introduced into the liquid reservoir or at a predetermined timing, whereby the introduction port is formed.
- a buffer for diluting a sample is introduced into the liquid reservoir or at a predetermined timing, whereby the introduction port is formed.
- the sample introduced into 217 it can be guided to detection tank 223 communicating with dispensing flow channel 222 opened by control unit 314. This makes it possible to dilute the sample to a concentration suitable for the detection reaction in the detection tank 223, so that high-sensitivity measurement is possible. It works.
- the chip of the present embodiment can be customized by selecting opening and closing of the adjustment unit 314, and thus can be suitably used for, for example, a clinical test. For example, it is possible to easily select items required for inspection in hospitals and inspection institutions, and to manufacture chips suitable for analyzing required items. Therefore, if a combination of inspection items is received online, for example, from a hospital or inspection organization, it is possible to easily produce a required number of chips with the received items set therein.
- the present embodiment relates to a chip capable of selecting a required item from a plurality of measurement items and providing the selected item for measurement by an external device.
- This chip has a plurality of measurement units corresponding to each detection item as analysis units.
- Each of the dispensing channels communicating with each of the measuring units is provided with an adjusting unit for adjusting the progress of the liquid downstream of the dispensing channel. By adjusting the opening and closing of each control unit, the sample is guided only to the measurement unit corresponding to the required items.
- FIG. 10 is a functional block diagram showing an example of a configuration of a chip according to the present embodiment.
- the chip 315 is different from the chip 311 described in the first embodiment in that a chip 315 includes a measuring unit 233 instead of the detecting unit 214.
- the measurement unit 233 is an area where a sample component to be used for measurement using an external device is stored.
- FIG. 11 is a diagram showing an example of the configuration of a chip 315 having the functions of FIG.
- the basic configuration of the chip 316 in FIG. 11 is the same as that of the chip 313 (FIG. 2) described in the first embodiment, except that a chip 235 is provided instead of the detection tank 223.
- Separation unit 235 has inlet 217 Is a liquid reservoir from which the sample introduced into the reservoir is collected.
- FIG. 12 and FIG. 13 are diagrams illustrating examples of the configuration of the measuring unit 233 having the sorting unit 235 as a main component.
- the separation unit 235 may be composed of only a liquid reservoir for storing a sample as shown in FIG.
- a measurement reagent 236 may be provided.
- the measurement reagent for example, a substance that can be used as the detection reagent 231 in the chip 313 described in the first embodiment can be used.
- the measurement reagent 236 specific components in a sample can be reliably analyzed by utilizing a color reaction or the like. Specifically, it can measure the transmitted light intensity in a wavelength region of, for example, about 350 to 640 nm.
- the opening and closing of the control unit 314 is set according to the necessity of evaluating the bias due to the coloring of the sample itself, and the number of the sorting units 235 used. Can be selected.
- FIG. 14 is a diagram schematically showing the configuration of a measuring device 237 that inserts the tip 316 and performs optical measurement on the sample components of the sorting section 235.
- the measuring device 237 has an insertion portion 244 into which the chip 316 is inserted, and a measurement unit 242 which irradiates light to the sorting portion 235 of the chip 316 inserted into the insertion portion 244 and measures optical characteristics.
- the measurement unit 242 includes a light source 238, a light collecting unit 243, and a light receiving unit 239.
- two measuring units 242 and a sorting unit 235 are shown for the sake of explanation. In practice, the measuring units 242 are provided by the number of measuring units 233 formed on the chip 316. be able to.
- the size of the measurement unit 242 is designed in accordance with the size of the sorting unit 235.
- the depth of the sorting unit 235 can be about lmm, and the interval between the sorting units 235 can be about lmm.
- the size of the light source 238, the light receiving unit 239, and the optical filter 240 is large. Again, it is designed accordingly.
- the light source 238 can be, for example, an LED, a laser diode, a semiconductor laser, or the like. Since the type of the light source varies depending on the measurement wavelength, it is appropriately selected in accordance with the wavelength of the color generated by the measurement reagent 236.
- the light collector 243 can be used, for example, by processing a Selfox lens into a predetermined shape and size.
- the light receiving section 239 can be, for example, a phototransistor, a photoelectric cell, or the like.
- FIG. 15 is a diagram showing a state where the chip 316 is inserted into the measuring device 237 of FIG. Measurement
- the sorting section 235 is inserted at a position corresponding to the measurement unit 242.
- the measuring units 242 are provided by the number of the sorting units 235 formed on the chip 316, the optical measurement can be performed on each of the sorting units 235 at once. Therefore, measurement can be performed in a short time.
- the measuring device 237 may include one measuring unit 242, and the optical measurement may be sequentially performed on the plurality of sorting units 235 by sliding the chip 316 in the insertion unit 244.
- FIG. 16 is a diagram showing another configuration of the measuring device 237.
- the measurement device 237 in FIG. 16 has the same basic configuration as the device in FIG. 14, but differs in that it has one light source 238, and has an optical filter 240 and a light shielding plate 241. Note that, in FIG. 16, the light collecting unit 243 is not provided, but the light collecting unit 243 may be provided.
- the optical filter 240 By providing the optical filter 240, of the light emitted from the light source 238, only light within a predetermined wavelength range can be applied to the sorting unit 235. Therefore, even when a light source 238 having a broad wavelength distribution of emitted light, such as a lamp light source, is used, spectroscopy and measurement can be performed with the optical filter 240 corresponding to the measurement wavelength. Further, since the optical filter 240 is supported by the light-shielding plate 241, it is possible to prevent the light emitted from the light source 238 from leaking to the other measurement units 242.
- optical filter 240 a material known as an optical filter can be processed into a predetermined size and used.
- the measuring device 237 shown in FIG. 14 or FIG. 16 light from an external light source is introduced by an optical fiber or the like without providing the light source 238, and the light is introduced into a position where the sorting unit 235 is inserted. Irradiation may be used. Further, in the above description, the transmittance in the fractionation unit 235 is measured, but the measurement unit 242 may be configured to measure the absorbance or the scatter.
- the configuration of the tip 316 and the configuration of the measuring device 237 applicable to the tip 315 shown in Fig. 10 are not limited to those described above, and may be various configurations.
- Chip 316 having the measuring unit 233 as the analyzing unit, by providing the adjusting unit 314 in the dispensing channel 222 communicating with the sorting unit 235, the chip 316 can be customized according to the analysis item.
- Chip 316 contains several analysis items that are assumed in advance. A sorting unit 235 capable of performing measurement corresponding to this is provided. Then, if only the dispensing flow path 222 communicating with the fractionation unit 235 corresponding to the required measurement is opened, no sample is introduced into the unnecessary fractionation unit 235, so it is necessary to use the minimum necessary sample. The ability to provide a sample for sufficient measurement is possible. For this reason, the components in the sample can be reliably analyzed by the simple method using the measuring device 237.
- the configuration of the chip 316 and the configuration of the measuring device 237 applicable to the chip 315 shown in FIG. 10 are not limited to those described above, and may be various configurations.
- a sorting section 235 can be provided on the dispensing channel 222, and the optical waveguide 245 can be formed below the sorting section 235.
- the optical waveguide 245 can be formed of, for example, a British material or an organic polymer material.
- Optical waveguide 245 is configured to have a higher refractive index than the surrounding material. In this case, light is introduced into the optical waveguide 245 from the bottom surface of the chip, and similarly, light is extracted from the bottom surface of the chip.
- FIG. 18 is a sectional view taken along the line DD ′ of FIG.
- a light source for introducing light into the light projecting optical waveguide 246 and a light receiving unit for receiving light from the light receiving optical waveguide 247 are provided on the bottom surface of the measuring device 237 or the like. be able to. With such a configuration, the exposed surface of the light emitting optical waveguide 246 and the light receiving optical waveguide 247 of the chip is brought into contact with the bottom surface of the measuring device 237, etc. The ability to introduce light into the 235 and to detect the light from the sorting unit 235 can be achieved.
- the chip shown in FIGS. 17 and 18 may not be provided with the optical waveguide 245.
- the chip shown in FIGS. 17 and 18 may not be provided with the optical waveguide 245.
- the light-projecting optical waveguide 246 and the light-receiving optical waveguide 247 by providing the light-projecting optical waveguide 246 and the light-receiving optical waveguide 247, light emitted from the light source is introduced into the sorting unit 235 via the light-projecting optical waveguide 246, and the light from the sorting unit 235 The emitted light can be received by the light receiving unit via the light receiving optical waveguide 247.
- the configuration of the chip can be simplified.
- the measuring device 237 is configured to detect the transmitted light of the sorting unit 235, but the light receiving unit 239 may be configured and arranged to detect the reflected light.
- the chip 316 is provided as it is to the measuring device 237, a mode may be adopted in which a sample collected in the sorting unit 235 of the chip 316 is extracted and used for measurement by an external device.
- ALT which is a kind of liver enzyme
- the sample is collected only by the separating unit 235 that is opened by the control unit 314.
- the measurement reagent 236 in the preparative section 235 opened by the control section 314 for example, L-alanine, monoketoglutaric acid, mononicotinamide adenine dinutretide reduced form (NADH), and lactate dehydrogenase (LDH )
- the ALT activity is calculated based on the change rate of the transmittance at 340 nm measured by the measuring device 237. Note that, in order to exclude non-specific absorption, two-wavelength measurement in which transmittance is also measured at 405 nm may be used.
- FIG. 19 and FIG. 20 are functional block diagrams showing the configuration of the chip according to the present embodiment.
- a separation part 213 is formed between the sample introduction part 212 and the adjustment part 312, and the selected analysis ( Detection or measurement).
- a chip FIG. 19 having a detection unit 214 as an analysis unit will be described as an example.
- FIG. 21 is a diagram showing an example of a configuration of a chip having a separation unit 213.
- the basic configuration of 326 is the same as that of the chip 313 in FIG. 2. The difference is that a separation area 218 including a part of the main flow path 221 is provided between the force introduction port 217 and the dispensing flow path 222.
- the chip 326 includes a waste liquid reservoir 219, a buffer inlet 220, and a flow path 230 in addition to the chip shown in FIG.
- the number of the detection tanks 223 can be appropriately selected.
