WO2007032467A1 - Procédé de fabrication de matrice de micro-canaux de résine et procédé de prise de sang employant ladite matrice - Google Patents

Procédé de fabrication de matrice de micro-canaux de résine et procédé de prise de sang employant ladite matrice Download PDF

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Publication number
WO2007032467A1
WO2007032467A1 PCT/JP2006/318349 JP2006318349W WO2007032467A1 WO 2007032467 A1 WO2007032467 A1 WO 2007032467A1 JP 2006318349 W JP2006318349 W JP 2006318349W WO 2007032467 A1 WO2007032467 A1 WO 2007032467A1
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WIPO (PCT)
Prior art keywords
substrate
resin
blood
microchannel array
flow path
Prior art date
Application number
PCT/JP2006/318349
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English (en)
Japanese (ja)
Inventor
Yuji Kikuchi
Taiji Nishi
Motohiro Fukuda
Original Assignee
National Agriculture And Food Research Organization
Kuraray Co., Ltd.
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Application filed by National Agriculture And Food Research Organization, Kuraray Co., Ltd. filed Critical National Agriculture And Food Research Organization
Publication of WO2007032467A1 publication Critical patent/WO2007032467A1/fr

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Classifications

    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B81—MICROSTRUCTURAL TECHNOLOGY
    • B81C—PROCESSES OR APPARATUS SPECIALLY ADAPTED FOR THE MANUFACTURE OR TREATMENT OF MICROSTRUCTURAL DEVICES OR SYSTEMS
    • B81C1/00—Manufacture or treatment of devices or systems in or on a substrate
    • B81C1/00015—Manufacture or treatment of devices or systems in or on a substrate for manufacturing microsystems
    • B81C1/00023—Manufacture or treatment of devices or systems in or on a substrate for manufacturing microsystems without movable or flexible elements
    • B81C1/00055—Grooves
    • B81C1/00071—Channels
    • 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
    • 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
    • B01L2200/12—Specific details about manufacturing devices
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/08—Geometry, shape and general structure
    • B01L2300/0887—Laminated structure

Definitions

  • the present invention relates to a method for producing a microchannel array made of a resin suitable for health management, disease diagnosis and treatment, and a blood measurement method.
  • the conventional method for measuring red blood cell deformability has been unreliable because the pores or grooves are clogged by the formed components in the blood sample during measurement.
  • Patent Document 1 Japanese Patent No. 2532707
  • the problem to be solved by the present invention is to provide a method for manufacturing a microchannel array made of a resin suitable for health management, disease diagnosis and treatment, and a blood measurement method.
  • the method of manufacturing a microfabricated resin microchannel array according to the first aspect of the present invention includes a plurality of depressions having at least one inlet at one end and a plurality of outlets at least at the other end.
  • a flat substrate that is bonded or pressure-bonded to the surface of the first substrate and the first substrate having a small groove communicating with the recesses in the wall portion that divides the recesses.
  • the ratio of the width and the depth of the flow path is in the range of 1:10 to 10: 1, respectively.
  • a structure having a pattern corresponding to the recess and the ridge or the groove by etching the substrate And the first substrate is formed on the basis of the structure.
  • a method of manufacturing a microfabricated resin microchannel array according to the second aspect of the present invention is the above-described manufacturing method, wherein the substrate is formed of glass or silicon. As a result, the productivity of a microchannel array made of resin suitable for health management and disease diagnosis and treatment can be improved.
  • a method of manufacturing a microfabricated resin microchannel array according to the third aspect of the present invention includes a plurality of depressions having at least one inlet at one end and a plurality of outlets at least at the other end.
  • a flat substrate that is bonded or pressure-bonded to the surface of the first substrate and the first substrate having a small groove communicating with the recesses in the wall portion that divides the recesses.
  • the Each of which is in the range of 1 to 50 / ⁇ ⁇ and the ratio of the width to the depth of the flow channel is in the range of 1:10 to 10: 1.