- the separation region 218 has a channel 230, a main channel 221 and a plurality of microchannels 229 communicating these, and is configured in a filter shape. Discharges unnecessary sample by communicating with channel 230 A waste liquid reservoir 219 is provided. Further, a buffer inlet 220 is formed in communication with the main channel 221.
- the configuration of the force isolation region 218 exemplifying the case where the isolation region 218 is a filter is not limited to this, and various configurations can be adopted.
- FIG. 22 is a diagram illustrating the configuration of the separation region 218.
- a flow channel 161a and a flow channel 161b (both having a width W and a depth D) are formed on a substrate 216, and a partition 165 is interposed between them.
- one of 161a and 161b is the main channel 221 and the other is the channel 230.
- Separation channels are formed regularly in the partition 165.
- the “separation channel” here has a configuration corresponding to the fine channel 229.
- the separation channel is orthogonal to the channel groove 161a and the channel groove 16lb, and the separation channel having a width dl is formed regularly at a predetermined interval d2.
- Each dimension shown in the figure is set to an appropriate value according to the sample to be separated or the like, and a suitable numerical value is selected from the following range, for example.
- the value of L which corresponds to the length of the separation channel, directly affects the separation characteristics, so it is important to design precisely according to the purpose of separation.
- the conformation of the molecules changes when passing through the separation channel, resulting in a change in enthalpy. Therefore, the total amount of enthalpy change accompanying the passage of molecules differs depending on the length of the separation channel, and the separation characteristics change.
- the flow path is formed by the groove, it can be manufactured by etching or molding, and the shape and size can be precisely controlled. As a result, a separation device having desired separation characteristics can be stably manufactured.
- the flow grooves 161a, 161b, and the separation flow path can be formed by various methods. When the values of dl and d2 are set to lOOnm or less, the electron beam cannot be finely processed. It is desirable to use dry etching that combines exposure techniques. [0129] A separation method using the separation region 218 having the structure shown in Fig. 22 will be described with reference to Fig. 23.
- FIG. 23 is a schematic diagram showing a schematic structure of this separation device when viewed from above. First, as preparation before sample separation, each channel groove is filled with a buffer solution serving as a carrier. In FIG. 23, the sample stock solution containing the mixture 150 flows downward in the figure into the flow channel 161b.
- the small molecules 151 in the mixture pass through the separation channel provided in the partition shown in the center of the figure, and enter the channel groove 161a in P contact.
- a solvent that does not cause a dangling reaction with the component to be separated flows upward in the figure. Therefore, the small molecules 151 that have entered the flow channel 161a are transported along the flow in the upward direction in the figure.
- the large molecules 152 in the flow channel 161b cannot pass through the separation flow channel, they flow through the flow channel 16 lb as they are, and are collected at the end of the flow channel. As described above, the small molecule 151 and the large molecule 152 are separated.
- the flow directions of the flow channel 161a and the flow channel 161b are reversed.
- the force S that can be oriented in the same direction, and when reversed, the separation efficiency is improved.
- the concentration difference force of the large molecules 152 in the flow channel 161a and the flow channel 161b decreases as the force in the flow direction increases, and becomes equal at a certain point. In a region beyond this point, the movement of the large molecule 152 from the flow channel 161b to the flow channel 161a occurs, and the separation becomes impossible.
- the concentration difference between the large molecules 152 in the channel groove 161a and the channel groove 161b is ensured, so that the separation channel is fixed. Even when formed over a region having a length, high separation ability can be ensured.
- the separation region 218 has the configuration including the bank portion as described below. May be.
- FIG. 45 is a diagram showing another configuration of the separation region 218, and the divided views A and B are a cross-sectional view and a perspective view, respectively.
- the substrate 216 is provided with two flow channel grooves 161a and 161b, and a partition wall 308 serving as a bank is provided so as to separate them.
- a lid 226 is provided on the substrate 166.
- lid 226 is not shown in FIG. 45B.
- a separation operation can be performed by flowing a sample containing a substance to be separated into the flow channel 161a and flowing a buffer solution into the flow channel 161b.
- a lid 226 made of a hydrophobic material such as polydimethylsiloxane or polycarbonate.
- a sample or buffer can be introduced into each channel without penetrating into the other channel, and at the stage when both channels are filled with the sample or the like, Mixing of the sample and the buffer solution in both channel grooves can be caused through the space.
- Such an effect can also be obtained by performing the operation without the lid 226 attached. At this time, it is considered that the air itself functions as a hydrophobic substance similarly to the lid 226.
- the sample when a sample is allowed to flow through the channel groove 161a, for example, with the lid 226 made of a hydrophilic material such as polyethylene terephthalate attached, the sample enters the other channel groove 161b. During this intrusion, only components having a size smaller than the space formed between the lid 226 and the partition wall 308 are filtered out, so that the components in the sample are separated.
- the channel groove 161a and the channel groove 161b are connected with a larger area than the partition wall 165 having the fine channel 229, so that the separation efficiency is improved. Can be improved. Further, even a long and slender substance can be easily moved between the flow paths through which the substance is clogged, so that it can be suitably used for separating a sample containing such a substance.
- Such flow channel grooves 161a and 161b and the partition wall 308 are obtained by, for example, performing a wet etching process on a (100) Si substrate.
- a (100) Si substrate is used, in a direction perpendicular or parallel to the (001) direction, etching proceeds in a trapezoidal shape as shown in the figure. Therefore, the height of the partition wall 308 can be adjusted by adjusting the etching time.
- a partition 308 may be provided on the lid 226.
- the lid 226 having such a partition wall 308 can be easily obtained by injection molding a resin such as polystyrene.
- the substrate 216 may be provided with only one channel by etching or the like. Therefore, this separation region 218 can be obtained by the simple process as described above. Therefore, it is suitable for mass production.
- the separation region 218 including a part of the main channel 221 it is possible to separate the components in the sample by, for example, introducing the liquid sample by capillary action and diffusing the sample. In addition, separation can be performed by utilizing the osmotic pressure difference of molecules.
- the sample introduced into inlet 217 is guided to channel 230 by capillary action.
- a predetermined buffer is introduced into the buffer inlet 220.
- the buffer is used as a developing solution for separating components in the sample.
- the buffer introduced into the buffer inlet 220 is guided to the main channel 221 by capillary action, and moves in the direction opposite to the moving direction of the sample in the channel 230.
- the fine channel 229 that connects the channel 230 with the main channel 221 has a smaller width or depth than the channel 230, and therefore, among the sample components in the channel 230, Only components having a size or shape can pass through the fine channel 229 and move to the main channel 221. Further, components that cannot pass through the fine channel 229 are discharged to the waste liquid reservoir 219. Thus, the components in the sample can be separated according to their size or shape in the mobile phase.
- the fine channel 229 may have a configuration in which a small hole is formed in a partition wall that separates the channel 230 from the main channel 221.
- a sample By using such a separation region 218, for example, a sample can be roughly separated, purified, or the like. In the case of coarse separation, solid components, cells, and the like in a sample can be separated and removed. In the case of a liquid sample, for example, separation of a low molecular weight component and a high molecular weight component is possible.
- the sample component in the main channel 221 is guided to the detection tank 223 from the dispensing channel 222 communicating with the main channel 221 and is dispensed.
- the chip 326 similarly to the chip 313 in FIG. 2, the separated sample is dispensed only into the detection tank 223 communicating with the dispensing flow channel 222 in which the adjustment unit 314 is opened.
- control unit 314 is provided in the dispensing flow path 222 communicating with the detection tank 223 provided downstream of the separation area 218, so that the sample introduced into the inlet 217 is specified. After performing the separation operation described above, it becomes possible to detect or measure the separated components according to the analysis item. Adjusters 314 provided in each of the plurality of dispensing channels 222 By adjusting the opening and closing of the chip 326, the tip 326 can be customized. Since the components in the sample can be separated in advance, detection with higher sensitivity can be performed in the detection tank 223.
- a blood glucose level can be measured.
- blood when blood is introduced into the inlet 217 as a sample, blood cells are separated in the separation region 218. A plasma component diluted by the buffer introduced into the buffer inlet 220 is dispensed into the detection tank 223.
- NAD / 3-nicotinamide adenine dinucleotide oxidized form
- ATP sodium adenosine triphosphate
- hexokinase glucose_6-phosphate dehydrogenase
- magnesium acetate are introduced as detection reagent 231.
- the blood sugar level can be easily measured depending on the degree of color development in the detection tank 223.
- FIG. 24 is a diagram showing an example of the configuration of a chip having a mixing section 248.
- the basic configuration of the chip 327 in FIG. 24 is the same as that of the chip 326 in FIG. 21 except that a mixing section 248 is provided in the main flow path 221 between the force separation area 218 and the dispensing flow path 222.
- the mixing section 248 is not particularly limited as long as the mixing section 248 is configured to be able to homogenize the concentration of the sample component in the liquid flowing in the main flow path 221. It can be configured as follows.
- FIG. 25 is a diagram showing an example of the configuration of the mixing section 248.
- the mixing section 248 in FIG. 25 is a run-up flow path utilizing the homogenizing effect of the counter flow.
- This flow path has a configuration in which the outward path 252 and the return path 253 of the main flow path 221 are communicated with each other by the fine mixing flow path 254.
- the mixing microchannel 254 can be a small hole provided in a partition separating the outward path 252 and the return path 253, for example.
- the surface of the mixing fine flow channel 254 is made more hydrophobic than the outward flow 252. By doing so, it is possible to adopt a configuration in which the liquid that has passed through the separation region 218 does not flow into the return path 253 from the fine mixing channel 254 until it fills the outward path 252.
- the forward path 252 is filled with the liquid and reaches the return path 253, the liquid enters the fine mixing channel 254 from the forward path 252 side and the return path 253 side.
- the outward path 252 and the return path 253 communicate with each other through the fine mixing channel 254. Then, mutual diffusion occurs between the liquid in the forward path 252 and the liquid in the return path 253, and the concentration of the liquid can be made uniform.
- the homogenized liquid is guided from the main flow path 221 to the detection tank 223 through the dispensing flow path 222.
- the main flow path 221 has a straight shape, but may have a zigzag shape or a spiral shape. This allows the mixing section 248 to have a compact shape. Therefore, the entire chip can be reduced in size.
- FIG. 26 is a diagram showing another configuration of the mixing section 248.
- a liquid reservoir 255 is provided in the main flow path 221, and a trigger flow path 256 that connects two locations of the main flow path 221 downstream of the liquid reservoir 255 is provided.
- the trigger flow path 256 is a flow path connecting two places downstream of the liquid reservoir 255.
- the trigger channel 256 can adjust the traveling speed of the liquid in the channel by appropriately adjusting the degree of hydrophilicity in the channel, the channel diameter, and the like. Thereby, the speed of the switch operation can be adjusted.
- a liquid switch section 257 is provided at the downstream side, that is, at the intersection on the dispensing flow path 222 side, of the two intersections of the trigger flow path 256 and the main flow path 221.
- the liquid switch section 257 is initially closed, and the liquid that has passed through the separation area 218 is stored in the liquid reservoir 255, and the concentration is homogenized.
- the liquid reservoir 255 is filled with the liquid, a part of the liquid flows into the trigger channel 256.
- trigger channel 2 When the liquid is filled in 56 and reaches the formation area of the liquid switch section 257, the liquid switch section 257 is opened, and the liquid homogenized in the liquid reservoir 255 flows into the dispensing channel 222.
- FIG. 27A to FIG. 27C are enlarged top views of the liquid switch portion 257 in FIG.
- the liquid switch unit 257 is a switch for controlling the flow of the liquid, and the liquid is a trigger for opening and closing the switch.
- FIG. 27A shows the switch closed state
- FIGS. 27B and 27C show the switch open state.
- a trigger channel 256 is connected to the side of the main channel 221.
- the traveling speed of the liquid in the channel can be adjusted by appropriately adjusting the degree of hydrophilicity, the channel diameter, and the like in the channel. Thereby, the speed of the switch operation can be adjusted.
- a damming section 258 is provided on the upstream side (upper side in the drawing) of the area where the main flow path 221 and the trigger flow path 256 intersect.
- the blocking portion 258 is a portion having a stronger capillary force than other portions of the flow path. The following is an example of a specific configuration of the blocking unit 258.
- the surface area force per unit volume of the channel in the damming section 258 is larger than that of the other portion of the channel. That is, when the main channel 221 is filled with the liquid, the damming portion 258 is configured such that the solid-liquid interface is larger than the other portions of the channel.
- damming portion 258 is configured so that the solid-liquid interface is larger than other portions of the flow path.
- damming portion 258 since the damming portion 258 has a lyophobic surface, the liquid is repelled and cannot pass therethrough.
- the columnar body can be formed by an appropriate method according to the type of the substrate.
- a glass substrate or a quartz substrate it can be formed using a photolithography technique and a dry etching technique.
- a plastic substrate When using a plastic substrate
- a mold having an inverted pattern of the pattern of the pillar to be formed is produced, and molding is performed using the mold to obtain a desired pillar pattern surface.
- Such Molds can be formed by using photolithography technology and dry etching technology.
- the porous body and beads can be formed by directly filling and adhering them to a predetermined portion of the flow channel.
- FIG. 28 is a top view of the damming section 258.
- FIG. A plurality of columnar bodies 260 are regularly arranged at substantially equal intervals. The area other than the columnar body 260 is the fine channel 261.
- the flow path surface area per unit volume of the flow path is larger than that of the other parts of the flow path. Therefore, the liquid that has entered the damming portion 258 is retained in the fine channel 261 by capillary force.
- FIG. 27A shows the liquid switch unit 257 in a standby state.
- the liquid sample 259 introduced into the main flow path 221 is held by the damming portion 258.
- the trigger liquid 262 bypassing the trigger flow path 256 is introduced at a desired timing from this state, the leading end of the liquid surface of the trigger liquid 262 advances as shown in FIG. 27B and comes into contact with the damming portion 258. It will be.
- the liquid sample 259 is held by the damming portion 258 by capillary force.
- the liquid sample 259 moves downward (downstream) in the figure.
- the trigger liquid 262 plays a role as priming water, and an operation as a liquid switch part for drawing out the liquid sample 259 to the downstream side is developed.
- the liquid sample 259 and the trigger liquid 262 are liquids that have passed through the liquid reservoir 255. Therefore, according to this configuration, the liquid that has passed through the separation area 218 fills the liquid reservoir 255, and the liquid flows into the dispensing flow path until it reaches the tip of the trigger flow path 256, that is, the intersection on the downstream side of the main flow path 221. It can be prevented from flowing into the 222 side. In the meantime, the concentration is homogenized in the liquid reservoir 255 by diffusion or the like, so that the concentration of the sample components can be surely homogenized.
- the timing at which the liquid flows into the dispensing channel 222 can be suitably adjusted according to the design of the length, shape, and the like of the trigger channel 256.
- the trigger channel 256 may be provided with a delay channel function that delays the timing at which liquid flows into the dispensing channel 222. Can do.
- FIGS. 29A to 29C are diagrams illustrating the configuration of the trigger channel 256.
- a flow channel extension region 263 is formed in a part of the trigger one flow channel 256.
- the channel expansion region 263 functions as a time delay tank in the trigger channel 256 and can be used as a delay channel. By doing so, the timing of opening the liquid switch 257 can be delayed.
- FIG. 29B shows a trigger channel 256 having the configuration shown in FIG. 29A, in which a hydrophobic region 264 is formed in a channel expansion region 263.
- the hydrophobic region 264 is formed so as to cross the channel expansion region 263 in a direction perpendicular to the direction in which the liquid in the trigger channel 256 advances.
- FIG. 29C shows an example of a trigger channel 256 having a zigzag shape.
- the delay time can be adjusted so that the liquid switch 257 can be opened at a desired timing.
- the shape of the trigger channel 256 is not limited to the shape shown in FIG. 29C as long as the shape occupies a small area, and may be, for example, a spiral shape.
- the concentration of the components separated in the separation region 218 can be homogenized in the mixing section 248 and then guided to the dispensing flow path 222. Therefore, after homogenizing the concentration of the liquid that has passed through the separation unit 213, the liquid can be guided to the detection unit 214. Therefore, a detection reaction with higher precision and accuracy can be performed for each detection item selected by opening and closing the control unit 314.
- the delay time in the delay channel can be customized. It takes a certain amount of time for the reaction required for detection to proceed sufficiently, and it takes a certain amount of time to mix the sample with the reagent.
- the delay channel is a channel provided to secure a waiting time for the delay.
- the waiting time differs for each type of reaction or each type of operation. For this reason, in a chip having the same basic configuration, in order to realize a plurality of different analysis processes in a plurality of analysis units (detection unit 214 or measurement unit 233), the waiting time of the delay channel is also required before use. It is preferable to be able to customize it. In this embodiment and other embodiments in this specification, the following With this configuration, it is possible to customize the waiting time of the delay channel.
- FIG. 47A, FIG. 47B, FIG. 48A, and FIG. 48B are plan views showing the configuration of a delay channel that allows customization of the delay time.
- the delay channel shown in FIGS. 47A and 47B corresponds to a configuration in which the channel expansion region 263 forming a part of the trigger channel 256 shown in FIGS. 29A and 29B is a customizable delay channel.
- the delay channel shown in FIGS. 47A and 47B basically has an inflow channel 800, an outflow channel 801 and a channel expansion region 802.
- the position where the custom obstacle 803 is provided is adjusted to an appropriate position.
- the custom obstacle 803 can be realized by, for example, pressing the heater unit shown in FIG. 41 to heat and deform the thermoplastic substrate material to form an obstacle that blocks the flow. By controlling the position where the heater unit is pressed, and changing the position where the custom obstacle 803 is formed, the length of the delay time can be customized.
- the custom obstacle 803 can also be formed as a hydrophobic surface formed by pressing a hydrophobic PDMS rubber or the like, or by performing a printing process using a hydrophobic ink.
- the liquid in the flow path can connect the inflow path 800 and the outflow path 801 with a short distance.
- the gas can pass through the flow path extension area 802 in a relatively short time.
- the custom obstacle 803 greatly protrudes toward the channel expansion region 802. Therefore, the liquid flowing in the channel expansion region 802 needs to make a circuit, and as a result, the liquid passes over a relatively long time. Therefore, the delay time can be customized by adjusting the position of the custom obstacle 803 in advance in accordance with the delay time required for each analysis process.
- the number of the custom obstacles 803 is not limited to one, and a longer delay time can be set by providing a plurality of the custom obstacles 803 in parallel in the flow channel expansion region 802.
- FIGS. 48A and 48B show a delay channel of a type in which the waiting time is customized by changing the length of the channel.
- the delay channel shown in FIGS. 48A and 48B has, as a basic configuration, an inflow channel 810, an outflow channel 811 and two extension channels 812 connected to each of these channels.
- a custom flow path 813 connecting two extension paths 812 It is formed at a predetermined position, and the formation position is roughly adjusted.
- the custom channel 813 can be provided, for example, by cutting the surface of the substrate so as to straddle the two extension channels 812 using an ultra-thin blade micro-cutting grindstone used for dicing. Since the cross section of the micro cutting wheel is sharp, the cross section of the extension path 812 and the custom channel 813 communicate with each other.
- the custom channel 813 can also be realized by forming a band of a highly hydrophilic substance, for example, a carboxymethyl cellulose gel, an agarose gel, or the like, so as to straddle the two extension paths 812. Since the aqueous solution travels while wetting the highly hydrophilic band, two extended paths are connected.
- Highly hydrophilic bands can be formed by stamping a gel of these substances, or printing and drying in a sol state.
- the custom flow channel 813 is formed at a position where the extension road 812 is left long. In this case, since the liquid in the flow path needs to flow over a long distance indicated by a dotted arrow, the delay time becomes long.
- the custom flow path 813 is formed at a position where the extension path 812 is short, the distance for connecting the liquid between the inflow path 810 and the outflow path 811 is short, and the delay time is also short. Accordingly, the delay time can be customized by controlling the cutting position of the cutting whetstone and changing the formation position of the custom channel 813.
- the two extension paths 812 are not in communication, but they do not hinder the formation of the custom flow path 813 that can be connected at the tip. Can take any shape.
- the chip can be provided in a predetermined channel or a trigger channel, and a delay time can be set and customized.