  • the substrate is mechanically cut to produce a structure having a pattern corresponding to the recess and the ridge or the groove, and a first substrate is formed based on the structure.
  • the productivity of the microchannel array made of resin suitable for health management, disease diagnosis and treatment can be improved.
  • a method of manufacturing a resin microchannel array according to the fourth aspect of the present invention is the above-described manufacturing method, wherein a resist pattern is formed on the substrate, and the resist pattern is formed on the surface. Then, the structure is manufactured by performing the etching or the mechanical cutting on the substrate and the ridge or the resist pattern. As a result, the productivity of the microchannel array made of resin suitable for health management, diagnosis and treatment of diseases can be improved.
  • a method for manufacturing a resin microchannel array according to the fifth aspect of the present invention is the above-described manufacturing method, wherein a resist pattern is formed on the structure, and a metal is formed on the resist pattern. To form a metal structure. As a result, the productivity of a microchannel array made of resin suitable for health management, disease diagnosis and treatment can be improved.
  • a method for manufacturing a resin microchannel array wherein the metal structure is machined or etched to process the metal structure, The resin microchannel array is formed using the processed metal structure as a mold.
  • a method of manufacturing a microfabricated resin microchannel array according to the seventh aspect of the present invention is the above-described manufacturing method, wherein the structure or the metal structure is used as a mold and the microchannel array made of resinous resin. Is formed. As a result, the productivity of a microfabricated microchannel array suitable for health management and disease diagnosis and treatment can be improved.
  • a method of manufacturing a microfabricated resin microchannel array according to the eighth aspect of the present invention is a pattern formed on the structure or the metal structure according to the above-described manufacturing method. Accordingly, the resin microchannel array is formed using a metal structure obtained by adhering metal as a mold. As a result, the productivity of the microchannel array made of resin suitable for health management, disease diagnosis and treatment can be improved.
  • a method of manufacturing a microfabricated resin microchannel array according to the ninth aspect of the present invention is based on the above-described manufacturing method, and the mold obtained on the basis of the microchannel array made of resin. It is characterized by using. As a result, the productivity of the microchannel array made of resin suitable for health management and disease diagnosis and treatment can be improved.
  • a blood measurement method is a blood measurement method using a microfabricated microchannel array manufactured by the above-described manufacturing method, wherein a single microchannel array made of a resin is used. Or, by supplying physiological saline, blood samples, and reagents individually or simultaneously from multiple inlets, and by having flow control systems near the inlet and Z or outlet near the measuring device It is characterized by repeatedly reproducing the optimal state for blood measurement. Thereby, an effective blood measurement can be performed.
  • the blood measurement method according to the eleventh aspect of the present invention is the optical system for irradiating light to the inflow port, the outflow port, or the flow channel portion of the recess communicated with the flow channel in the blood measurement method described above. And a measurement system for measuring a variable amount of light reflected or transmitted from the flow path. Thereby, an effective blood measurement can be performed.
  • the blood measurement according to the twelfth aspect of the present invention is the blood measurement method using the micro-channel array made of resin manufactured by the above-described manufacturing method. Measure the flow characteristics or activity of each tangible component of blood by measuring the increase or decrease in the number of each tangible component of blood at the outlet or the clogging of the groove channel due to each tangible component of blood. It is characterized by. Thereby, an effective blood measurement can be performed.
  • the blood measurement according to the thirteenth aspect of the present invention is the blood measurement method using the micro-channel array manufactured by the above-described manufacturing method.
  • leukocyte migration occurs through the channel, and the number of leukocyte fractions in each subsequent depression is increased or decreased, or the channel of the channel due to leukocytes is increased.
  • Measure occlusion status thereby migration ability of leukocyte fraction, adhesion It is characterized by seeking performance. Thereby, an effective blood measurement can be performed.
  • a blood measurement method is characterized in that in the blood measurement method described above, blood measurement is performed on a blood sample after exposure to a physiologically active substance. Thereby, an effective blood measurement can be performed.