- FIG. 30 and FIG. 31 are functional block diagrams showing the configuration of the chip according to the present embodiment. 30 and 31, a detection unit 214 and a measurement unit 233 are provided as analysis units, respectively. In both the chip 329 of FIG. 30 and the chip 330 of FIG. 31, the pretreatment section 266 is formed between the sample introduction section 212 and the separation section 213.
- the detection unit 214 shown in FIG. 30 will be described as an example.
- FIG. 32 is a diagram illustrating an example of a configuration of a chip that can be used as the chip 329.
- a pre-processing unit 266 having an adjusting unit is formed between the inlet 217 and the separation region 218.
- a treatment for solubilizing extracellular components for example, collagen
- a viscous biological sample for example, saliva or nasal discharge
- FIG. 33 is an enlarged view of pre-processing section 266 of FIG.
- the pretreatment section 266 includes a flow path 300 communicating with the main flow path 221, a pretreatment tank 269 provided in the flow path 300, a flow path 332 and a flow path 333 communicating with the pretreatment tank 269, a flow path 332 and a flow path.
- a reagent tank 301 and a reagent tank 302 communicating with the passage 333, respectively, a trigger passage 334 branching from the main passage 221 downstream of the passage 300 and communicating with the passage 332, and a branch portion 336 on the trigger passage 334.
- Trigger flow path 334 Force Divided, has a flow path expansion area 263 as a time delay tank, and has a trigger flow path 335 communicating with the flow path 333 and a main flow path 221 upstream of a branch point where the flow path 300 branches. , And merges with the main flow path 221 via the liquid switch portion 257 on the downstream side of the trigger flow path 334, and has a trigger flow path 256 having a flow path expansion area 263.
- the preprocessing unit 266 further includes a control unit on the flow channel 300, on the trigger flow channel 334 upstream of the branch unit 336, on the trigger flow channel 334 downstream of the branch unit 336, and on the trigger flow channel 335. It has 314p, 314q, 314r, 314s.
- the pretreatment tank 269, reagent tank 301, reagent tank 302, trigger channel 256, trigger channel 334, and trigger channel 335 have air holes 225.
- the pretreatment in the pretreatment tank 269 can be a one-step process or a two-stage process. . If the pre-processing is unnecessary, the pre-processing may not be performed. [0183] (a) When pretreatment is not performed in pretreatment tank 269
- the adjustment units 314p and 314q in the preprocessing unit 266 are closed.
- the configuration of the adjustment units 314p and 314q can be, for example, the configuration described in the first embodiment.
- the sample stops at the liquid switch 257 on the main flow path 221. Further, a part of the sample moves from the main flow path 221 to the trigger flow path 256 and reaches the liquid switch section 257.
- the liquid switch unit 257 opens as described in the third embodiment, and the sample in the main channel 221 moves toward the separation region 218.
- a setting is made so as to minimize the time delay due to the flow path expansion area 263, or the main flow path 221, the trigger flow path 256, the liquid switch section 257, the flow path expansion area 263, and the liquid switch section 257 are omitted in advance. You can keep it.
- control units 314p, 314q, 314r on the flow path 300 are opened, and the control unit 314s is closed.
- the pretreatment tank 269 is a liquid reservoir for performing a predetermined pretreatment on the sample introduced into the introduction port 217.
- a pretreatment reagent such as an enzyme used for the pretreatment, for example, collagenase or lysozyme chloride, may be introduced into the pretreatment tank 269 as much as possible. Further, when an operation such as incubation is simply performed as a pretreatment, the pretreatment reagent may not be introduced.
- a buffer having substantially the same volume as the volume of the pretreatment tank 269 is set.
- the water level in the reagent tank 301 is equal to or higher than the height of the upper end of the main flow path 221 in order to cause the sample treated in the pretreatment tank 269 to flow backward in the main flow path direction.
- the liquid switch 257 provided in the flow path connecting the pretreatment tank 269 and the reagent tank 301 can hold a buffer in the reagent tank 301 by, for example, having a configuration shown in Fig. 53 described later. it can.
- the pretreatment reagent is introduced into the pretreatment tank 269, it is mixed with the set reagent and a predetermined pretreatment reaction occurs. A part of the sample in the pretreatment tank 269 moves from the pretreatment tank 269 into the flow path 332 and the flow path 333, and the liquid switch 257 provided on the flow path 332 and the flow path 333, respectively. Is blocked by.
- a part of the sample moves into the trigger channel 334 branched from the main channel 221 downstream of the channel 300, and the liquid switch provided in the channel connecting the pretreatment tank 269 and the reagent tank 301. Part 25 7 is opened. Then, the buffer in the reagent tank 301 flows backward in the direction of the pretreatment tank 269, and the contents of the pretreatment tank 269 are supplied to the main flow path 221.
- the delay time until the trigger flow channel 334 opens the liquid switch portion 257 is set to be equal to or longer than the reaction time required for the pretreatment. Therefore, a flow channel expansion region may be added on the trigger flow channel 334.
- a part of the sample moves from the main flow path 221 to the trigger flow path 256 and reaches the liquid switch section 257.
- the liquid switch 257 opens, and the sample in the main channel 221 moves toward the separation area 218.
- the trigger channel 256, the channel expansion region 263, and the liquid switch 257 are provided to keep the main channel 221 closed until the sample is sufficiently processed in the pretreatment tank 269.
- the delay time in the extension area 263 is set to a time sufficient to fill the pretreatment tank 269.
- extracellular collagen and the like are decomposed and cells (eg, insulin cells, glucagon cells) contained in a sample (eg, tissue such as islets of Langerhans) are removed.
- a chemical solution eg, glucose
- components eg, insulin
- the controller 314p, controller 314q, controller 314r, and controller 314s on the channel 300 are opened.
- a pretreatment reagent eg, freeze-dried collagenase
- predetermined reagents and buffers eg, gnocholose solution
- a buffer for flushing the pretreated sample to the main flow path Is set.
- Reagent tank 301 and The water level of the reagent tank 302 is higher than the height of the upper end of the main flow path 221, and the volume thereof is substantially equal to or larger than the volume of the pretreatment tank 269.
- the sample introduced into the inlet 217 fills the pretreatment tank 269, and the first-stage reaction (for example, cell exposure due to collagen dissolution and cell precipitation) occurs.
- the sample continues to travel in the main channel 221 and partially bypasses the trigger channel 334.
- the sample flowing in the trigger channel 334 opens the liquid switch 257 between the pretreatment tank 269 and the reagent tank 301 after a sufficient delay time for the first-stage reaction.
- the reagent for example, glucose solution
- the reagent necessary for the second-stage reaction held in the reagent tank 301 moves to the pretreatment tank 269, and flushes the liquid inside the pretreatment tank 269 to the main flow path,
- the solution in the pretreatment tank 269 is replaced.
- the liquid that has been flushed into the main flow path flows back through the main flow path because the liquid switch portion 257 provided downstream of the main flow path is not opened.
- the pretreatment tank 269 When a delay time sufficient for the second stage reaction (for example, a reaction in which insulin cells secrete insulin by reacting with a glucose solution) in the trigger channel 335, the pretreatment tank 269 When the liquid switch 257 provided in the flow path connecting the reagent tank 302 to the reagent tank 302 is opened, the buffer in the reagent tank 302 replaces the contents of the pretreatment tank 269 (for example, a glucose solution containing secreted insulin) with a new one. The sample is supplied to the main channel 221 as a simple sample.
- part of the sample moves from the main channel 221 to the trigger channel 256 and reaches the liquid switch 257.
- the liquid switch section 257 opens, and the pretreated sample moves to the separation area 218.
- a one-step reaction or a two-step reaction can be performed at a predetermined timing without using an external control device or the like by a configuration of the chip itself.
- the reaction unit 275 may be provided between the separation unit 213 and the adjustment unit 312, and the reaction unit may be further provided with the adjustment unit 314.
- FIG. 34 and FIG. 35 are functional block diagrams showing the configuration of the chip according to the present embodiment. 34 and 35, a detection unit 214 and a measurement unit 233 are provided as analysis units, respectively. With the chip 337 in Fig. 34 and the chip 338 in Fig. 35, A reaction section 275 is provided therebetween.
- FIG. 36 is a diagram illustrating an example of a configuration of a chip corresponding to the chip 337.
- a reaction section 275 is formed between the separation area 218 of the main flow path 221 and the dispensing flow path 222.
- FIG. 37 is a view for explaining the configuration of the reaction section 275 of FIG.
- the reaction unit 275 shown in FIG. 37 has the same basic configuration as the pre-processing unit 266 shown in FIG. The only difference is that a reaction tank 340 is provided instead of the pretreatment tank 269.
- a reaction tank 340 is a liquid reservoir for performing a predetermined reaction on the sample separated in the separation area 218.
- the reaction unit 275 also has adjustments 314p, 314q, 314r, and 314s in the same manner as the pretreatment described in the fourth embodiment.
- the reaction in the reaction section 275 can be prevented from being performed at the same time, or the reaction section 275 can perform a one-step or two-step reaction.
- the one-step reaction includes, for example, solubilization of cells and mixing with a reagent, and the two-step reaction includes collection of cell secretions such as insulin described in the fourth embodiment. Can be mentioned.
- the processing steps are the same as those of the preprocessing unit 266.
- control unit 314p, the control unit 314q, and the control unit 314r on the reaction unit 275 are opened, and the control unit 314s is closed.
- a surfactant for solubilizing the cell membrane which is a lipid membrane, and a freeze-dried lipase for decomposing the lipid
- a buffer may be set in the reagent tank 301.
- a separation region 218 may be further provided downstream of the reaction section 275. By doing so, the sample after the reaction is further separated in the separation region 218 formed downstream of the reaction tank 340. Therefore, for example, in the case of the sample after the above-described solubilization reaction, insoluble components that have not been solubilized by the above series of reactions can be removed in the separation region 218 provided downstream of the reaction tank 340.
- reaction section 275 may have three or more reagent tanks.
- a plurality of reaction sections 275 are provided on the force chip, which illustrates a chip having one reaction section 275. You can also
- the analysis unit (the detection unit 214 or the measurement unit 233) may communicate with the liquid reservoir, and the adjustment unit 312 may be provided on these paths.
- the configuration of the analysis unit can be a configuration generalized to a typical reaction. Further, by providing a predetermined number of general-purpose analysis units on a substrate, the analysis unit can be suitably used as a general-purpose chip.
- the detection unit 214 includes a plurality of detection tanks 223 and peripheral members. Can be formed on the chip.
- FIG. 49 is a diagram illustrating the configuration of the detection unit 214.
- the detection unit 214 shown in FIG. 49 has the same basic configuration as the pre-processing unit 266 shown in FIG. The difference is that a detection tank 223 is provided instead of the pretreatment tank 269.
- the detection tank 223 is a reservoir for performing a predetermined detection reaction on the sample introduced into the inlet 217.
- the detection unit 214 includes the adjustment unit 314, so that the reaction in the detection unit 214 is performed by adjusting the opening and closing of these adjustment units 314.
- the detection unit 214 can perform a one-step or two-step reaction.
- the sample separated in the separation region 218 flows into the detection tank 223 as necessary, and is subjected to a predetermined reaction. Since the liquid switch section 257 is provided downstream of the detection tank 223, initially, the liquid that has passed through the detection tank 223 does not flow downstream of the liquid switch section 257.
- the configuration of the trigger channel 256 can be designed according to the time required for the detection reaction in the detection tank 223. For example, if the time required for the detection reaction is long, the channel expansion region 263 can be enlarged. Further, the trigger channel 256 may have the above-described delay channel, and the delay time of the delay channel may be customized. [0209] In FIG.
- reagent tank 301 two reagent tanks, ie, a reagent tank 301 and a reagent tank 302 are provided for one detection tank 223, but one reagent tank 223 is provided for one detection tank 223.
- a configuration having a tank 301 can also be employed. Further, three or more reagent tanks may be provided for one detection tank 223.
- Fig. 58 is a diagram showing a configuration in a case where one reagent tank 301 is used in Fig. 49.
- the control units 314p and 314q are opened, and when the detection tank 223 is not used for the detection reaction, the control units 314p and 314q are closed.
- FIG. 58 a closing switch 640 is provided between the adjustment unit 314p of the flow channel 300 and the detection tank 223.
- FIG. 52 is a plan view showing the configuration of the closing switch 640 provided in the detection unit.
- the closing switch 640 is provided to prevent the reacting liquid from flowing back from the liquid reservoir group to the main flow channel 221 side.
- the closing switch 640 includes an expansion portion 641 provided in the flow path and an expansion body 642 provided therein. When the liquid passes through the flow path 607 and the expansion section 641, it interacts with the liquid in the flow path and the expansion body 642 gradually expands, and finally the expansion section 641 is completely closed. 607 can be closed.
- the expanded body 642 can be, for example, beads made of polyacrylamide, a water-absorbing polymer, or the like in a dried and contracted state.
- the expansion body 642 is fixed in the expansion section 641 by a method of making the diameter larger than the width of the flow path 607 or a method of bonding to a part of the expansion section 641.
- FIG. 58 by providing one reagent tank 301 for one detection tank 223, the configuration of the apparatus can be simplified. This configuration can be applied, for example, to a chip for one-stage detection and application. Note that in FIG. 58, a force adjusting section showing a configuration in which two adjustment sections 314p and 314q are provided, one each for the flow path 300 and the trigger channel 334, is provided with at least the adjustment section 314p. It should just be. By providing the adjusting section 314q also in the trigger channel 334, waste of the liquid sample can be suppressed more reliably.
- the detection unit 214 may be configured to have five reservoirs. These liquids The reservoir is used as a detection tank, a waste liquid reservoir, a reagent tank, a buffer tank, etc., depending on the type of the detection reaction.
- FIG. 50 is a plan view showing a detection unit 635 which is another configuration example of the detection unit 214.
- the detection section connects the liquid reservoir group consisting of the five night reservoirs 630, ⁇ night reservoir 631, ⁇ night reservoir 632, liquid reservoir 633, and liquid reservoir 634, and connects the liquid reservoir group to the main flow path 221.
- a trigger channel group including a channel 620, a trigger channel 621, and a trigger channel 622, and a delay channel 610, a delay channel 611, and a channel 607 and a trigger channel provided on these trigger channels are opened and closed.
- An adjusting unit 600, an adjusting unit 601 and an adjusting unit 602 for customizing are provided.
- a trigger channel 256, a channel expansion region 263, and a liquid switch 257 may be provided for the purpose of closing the main channel 221 until the sample sufficiently fills the liquid reservoir 630.
- the five reservoirs 630, 631, 631, 633, 634, 634, and 635 are provided with air holes 225, respectively.
- the reservoir 630 is mainly used as a detection tank.
- the reservoir 631 and the reservoir 632 mainly serve as a waste reservoir.
- the liquid reservoir 633 and the liquid reservoir 634 are mainly used for supplying a reagent liquid to the liquid reservoir 630.
- the branch portion of the trigger flow channel 256, the branch portion of the flow channel 607, the branch portion of the trigger flow channel 620, and the junction of the trigger flow channel 256 (that is, the liquid switch)
- the toes 257) are provided in this order.
- the flow path 607 branched from the main flow path 221 includes a control section 600, a closing switch 640, a first branch section of the flow path 607, a liquid reservoir 630, a liquid switch section 623, a liquid reservoir 631, and a liquid switch section 62. 4, and the reservoir 632 are connected in this order from upstream to downstream.
- a second branch of the flow channel 607 is provided downstream of the first branch of the flow channel 607, and the liquid switch 625 and the liquid reservoir 625 are provided in one of the flow channels 607 branched by the second branch. 633 are connected in this order.
- a liquid switch 626 and a liquid reservoir 634 are connected in this order to the other of the flow path 607 branched at the second branch.
- an adjusting unit 601 and a delay channel 610 are provided in this order from the upstream side, and the trigger channel 620 branches into a trigger channel 621 and a trigger channel 622 downstream of the delay channel 610.
- a liquid switch part 623 and a liquid switch part 625 are connected to the trigger one flow path 621 in order from the upstream side, and the leading end communicates with the air hole 225.
- a control section 602, a delay channel 611, a liquid switch section 624, and a liquid switch section 626 are connected to the trigger flow path 622 in order from the upstream side, and the distal end communicates with the air hole 225.
- FIG. 51A and FIG. 51C are cross-sectional views showing the configuration of a chip having the detection unit 635 shown in FIG. FIG. 51A to FIG. 51C show a cross section taken along line XX ′ of FIG.
- the chip shown in FIG. 51A to FIG. 51C is composed of the substrate 701 and the lid 700 and a force, and all the channel systems except the air holes 225 are formed in the substrate 701 at substantially the same depth as the main channel 221. .
- the lid 700 has an air hole 225 communicating with each reaction tank.
- the lid 700 arranges the reagents necessary for the detection reaction in the liquid reservoir 630-liquid reservoir 634 on the substrate 701, and adjusts the control section 600, the control section 601, the control section 602, the delay channel 610, the delay channel 611, After the delay channel 612 and the like are customized, it is joined to the substrate 701.
- the main channel 221 and the liquid reservoir 630—the liquid reservoir 634 are machined to approximately the same depth. Since the liquid is driven by the capillary effect based on the hydrophilicity of the flow channel, horse power can be obtained even at substantially the same depth.
- FIG. 51B is a cross-sectional view of a chip that also uses a water level difference.
- the channel system on the substrate 701 is formed from four different depths, from the shallowest level 0 to the deepest level 3, in order to utilize the water level difference.
- the main flow path 221, the trigger flow path group, and the delay flow path group are at level 0,
- the liquid reservoir 630 is at level 1
- the liquid reservoirs 631 and 632 which mainly serve as waste liquid reservoirs, are at level 2 and level 2, respectively. 3 is formed.
- a water level difference occurs between the liquid reservoirs communicated by the capillary effect, and a driving force is generated from the main flow path 221 toward the liquid reservoir 632.
- a reservoir 633 and a reservoir 634 mainly for supplying a reagent solution to the reservoir 630 are formed at level 0.
- FIG. 51B shows the liquid reservoir in FIG.51B.
- FIG. 10 is a cross-sectional view showing a configuration of a chip in which the volumes of the reservoir 630, the reservoir 631, and the reservoir 632 are constant.
- the substrate of the chip shown in FIG. 51C is made by laminating four lamination substrates 702 and 701, and the through-holes penetrating the respective lamination substrates 702 are laminated to form a liquid substrate.
- the reservoir group, the channel 607, the trigger channel group, and a part of the air hole 225 are formed.
- the trigger flow path group like the air hole 225, forms a liquid switch portion with a level 0 and then descends vertically to communicate with the liquid reservoir.
- a lid 700 having an air hole 225 is joined to the upper end of the chip as in FIG. 51B.
- the material of these chips can be a material having high transparency, such as a resin such as PET or PMMA, or glass or quartz.
- a resin such as PET or PMMA
- glass or quartz In order to use the transport by the capillary effect, it is desirable that the inside of the liquid sending flow path system is hydrophilic.
- the inner surface of the flow channel system can be made hydrophilic by coating it with a surface treatment agent such as MPC or acrylamide gel, and can be made highly hydrophilic.
- a member having a hydrophobic surface such as a liquid switch may be formed by subjecting a part of the surface of the flow channel which has already been made hydrophilic to a hydrophobic treatment.
- FIG. 53 is a plan view showing the basic structure of the liquid switch 623 to the liquid switch 626 of the detection unit 635 shown in FIG.
- the liquid switch section 623—the liquid switch section 626 includes a flow path 607, a trigger flow path 651, a damming section 650, and an air hole 652 provided at the tip of the trigger flow path 651. Consists of The air holes 652 correspond to the air holes 225 in FIG.
- the trigger channel 651 corresponds to the trigger channel 621 or the trigger channel 622.
- the difference between the liquid switch shown in FIG. 53 and the above-described embodiment is that the damming portions 650 are provided on both sides of the trigger channel 651. is there . Since the damming portion 650 is provided at two places with the trigger channel 651 interposed therebetween, even if there is no liquid in the channel 607, the liquid in the trigger channel 651 does not flow into the channel 607. The effect is obtained. In the state where the liquid is present on either side of the flow path 607, even if the liquid advances, the damming portion 650 is provided so that the two liquids do not communicate with each other. The communication when the passage 651 is filled is the same as in the case of the liquid switch section described above.