  • the blood measurement according to the fifteenth aspect of the present invention is the blood measurement method described above, wherein the blood measurement is performed by fluorescently coloring each blood cell or liquid component with a fluorescent substance in the blood measurement method. It is characterized by. Thereby, an effective blood measurement can be performed.
  • the blood measurement according to the sixteenth aspect of the present invention is performed by depositing a thin film such as gold on either the first substrate or the second substrate in the blood measurement method described above, and It has a measurement system that detects a change in the dielectric constant of the inlet, outlet, or flow path of the hollow that communicates as a change in reflected light intensity due to the surface plasmon resonance phenomenon. Thereby, an effective blood measurement can be performed.
  • the blood measurement according to the seventeenth aspect of the present invention is the above-described blood measurement method, in which the electrochemically weak electric current is applied to the inflow port, the outflow port, or the flow channel portion of the recess communicated by the flow channel. It has a sensor that detects the amount of air displacement, and performs electrical amplification for quantitative evaluation. Thereby, an effective blood measurement can be performed.
  • Blood measurement according to the eighteenth aspect of the present invention is the above-described blood measurement method, in which the weak frequency generated by ultrasonic waves is applied to the inflow port, outflow port, or flow path portion of the recess communicated by the flow path. It has a sensor that detects the range of change, and performs conversion to an electrical signal and amplification part for quantitative evaluation. Thereby, an effective blood measurement can be performed.
  • FIG. 1A is a schematic diagram showing a process for forming a microchannel array made of resin in the present invention.
  • FIG. 1B is a schematic diagram showing a process for forming a microchannel array made of resin in the present invention.
  • FIG. 1C it is a schematic diagram showing a process of forming a microchannel array made of resin.
  • FIG. 1D it is a schematic diagram showing a step of forming a microchannel array made of resin.
  • FIG. 1E it is a schematic diagram showing a step of forming a microchannel array made of resin.
  • FIG. 1G is a schematic diagram showing a step of forming a microchannel array made of resin.
  • FIG. 1H is a schematic diagram showing a step of forming a microchannel array made of resin.
  • FIG. 2A is a schematic diagram showing a process of forming a microchannel array made of resin in the present invention.
  • FIG. 2C is a schematic diagram showing a process for forming a microchannel array made of resin in the present invention.
  • FIG. 2D is a schematic view showing a step of forming a microchannel array made of resin in the present invention.
  • FIG. 3A is a plan view of a resin microchannel array that can be manufactured according to the present invention.
  • 3B] is a cross-sectional view of a resin microchannel array that can be manufactured according to the present invention.
  • FIG. 4A] is a detailed view of the outer shape of a resin microchannel array substrate that can be manufactured according to the present invention.
  • FIG. 4B is an enlarged view of a P portion and a Q portion in FIG. 4A.
  • FIG. 5A is a detailed view of the outer shape of a resin microchannel array substrate that can be manufactured according to the present invention.
  • FIG. 5B is an enlarged view of a P portion and a Q portion in FIG. 5A.
  • Blood is roughly divided into a blood cell (tangible) component and a plasma (liquid) component, and the proportion of the blood cell component is about 40 to 45% and the plasma component is about 55 to 60%.
  • red blood cells account for about 96%
  • white blood cells and platelets are white blood cells and platelets. The size is about 7-8 m in diameter for red blood cells, about 12-14 ⁇ m for white blood cells, and about 3 ⁇ m for platelets.
  • the blood measurement method comprises a plurality of depressions having an inlet at least at one end thereof, A plurality of depressions having outlets at least at the other end and a first substrate having a minute groove communicating with the depressions on a wall that separates the depressions from the first substrate and the first And a second substrate having a flat surface to be bonded or pressure-bonded to the surface of the substrate, and a flow path through a space formed by the recess and groove in the bonding portion or pressure-bonding portion between the first substrate and the second substrate. It can be appropriately performed by a microchannel array made of resin used as a resin. The depth of the dent can be formed to be different in multiple stages.