- one-step or multi-step detection reactions in the detection unit 214 can be selectively performed. Even in a chip provided with a measuring unit 233 in place of the detecting unit 214, by applying the above configuration to the sorting unit 235 instead of the detecting tank 223, one-step or multi-step The reaction can be selected and performed.
- a clinical biochemical test using the chip shown in FIGS. 50 to 53 will be described later in an eighth embodiment.
- the detection reaction in one detection tank 223 has been described in order to explain the configuration of the detection unit 214.
- a method of providing a plurality of detection tanks 223 in the detection unit 214 will be described.
- the chip having the detection unit 214 includes three detection tanks 223 will be described as an example.
- the number of the detection tanks 223 may be two or four or more.
- FIG. 38 is a diagram showing a configuration of the detection unit 214 according to the present embodiment.
- the detection unit 214 has three dispensing channels, a dispensing channel 222a, a dispensing channel 222b, and a dispensing channel 222c, which are sequentially communicated from the downstream side of the main channel 221.
- a detection tank 223a, a detection tank 223b, and a detection tank 223c communicate with the roads as detection tanks 223, respectively.
- the dispensing channel 2 22a and the dispensing channel 222c are provided with an adjusting unit 314a and an adjusting unit 314c, respectively.
- the detection tank 223a is connected to a reagent tank 301a via a flow path 332a, and the reagent tank 302a is connected to the detection tank 223a via a flow path 333a.
- a reagent tank 301b communicates with the detection tank 223b via a flow path 332b
- a reagent tank 302b communicates with the detection tank 223b via a flow path 333b.
- a reagent tank 301c communicates with the detection tank 223c via a flow path 332c
- a reagent tank 302c communicates with the detection tank 223c via a flow path 333c.
- a trigger flow path 334 branches downstream of the dispensing flow path 222a.
- An adjustment section 314d is provided in the trigger channel 334, and a downstream of the adjustment section 314 is connected to a trigger channel 334a connected to the channel 332a via the liquid switch section 257, and via another liquid switch section 257.
- the trigger channel 335a connected to the channel 333a branches.
- the one trigger channel 334 is connected to the channel 332c via the liquid switch 257 downstream thereof.
- the trigger channel 335a branches from the trigger channel 334a.
- An adjusting section 314e is provided in the trigger channel 334a downstream of a branch point with the trigger channel 335a.
- the trigger channel 335a is provided with a channel expansion region 263 and an adjusting unit 314f.
- a trigger flow path 334b branches downstream from a branch point with the trigger flow path 334a.
- the trigger channel 335b further branches off from the trigger channel 334b.
- the trigger flow path 334b is provided with an adjustment section 314g upstream of a branch point with the trigger flow path 335b, and an adjustment section 314h downstream of the branch point.
- the trigger flow path 335b is provided with a flow path expansion area 263 and an adjusting section 314i.
- the trigger channel 334b is connected to the channel 332b via the liquid switch 257, and the trigger channel 335b is connected to the channel 333b via the other liquid switch 257.
- the trigger channel 335c branches further downstream than the branch point of the trigger channel 334b.
- the trigger flow path 334 is provided with an adjustment portion 314j downstream of the branch point with the trigger flow path 334b and upstream of the branch point with the trigger flow path 335c.
- An adjustment unit 314k is also provided on the downstream side.
- the trigger flow path 335c is provided with a flow path expansion area 263 and an adjustment section 3141.
- the trigger channel 334 is connected to the channel 332c via the liquid switch 257, and the trigger channel 335c is connected to the channel 333c via the other liquid switch 257.
- the number of detection tanks to be used can be appropriately selected by setting the opening and closing of the adjustment unit 314a—the adjustment unit 3141. Further, the detection reaction performed in each detection tank can be appropriately selected from a one-step reaction to a two-step reaction.
- Table 1 is a table showing adjustment units that are opened or closed when each of the detection tank 223a and the detection tank 223c is used. For each of the detection tank 223a and the detection tank 223c, the open / close state of the control unit 314a and the control unit 3141 is shown according to the usage state of the communicating reagent tank 301a—reagent tank 301c and reagent tank 302a—reagent tank 302c. .
- the reagent tank 302c in the table indicates the case where it is used and the symbol X indicates the case where it is not used.
- “ ⁇ ” in the table indicates a case where it needs to be opened
- “X” indicates a case where it needs to be closed.
- the open / closed state of the adjustment unit that is blank in the table varies depending on the usage of other detection tanks and liquid reservoirs.
- the detection unit 214 As a multi-step reaction in the detection unit 214, for example, insulin in plasma can be detected.
- a case where only the detection tank 223a is used will be described as an example.
- the control unit 314a, the control unit 314d, the control unit 314e, and the control unit 314f are opened.
- the control unit 314b, the control unit 314c, and the control unit 314g—the control unit 3141 are closed.
- an anti-insulin antibody is immobilized in advance as a primary antibody.
- a liquid containing an anti-insulin antibody (hereinafter referred to as “enzyme-linked antibody”) on which an enzyme for color reaction is immobilized is introduced as a secondary antibody.
- a liquid containing a coloring reagent that is colored by the action of a coloring reaction enzyme is introduced.
- the sample flows through the main flow path 221 in this state, the sample is guided to the detection tank 223a. Further, a part of the sample moves to the trigger channel 334 on the downstream side of the detection tank 223a. In the time until the sample that has entered the trigger channel 334 opens the liquid switch 257 on the trigger channel 334a, the insulin in the sample is specific to the anti-insulin antibody immobilized on the surface of the detection tank 223a. Interact with each other.
- a part of the sample in the trigger channel 334 enters the trigger channel 334a, and when the sample reaches the liquid switch 257 on the trigger channel 334a at a predetermined timing, the liquid switch 257 is opened. Then, the enzyme-linked antibody in the reagent tank 301 moves into the detection tank 223a.
- the liquid level in the reagent tank 301 be higher than the liquid level in the detection tank 223a. In this case, when the liquid switch portion 257 on the trigger channel 334a is opened, the reagent in the reagent tank 301 is preferably pushed out to the detection tank 223a.
- a part of the sample moving in the trigger channel 334 further enters the trigger channel 335a from the trigger channel 334a, and after a time delay by the channel expansion region 263, the sample on the trigger channel 335a
- the liquid switch section 257 is reached. Then, the liquid switch portion 257 is opened, and the coloring reagent in the reagent tank 302a is introduced into the detection tank 223a via the flow path 333a. It is preferable that the liquid level in the reagent tank 302a is also higher than the liquid level in the detection tank 223a.
- the water levels of the detection tank 223a-the detection tank 223c, the reagent tank 301a-the reagent tank 301c, and the reagent tank 302a-the reagent tank 302c are set in the preprocessing unit 266 in the fourth embodiment.
- the capillary phenomenon can be suitably used for the movement of the liquid in the detection unit 214. For this reason, it is possible to adopt a simple configuration in which it is not necessary to provide an external driving device for moving the liquid in the detection unit 214.
- the plurality of reservoirs communicate with the detection unit 214, and the adjustment unit 314 is provided on each of the communication channels to adjust the opening and closing of the adjustment unit.
- insulin in the sample can be detected by a color reaction.
- the chips described in the above embodiments can be applied to biochemical tests.
- an example of a biochemical test chip for examining liver function using blood as a sample will be described.
- the basic configuration of the chip is, for example, the chip described in the third embodiment.
- the detection unit 214 for example, a detection tank 223 corresponding to the inspection items in Table 2 can be formed.
- the items in Table 2 can be measured by a one-step reaction by introducing a detection reagent into each detection tank 223 in advance.
- the adjustment unit 314 provided on the flow path connecting them is closed in advance.
- FIGS. 50 to 53 steps for realizing a clinical biochemical test using the analysis unit (FIGS. 50 to 53) described in the sixth embodiment will be described.
- the chips shown in FIGS. 50 to 53 have a configuration including a detection unit 635 as an analysis unit, but the following configuration can also be applied to a chip in which the analysis unit is a measurement unit 233.
- the analysis units shown in Figs. 50 to 53 have adjustment units, and these adjustment units can be set. Thus, it is a general-purpose analyzer capable of responding to various types of detection reactions.
- Clinical biochemical tests can be classified into one-step, two-step, and three-step reactions according to the number of reaction steps.
- colorimetric, enzymatic, UV, latex agglutination (LA), latex agglutination immunoturbidimetry (LA TIA), immunoturbidimetry (TIA method) and the selective inhibition method are basically one-step reactions, and can be realized by two-step reactions even if pretreatment is included.
- Radioimmunoassay (RIA), chemiluminescence immunoassay (CLIA), chemiluminescence enzyme immunoassay (CLEIA), and enzyme-linked immunosorbent assay (ELISA) can be basically realized in three steps.
- the one-step reaction is a reaction that enables detection and measurement by directly mixing a reagent and a sample.
- the one-step reaction can be realized by the detection unit 635 in which the control unit 601 is closed in FIG. 50 (this type of detection unit is called a class 1 detection unit).
- the reservoir 630 is used as a detection tank.
- necessary reagents are set in advance according to the type of the substance to be detected and the measurement method. After setting those reagents immediately before use, the lid 700 may be joined.
- the reagent is a coloring reagent that reacts with the substance to be detected and develops a color, or a dye used for quantitative determination of albumin.
- the reagent consumes the substance to be detected.
- the UV method it is a substrate or coenzyme (NAD + / NADH or NADP + / NADPH) that is consumed by the test substance enzyme, such as latex agglutination, latex agglutination
- the test substance enzyme such as latex agglutination, latex agglutination
- the test substance enzyme such as latex agglutination, latex agglutination
- the reagents are set so as to have an appropriate volume ratio with the sample. These reagents are appropriately selected according to a written book (for example, “Recommended Clinical Laboratory Methods”, 31st edition, written by Izumi Kanai, Masamitsu Kanai, Kanehara Shiden Edition Co., Ltd.).
- the sample advances in the main flow path 221 and reaches the branch part of the flow path 607, which is a branch part to the liquid reservoir 630, the force that fills the liquid reservoir 630 through the control part 600 in the open state.
- the sample stops when the 630 is filled.
- the expanding body 642 in the closing switch 640 is made of such a material that the expansion rate is such that the flow path is closed after the liquid reservoir 630 is sufficiently filled, so that the liquid under reaction flows to the main flow path 221. And prevent backflow.
- the detection reaction proceeds.
- the diffusion phenomenon is relatively promoted, so that the mixture is relatively early.
- the sample proceeds further in the main flow path 221 but cannot flow into the trigger flow path 620 because the control section 601 is closed, so that the liquid switch section 623 is kept closed.
- the mixture of the sample and the detection reagent is allowed to react for a certain period of time, and then the absorbance is measured using the liquid reservoir 630 as an optical cell. For example, light is irradiated from the direction of the footer 700, and a light receiving device is placed on the side of the substrate 701 to measure the absorbance.
- the consumption state of a coenzyme (NAD + / NADH or NADP + / NADPH) that absorbs ultraviolet light (UV) is measured at regular intervals, and the enzyme that is the test substance is determined based on the consumption rate. The activity of is measured.
- the substrate 701 and the lid 700 should be made of quartz glass that transmits UV light well.
- the absorbance of the liquid reservoir 630 is measured.
- the bottom surface of the liquid reservoir 630 may be formed in a conical shape or a bowl shape. If the test substance is not present in the sample, the beads will not adsorb to the bottom surface and will precipitate, resulting in concentration at the top of the conical or bowl-shaped bottom surface, resulting in high light transmittance.
- the beads will be large; the beads will spread over the entire bottom surface due to the formation of aggregates and adsorption to the bottom surface, and the light transmittance will decrease. Therefore, the presence or absence of the test substance can be determined by measuring the transmittance of the liquid reservoir 630.
- the turbidity is measured at regular time intervals without waiting for precipitation, and the test is performed by measuring the rate at which turbidity decreases due to the formation of aggregates. Quantify the substance.
- the immunoturbidimetric assay measures changes in turbidity due to antigen-antibody aggregates formed by the test substance and the antibody in the sample.
- Two-step reactions are mainly one-step It is used in the pretreatment process of the sample used in the reaction.
- a detector 635 of a type in which the controller 600 and the controller 601 are opened and the controller 602 is closed in FIG. 50 is used (hereinafter, this type of detector is referred to as a class 2 detector).
- this type of detector is referred to as a class 2 detector.
- the reservoir 630 is used for measurement instead of the reservoir 630.
- Reservoir 631 contains reagents used in the one-step reaction, and reservoir 630 contains reagents necessary for sample pretreatment, such as heparin, EDTA, Alternatively, set at least one of citric acid in a dry state. Leave nothing in reservoir 633.
- the procedure until the sample fills the reservoir 630 via the control unit 600 can be the same as that of the class 1 reaction unit.
- the sample travels through the delay channels 610 and the trigger channels 620 and 621 to open the liquid switch unit 623.
- the delay time of the delay channel 610 is a time sufficient for the sample and the reagent to mix well in the liquid reservoir 630.
- a detector 635 of a type in which the control unit 600, the control unit 601 and the control unit 602 are all open in FIG. 50 is used (hereinafter, this type of the detector 635 is referred to as a class 3 detector). Call).
- radioimmunoassay When radioimmunoassay (RIA) is realized using a class 3 reaction part, an antibody to a test substance is bound to the inner surface of the reservoir 630 in advance, and radioactivity is added to the reservoir 633.
- a radioactive standard sample solution marked with an isotope and an emulsified liquid scintillator solution for converting radioactivity to luminescence are set in the reservoir 634.
- the method of binding the antibody to the surface of the liquid reservoir 630 may be a physical phenomenon that naturally adsorbs to a clean material surface, or may be a chemical bond using a coupling agent having an amino or carboxy group. You may.
- the case of the one-step reaction is different.
- a similar procedure can be used.
- the test substance contained in the sample binds to the antibody on the inner surface of the reservoir 630.
- the control section 601 and the control section 602 are open, so that the sample passes through the delay channel 610 and travels through the trigger channels 620 and 621, and the liquid switches 623 and 625 sequentially. Let it open.
- the liquid reservoir 630 and the liquid reservoir 631 communicate with each other, and a part of the sample flows out to the liquid reservoir 631 used as a waste liquid reservoir.
- the delay time of the flow channel 610 is a time sufficient for the binding between the sample and the antibody.
- the liquid in the liquid reservoir 631 flows out to the liquid reservoir 632, and is then set in the liquid reservoir 634. It flows through the emulsified liquid scintillator hydraulic flow path 607, and flushes the contents of the reservoir 630 toward the reservoirs 631 and 632.
- the delay time of the delay channel 611 is a time sufficient for the binding reaction between the radioactive standard sample and the test substance in the sample and the antibody to reach equilibrium.
- chemiluminescence immunoassay (CLIA method) is realized using the class 3 detection unit 635, an antibody against the test substance is bound to the inner surface of the liquid reservoir 630.
- Reservoir 633 contains an antibody to the substance to be detected and a chemiluminescent substance (such as ataridinium ester).
- a solution of the photoantibody is set, and a buffer for washing is set in the reservoir 634.
- the sample fills the liquid reservoir 630 in the same step as the one-step reaction, and reacts with the antibody in the liquid reservoir 630 until the liquid switch 623 and the liquid switch 625 are sequentially opened.
- the delay time of the delay channel 610 is a time sufficient for the test substance in the sample to bind to the antibody.
- the liquid in the liquid reservoir 631 flows out to the liquid reservoir 632 and then to the liquid reservoir 634. It flows through the flow path 607 of the cleaning buffer that has been set, and flushes the contents of the liquid reservoir 630 toward the liquid reservoir 631 and the liquid reservoir 632.
- the delay time of the delay channel 611 is a time sufficient for the test substance bound to the inner surface of the liquid reservoir 630 and the luminescent antibody to bind. The flow stops when reservoir 632 is full, at which point reservoir 630 is full of wash buffer. In the liquid reservoir 630, the more the test substance in the sample, the more luminescent antibodies are bound. Therefore, by measuring the luminescence intensity, the amount of the test substance contained in the sample is reduced. Know the amount.
- the chemiluminescence enzyme immunoassay (CLEIA method) can also be realized using the class 3 detector 635 in the same steps as the chemiluminescence immunoassay method (CLIA method).
- CLIA method chemiluminescence enzyme immunoassay
- an antibody against a test substance bound to an enzyme that reacts with a luminescent substrate to generate light is set in the liquid reservoir 633.
- a luminescent substrate solution in the liquid reservoir 634 instead of the washing buffer, measurement can be performed in exactly the same steps as in the case of the CLIA method.
- Fig. 54 to Fig. 57 are diagrams collectively showing a set of main test items to be measured at the re-examination, a measurement method, and a class of a reaction unit capable of realizing the method. From FIG. 54 to FIG. 57, it can be seen that most commonly used re-examination test items can be measured with a chip having a class 1 or class 3 reaction part. In addition, a general-purpose analysis chip standardized in advance for each re-examined disease group shown in FIGS. 54 and 57 can be produced.
- a chip provided with one or more class 1 reaction units and one or more class 3 reaction units can be manufactured. If this chip is used, a test for diabetes can be performed easily and reliably on the spot. At this time, at least one of the reaction units holds a diabetic test reagent.
- the reagent used for holding the reagent in the class 1 reaction zone is, for example, the reagent necessary for measuring hemoglobin Alc, 1,5_anhydro_D-darcitol, or glycoalbumin.
- the reagent to be retained in the class 3 reaction section is, for example, a reagent necessary for measuring an anti-glutamate decarboxylase antibody.
- the chip may have a reaction part in which no reagent is held.
- the generalized reaction unit can be customized for each individual by using a chip in a later step.
- Fig. 54 to Fig. 57 for example, obesity, hyperlipidemia, hepatic dysfunction, nephrosis, hypertension, adrenal gland, gout, thyroid dysfunction, anemia (microcytic, large It is possible to obtain a general-purpose chip suitable for measurement of (sphericity) and the like. Also in these cases, the reagents necessary for the measurement items shown in FIGS. 54 and 57 can be provided in the reaction section of the class corresponding to the items by using the method described above for diabetes.
- such a general-purpose chip has the same number of analysis units as the analysis units used for measurement on a sample, and is configured to perform the same measurement as the sample using a standard solution. May be. In this way, more accurate measurements can be made using a general-purpose tip Can do.
- FIG. 39 is a conceptual diagram showing an example of the chip manufacturing apparatus of the present embodiment.
- the chip manufacturing apparatus 342 shown in FIG. 39 is an apparatus capable of manufacturing a chip customized according to a request of an inspection organization.
- a case where a chip having the detection unit 214 as the analysis unit is manufactured will be described as an example, but the manufacturing apparatus according to the present embodiment can also be applied to the manufacture of a chip having the measurement unit 233 as the analysis unit. it can.
- the chip manufacturing apparatus 342 includes a reception unit 343, a selection unit 346, a substrate loading unit 349, and a substrate storage unit.
- a substrate holding unit 351 a pre-placement processing unit 352, a reagent loading unit 353, a reagent storage unit 354, a reagent placing unit 355, a post-placement processing unit 356, and a chip unloading unit 359.
- the substrate storage unit 350 receives and stores the substrate 216 from the substrate loading unit 349.
- reagents, buffers, and the like necessary for a detection reaction in the detection tank 223 or a reaction related to measurement in the measurement unit 233 are loaded into and stored in the reagent storage unit 354 from the reagent loading unit 353.
- the reagent may be supported on beads serving as a carrier and stored in the form of reagent beads.
- the receiving unit 343 receives an input from an inspection organization or the like that uses the chip.
- the reception unit 343 has a measurement item reception unit 344 and an institution ID reception unit 345.
- the measurement item receiving unit 344 receives an input of information on a measurement item to be measured using the chip.
- the institution ID reception unit 345 receives the ID of a testing institution or a physician who has requested chip production.
- the selection unit 346 selects the substrate 216 and the detection reagent based on the information input to the reception unit 343.
- the substrate selection unit 347 selects a substrate 216 used for manufacturing a chip, and loads the selected substrate 216 from the substrate storage unit 350 to the substrate holding unit 351.
- the reagent selection section 348 selects a reagent such as a detection reagent or a buffer to be filled in the detection tank 223, the reagent tank 301, the reagent tank 302, or another liquid reservoir, and stores the selected reagent in the reagent storage section 354. Load the reagent into the reagent dispensing unit 355 from.