  • platelet aggregation is the main reaction of contraction and movement of contractile proteins in cells. Therefore, the ability of platelets to pass through the channel or blockage of the channel due to platelet aggregates may be an indicator here. Become.
  • the amount of change in flow passage ability including flow passage blockage after stimulation with a certain amount of physiologically active substance can be used as an index.
  • the width and depth of the flow channel are preferably selected from the range of 1 to 50 ⁇ m, depending on the blood cell component to be measured, in the range of 1 to 20 / ⁇ ⁇ . It is more preferable.
  • the ratio between the width and the depth of the flow path is preferably selected within the range of 1:10 to 10: 1 according to the shape and deformability of the target blood cell component.
  • a microchannel array made of resin and an aqueous system such as physiological saline, blood sample, and reagent used It is preferable that the difference in wettability with the liquid is small. If the difference in wettability is large
  • the aqueous liquid does not flow through the flow path.
  • the measurement value of the passage time of the target blood cell component may not be reproduced due to the mixing of bubbles. is there.
  • the contact angle of water on the surface of the resin microchannel array with water is usually relatively large (for example, polymethyl methacrylate resin is about 68 °, polycarbonate resin is about Therefore, it is necessary to reduce the contact angle to 0.5 ° or more and 70 ° or less.
  • Chemical treatment techniques include chemical treatment, solvent treatment, coupling agent treatment, monomer coating, polymer coating, steam treatment, surface grafting, electrochemical treatment, anodization and the like.
  • Physical treatment techniques include ultraviolet irradiation treatment, Examples include plasma contact treatment, plasma jet treatment, plasma polymerization treatment, ion beam treatment, and mechanical treatment.
  • modification techniques there is a technique characterized in that, for example, adhesiveness is exhibited in addition to the hydrophilicity of the surface of the thermoplastic resin. In some cases, it is not desirable to maintain a large number of fine channel shapes in a microchannel array made of resin. Therefore, it is necessary to select an appropriate modification technique according to the required contact angle. is there.
  • the following describes a modification method that can be applied as an example.
  • a reforming effect can be obtained with a relatively simple process without requiring a large apparatus, and low cost can be expected. On the other hand, there is a concern about a decrease in the reforming effect due to ultrasonic cleaning or the like. For example, it is preferably used for a disposable use.
  • Vacuum evaporation is one of inorganic and thin film fabrication methods, in which a thin film is heated and evaporated in a vacuum (pressure less than 10 _2 Pa), and the vapor is deposited on an appropriate substrate surface. It is. Processing is possible with a relatively low degree of vacuum without the need for large equipment, and cost reduction can be expected.
  • Sputtering means that positive ions generated by low-pressure glow discharge are accelerated by an electric field and collide with the cathode, and the cathode-side material is knocked out and deposited on the anode side.
  • the sputtering method is rich in materials that can be deposited, for example, using inorganic materials such as SiO.
  • the material surface hydrophilic by depositing 10 nm to 300 nm.
  • the sputtering method can make the thickness of the deposited film uniform. For example, a 10 to 50 nm SiO film can be deposited.
  • the inorganic film When the inorganic film is deposited on the microchannel array made of resin, moisture absorbed by the microchannel array made of resin may be released during sputtering, and adhesion with the inorganic film may be reduced. Sufficient degassing is necessary before sputtering. Further, as another method for improving the adhesion between the surface of the resin and the inorganic film, an etching treatment with argon gas or the like on the surface of the resin microchannel array, or an inorganic material having good adhesion, for example, chromium. And the like, and then a desired inorganic film is deposited. When selecting a sputtering method, it is necessary to have a heat-resistant temperature of about 50 ° C to 110 ° C. 1) Select a glass transition temperature higher than that, for example, polycarbonate, etc. 2) Sputter treatment It is important to select conditions such as shortening the time (thinning the film thickness).
  • plasma processing in particular, an implantation action can be given.
  • the implantation action is that molecules are activated by plasma, radicals generated on the polymer surface recombine, and new functional groups are introduced on the polymer surface. By introducing this functional group, a polymer surface having novel properties can be produced.
  • plasma treatment and in particular, plasma polymerization treatment can be given.
  • a polymer film is formed on a substrate by vaporizing an organic material as a raw material of the polymer material and transporting it in a gas phase, and activating the organic material by electron collision excitation in plasma to cause a polymerization reaction.
  • Technology Since the plasma polymerization method is used by vaporizing the raw material molecules, a solvent that can be an impurity is unnecessary, and the film thickness can be easily controlled. Since no residual monomer exists, it is possible to cope with cytotoxicity required for bioengineering applications.
  • the plasma polymerization process activates an organic material by electron impact excitation in plasma to cause a polymerization reaction, whereas the vapor deposition polymerization method causes a polymerization reaction by heat.
  • ultraviolet treatment especially excimer UV treatment, can be mentioned. It can also be applied to polymethylmethalate with a glass transition temperature of 100 ° C, which requires a low heat-resistant temperature in making hydrophilic thermoplastic resin hydrophilic.
  • Excimer UV treatment uses an excimer lamp that uses a discharge gas such as argon, krypton, or xenon, and the emission center wavelength is 120 ⁇ ! Irradiate ultraviolet rays in the range of ⁇ 3 lOnm.
  • a discharge gas such as argon, krypton, or xenon
  • the emission center wavelength is 120 ⁇ ! Irradiate ultraviolet rays in the range of ⁇ 3 lOnm.
  • the contact angle with water on the surface of the microchannel array made of resin is 0.5.
  • the angle is preferably from 70 ° to 70 °, more preferably from 50 ° to 50 °. Outside this range, stable data such as blood cell passage time measurements cannot be obtained due to the formation of aggregates due to the adhesion of blood cells that make it difficult to introduce blood samples into fine channels. It is preferable to have an inner contact angle.
  • the above technique can be applied not only to a resin microchannel array but also to a silicon plate manufactured by applying a semiconductor processing technique.
  • the contact angle with water It is preferable to set the angle between 5 ° and 70 °.
  • the platelet adhesion ability on the surface of the microchannel array made of greaves will be described. Since blood cells are easy to immobilize on a hydrophobic surface, in addition to the need to make them hydrophilic, it may be necessary to suppress the formation of aggregates by inhibiting the adhesion of platelets with blood coagulation. is there. When blood and materials come into contact, platelets and proteins are first adsorbed. On the surface of platelets, the shape is deformed, causing an activity such as the release of substances therein, resulting in aggregation of blood components. In order to improve the reproducibility of data such as blood cell passage time measurements, it may be necessary to suppress platelet adhesion. Moreover, platelet adhesion portion of ⁇ made microchannel array surface, as possible out to the 100 positions ZCM 2 below.
  • the material for not coagulating the blood! / Is a material that does not coagulate the blood! / And contains the drug heparin.
  • the second is a material with an immobilized enzyme called urokinase that dissolves the formed thrombus.
  • the third is a material that prevents blood platelets and proteins from sticking to the surface.
  • a polymer with a high water content such as polybutyl alcohol, acrylamide, or polyethylene glycol is attached to the surface of the material.
  • the fourth is a material that prevents platelet activity. This material has a surface structure similar to a microphase-separated structure.
  • the separation size of the fourth microphase separation structure is 20 ⁇ ! It has a microdomain structure uniformly in the range of ⁇ 20 ⁇ m. Inhibition of platelet adhesion by microphase separation is possible by a combination of amorphous “non-amorphous, hydrophilic” hydrophobic, crystalline “amorphous”, glassy state, liquid state, and the like.