- the pre-arrangement processing unit 352 controls the substrate 2 so that the selected detection reagent is efficiently adsorbed on the surface of the substrate 216 selected by the selection unit 346 based on the information input to the reception unit 343. Activate 16 surfaces. Further, a process of providing a cover around these areas may be performed so that the reagents are not scattered in areas other than the area where the reagents are filled.
- the reagent disposing unit 355 includes the detection tank 223 and the reagent tank of the substrate 216 held by the substrate holding unit 351.
- a certain amount of the reagent liquid may be sucked into a cylinder, and a part or all of the liquid reagent may be injected into a predetermined region. Thereafter, the reagent solution injected into dry air or nitrogen gas or the like may be exposed to evaporate the liquid component to dry and solidify.
- beads may be prepared such that each particle contains a sufficient amount of reagent for the detection reaction in one detection tank 223, and the beads may be arranged in the detection tank 223. .
- Post-placement processing section 356 closes and opens adjustment section 314 on the chip according to the inspection item input to measurement item receiving section 344.
- the post-placement processing unit 356 includes an enclosing unit 357 and an institution ID recording unit 358.
- the sealing portion 357 adheres the seal 227 to the surface of the substrate 216 and seals the upper surface of the substrate 216. Further, the sealing section 357 may select and seal the flow path detecting tank 223, the sorting section 235, and other liquid storage portions on the substrate 216.
- the institution ID recording unit 358 writes the ID input to the institution ID reception unit 345. This ID may be written on the substrate 216 or may be written on the outer package of the substrate 216.
- the substrate holding unit 351 sends out the chips obtained through the above steps to the chip unloading unit 359. If necessary, the chip may be placed in a bag-shaped airtight packaging material, filled with an inert gas such as nitrogen gas, and then the packaging material may be sealed.
- an inert gas such as nitrogen gas
- FIG. 44 is a diagram showing a chip manufacturing procedure using the chip manufacturing apparatus of FIG. 44, first, an input of an ID or a measurement item is received by the receiving unit 345 (S101). Then, based on the input information, the substrate selection unit 347 selects a substrate (S102), and further selects a flow path on the substrate (S103). Further, the reagent selection unit 348 selects a reagent to be used according to the measurement item (S104). Then, the selected substrate is carried in (S105), and the pre-arrangement processing unit 352 closes a predetermined adjustment unit so that the sample moves in the selected flow path (S106).
- the reagent disposing unit 355 introduces a predetermined reagent to a predetermined position on the substrate (S107). After that, through the post-processing step in the post-arrangement processing unit 356 (S108), the obtained chip is It is carried out (S109).
- the selection of the substrate in step 102 and the selection of the reagent in step 104 may be performed before or after.
- the substrate may be selected in step 102, and after the substrate is further loaded, the reagent may be selected in step 104.
- the chip manufacturing apparatus 342 By using the chip manufacturing apparatus 342, it is possible to easily manufacture a chip customized according to the measurement item input to the reception unit 343. Therefore, the configuration of the chip can be easily optimized according to the needs of many clients using the chip.
- Fig. 40 is a conceptual diagram showing an example of a chip manufacturing apparatus that can be customized according to the health condition of a person to be inspected in an inspection room or the like of an inspection organization.
- the chip manufacturing device 364 in FIG. 40 has a chart ID receiving unit 360 instead of the institution ID receiving unit 345, and has a schematic configuration similar to that of the chip manufacturing device 342 in FIG. The difference is that a medical record ID recording unit 361 is provided and a digitizing unit 362 and an output unit 363 are further provided.
- the medical record ID reception unit 360 receives input of information regarding the ID of a person to be examined, such as a patient in a hospital. Further, the chart ID recording unit 361 records the chip or the exterior body of the ID of the person to be inspected.
- the digitizing unit 362 digitizes the inspection result using the chip and sends it to the output unit 363.
- the output unit 363 displays the inspection result on a screen or the like.
- the doctor or the like who performs the test can surely grasp which patient's chip is. Further, by digitizing the inspection result in the digitizing unit 362, it is also possible to easily add the inspection result to the electronic medical record data.
- the configuration of the digitizing unit 362 can be, for example, the same as the configuration of the measuring device 237 described in the second embodiment.
- FIG. 43 is a diagram showing a configuration example of such a chip manufacturing apparatus.
- the input unit corresponds to the reception unit of the device shown in FIG. 39 or 40, and includes a measurement item input unit and an ID input unit.
- the control unit includes a substrate control unit, a reagent control unit, and a measurement unit control. Includes your department.
- the substrate control unit controls the selection of the substrate and the flow path, the operation until the selected substrate is loaded and unloaded, and the like. Further, the reagent control unit controls operations such as selection of the reagent and filling of the selected reagent into a predetermined position based on the information input to the input unit. In addition, when the measurement unit is provided in the device itself, the measurement unit control unit controls the measurement unit, the calculation unit that processes the measurement result, and the display unit that displays the measurement result.
- the chip can be customized also in an inspection organization.
- the opening and closing of the adjustment unit 314 can also be customized by manual adjustment at the inspection stage in the inspection organization.
- a configuration is adopted in which the sample is guided to other flow paths by closing the adjustment unit provided in some flow paths.
- a part may be provided.
- all control units should be closed at first, and the flow path to be used should be determined according to the sample and the type of treatment.After that, only the control unit for guiding the sample in that flow path should be selected and opened. By doing so, the sample can be guided to the selected flow path. Even with such a configuration, it is possible to customize the chip according to the type of sample and the analysis item.
- Examples of a method of closing the adjusting unit 314 and selecting and opening the adjusting unit 314 as appropriate include closing by a hydrophobic surface treatment and opening by ultraviolet light irradiation.
- the hydrophobic treatment of the flow channel surface in the adjustment unit 314 can be performed by forming a silane coupling agent, silicone oil, a PDMS thin film, or the like. These organic thin film materials are oxidatively decomposed by ultraviolet light irradiation, and become hydrophilic compounds. Therefore, first, a surface treatment for making the channel surface in the adjustment unit 314 hydrophobic or water-repellent with these materials is performed. After that, when, for example, the ultraviolet light narrowed down by the lens system is irradiated to the adjusting unit 314 to be released, the light-irradiated adjusting unit 314 can be opened.
- paraffin can be used as the organic substance having a low boiling point.
- the substrate 216 is heated to a temperature near the melting point of paraffin, and a thin rod-shaped paraffin is brought into contact with the adjusting section 314 for a short time to cause the softened and melted paraffin to adhere to the flow channel surface.
- the adjustment part 314 can be closed.
- the paraffin absorbs infrared rays, the paraffin can be evaporated by irradiating the adjusting section 314 with an infrared laser and heating it to a temperature higher than the boiling point of paraffin. By irradiating infrared light more widely than the region where paraffin exists, the nofin can be completely evaporated and the adjustment unit 314 can be opened.
- the configuration has one inlet 217 as the sample inlet 212, but a configuration having a plurality of inlets 217 may be adopted.
- a plurality of inlets 217 By providing a plurality of inlets 217, a plurality of samples from an individual, for example, a plurality of blood, saliva, urine, nasal discharge, and the like can be processed on one chip.
- a plurality of human samples such as blood of a plurality of patients, on a single chip in parallel.
- the adjusting section 314 can be provided between the sample introducing section 212 and the separating section 213. In this way, it is possible to select the moving path of the sample depending on the necessity of the separation unit 213.
- the configuration in which the adjusting section 314 is provided in all of the dispensing channels 222 has been described, but a configuration in which some of the dispensing channels 222 include the adjusting section 314 may be employed.
- the detection unit corresponding to the inspection item to be always performed may not be provided with the adjustment unit 314.
- the shape of the detection tank and the sorting portion provided on the chip is mainly cylindrical has been exemplified, but these are for analyzing the contents (detection or measurement).
- the shape of the detection tank and the sorting section can be a prism such as a square prism.
- the detection tank and the sorting section may not be in the shape of a diverticulum.
- the sorting section may be in the form of a flow path.
- the other liquid reservoirs provided on the chip other than the detection tank and the sorting section are also sufficient to hold the liquid introduced or collected in each of the liquid reservoirs.
- it can be formed into a shape other than a cylindrical shape.
- the shape of the liquid reservoir provided on the chip can be, for example, a prism such as a quadrangular prism, or a flow path having a predetermined planar shape.
- the shape of the liquid reservoir functioning as the waste liquid reservoir may be, for example, a zigzag type flow path shape in plan view, or a columnar shape having irregularities on the inner surface. In this case, the surface area of the waste liquid reservoir can be increased, so that the capillary effect can be further improved, and a configuration can be obtained in which the waste liquid can be collected more reliably.
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Dispersion Chemistry (AREA)
- Analytical Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Hematology (AREA)
- Clinical Laboratory Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Automatic Analysis And Handling Materials Therefor (AREA)
- Investigating Or Analysing Biological Materials (AREA)
- Apparatus Associated With Microorganisms And Enzymes (AREA)
- Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
Abstract
Description
Claims
Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
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JP2005513670A JPWO2005024436A1 (ja) | 2003-09-02 | 2004-09-02 | カスタマイズ可能なチップおよびその製造方法 |
US10/570,423 US20070099290A1 (en) | 2003-09-02 | 2004-09-02 | Customizable chip and method of manufacturing the same |
Applications Claiming Priority (2)
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JP2003-309683 | 2003-09-02 | ||
JP2003309683 | 2003-09-02 |
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WO2005024436A1 true WO2005024436A1 (ja) | 2005-03-17 |
WO2005024436B1 WO2005024436B1 (ja) | 2005-05-12 |
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PCT/JP2004/012753 WO2005024436A1 (ja) | 2003-09-02 | 2004-09-02 | カスタマイズ可能なチップおよびその製造方法 |
Country Status (3)
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US (1) | US20070099290A1 (ja) |
JP (1) | JPWO2005024436A1 (ja) |
WO (1) | WO2005024436A1 (ja) |
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Also Published As
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JPWO2005024436A1 (ja) | 2007-11-08 |
WO2005024436B1 (ja) | 2005-05-12 |
US20070099290A1 (en) | 2007-05-03 |
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