  • the material include a copolymer of HEMA-styrene and HEMA-butadiene, a block copolymer of hydrophilic PHEMA and hydrophobic styrene, and a blend of crystalline nylon 610 and amorphous polypropylene oxide. It is done.
  • the narrowed portion due to the uneven shape is also effective when only specific blood cells are fixed in the flow path and optical detection or the like is performed.
  • leukocytes with a diameter of about 12 m
  • a narrow part with a width of 6 m in a flow path with a width of 12 m and a depth of 12 / zm red blood cells and platelets pass through. Only white blood cells can be captured in the flow path.
  • the minimum unit of the fine concavo-convex shape to be manufactured is, for example, a width of 1 ⁇ m or less by using a reduction exposure machine called a stepper in an exposure process when manufacturing a structure serving as a master. Since it is predicted that the mask used for force exposure will be expensive, it is preferable to select after considering the production cost and application.
  • the depth of the dent differs in the multi-stage shape, it is possible to clarify the difference for each specimen in the measurement of the speed, number, deformability, etc. of blood cells that pass through the minute flow path. Become.
  • the blood sample introduced by the inflow locuser is guided to a fine flow path provided in the wall portion through the depression.
  • the depth and width of the recess necessary for introducing the blood sample is preferably at least 30 ⁇ m and more preferably at least 80 m.
  • the depth and width of the dent is 80 / ⁇ ⁇
  • the depth and width of the flow path is 5 m
  • the blood sample will be led from a wide space to an extremely narrow space, and it will be in an average state. Even if the blood sample shows a difference, it may not be possible to find differences between specimens due to changes in the activity of platelets.
  • the depth of the depression is preferably a multistage shape, for example, 30 m, 50 m, and 80 m, similar to capillaries in the human body.
  • the production method of the present invention is characterized in that a structure serving as a master is manufactured, and a plurality of resin microchannel arrays with high accuracy and good reproducibility can be produced from the single structure.
  • Silicon plate manufacturing by etching using semiconductor cache technology requires etching according to the required number of steps, and there are variations in processing accuracy and high cost.
  • a structure that satisfies the dimensional accuracy By using, it is possible to achieve both machining accuracy and low cost.
  • the microchannel array made of sallow can be incinerated as an infectious waste, as is the case with thermoplastic scabs such as blood circuits used in blood purification treatments such as artificial dialysis and plasma exchange. Silicon plates produced by conventional etching methods are inorganic materials and cannot be incinerated. As industrial waste, in order to perform landfill processing, sterilization processing is required, resulting in high costs. Also, adaptability to the recent increase in awareness of environmental issues is low.
  • thermoplastic resin such as polymethylmetatalylate that does not contain rosin and rhogen can avoid the generation of the harmful substance dioxin, and can be used at the normal temperature used for incineration of general waste. Incinerators can be easily incinerated and reused as heat resources
  • a microchannel array made of resin and an overlay substrate Must be transparent, for example, depending on the measurement of reflected or transmitted light.
  • the substrate on the optical system side may be a transparent plate and the opposite substrate may be opaque.
  • an opaque grade is selected at the material selection stage, or an inorganic film such as aluminum is deposited on the front or back surface of the transparent substrate, for example, by vapor deposition. .
  • the flow path can be directly observed through the transparent plate, and appropriate measures such as adjustment and stop of the flow rate can be taken.
  • the optical properties that define transparency are preferably a total light transmittance of 80% or more and a haze value of 10% or less in a 1 mm thick plate.
  • a material that does not have a ring structure in its molecular structure for example, uses a material to which no ultraviolet absorber is added, depending on the wavelength of light used. It is preferable to select appropriately such as use.
  • a step of forming a resist pattern on the substrate, and the resist formed on the substrate The steps of etching the substrate through the strike pattern to form a structure and forming the resin microchannel array based on the structure will be described.
  • a microchannel array made of resin of this form is
  • a structure having a pattern corresponding to the trenches, grooves and depressions is formed.
  • a resin molded product is formed using the structure having the pattern formed in the above-described process as a mold (stamper). Thereby, a microchannel array made of resin is manufactured.
  • the etching processing time through the first resist layer and the etching processing time through the second resist layer are adjusted. Thereby, a pattern having a desired depth is formed on the substrate.
  • FIGS. 1A to 1I are process cross-sectional views illustrating a method for manufacturing a microchannel array made of resin according to the present invention.
  • FIG. 1A shows a state where the first resist layer 2 is formed on the substrate 1.
  • the substrate for example, a glass substrate or a silicon substrate can be used.
  • the method of forming the first resist layer 2 on the substrate 1 is not limited in any way, but generally, a spin coating method, a dating method, a roll method, bonding of a dry film resist, and the like are performed. Can be mentioned.
  • the spin coating method is a method of applying a resist on a rotating glass substrate, and has an advantage of applying a resist to a glass substrate having a diameter of more than 300 mm with a high flatness. Accordingly, the spin coating method is preferably used from the viewpoint of realizing high flatness.
  • the first resist layer 2 There are two types of resists used as the first resist layer 2: positive resists and negative resists. In either case, the depth of focus of the resist varies depending on the resist sensitivity and exposure conditions.For example, when using a UV exposure system, it is desirable to select the exposure time and UV output value according to the resist thickness and sensitivity type. .
  • the resist used is a wet resist, for example, to obtain a predetermined resist thickness by a spin coating method, there are a method of changing the spin coating rotational speed and a method of adjusting the viscosity.
  • the method for changing the spin coat rotational speed is to obtain a desired resist thickness by setting the spin coater rotational speed.
  • the method of adjusting the viscosity is to adjust the viscosity according to the flatness required in actual use because there is a concern that the flatness may decrease when the resist thickness is large or the coating area increases. is there.
  • the thickness of the resist layer applied at one time is preferably 10 to 50 ⁇ m, more preferably 20 to 50 ⁇ m in consideration of maintaining high flatness. It is desirable to be within this range. In order to obtain a desired resist layer thickness while maintaining high flatness, it is possible to form a plurality of resist layers.
  • the exposure of the first resist layer 2 using the mask A3 will be described.
  • the mask A3 used in the process shown in FIG. 1B is not limited in any way, but examples include an emulsion mask and a chrome mask.
  • the size and accuracy depend on the mask A3 used.
  • the dimensions and accuracy are also reflected in the resin molded product. Therefore, in order to make the dimensions and accuracy of the microchannel array made of resin uniform, it is necessary to specify the dimensions and accuracy of the mask A3.
  • the method for increasing the accuracy of the mask A3 is not limited in any way.For example, the laser light source used to form the mask A3 pattern can be changed to one with a shorter wavelength, but the equipment cost is high. Since the manufacturing cost of the mask A3 is high, it is desirable that the microchannel array made of resin should be appropriately specified according to the accuracy required for practical use.
  • the material of mask A3 is the thermal expansion coefficient and the surface strength of UV transmission absorption performance. While quartz glass is preferred but relatively expensive, the strength of the resin molded product is also specified according to the accuracy required for practical use. It is desirable to do. To obtain structures with different desired depths or heights as designed, or structures with different first and second resist patterns, the first resist layer 2 and the second resist layer 4 can be exposed.
  • the pattern design of the mask to be used (transmission Z shading part) must be reliable, and simulation using CAE analysis software is one of the solutions.
  • the light source used for the exposure is preferably ultraviolet light or laser light, which has a low equipment cost.
  • the synchrotron radiation has a deep exposure depth, the cost of such equipment is high, and the price of the microchannel array made of resin is substantially high, so it is not industrially practical.
  • exposure conditions such as exposure time and exposure intensity vary depending on the material, thickness, and the like of the first resist layer 2, it is preferable to adjust appropriately according to the pattern to be obtained. Especially for pattern dimensions and accuracy such as flow path width, depth, container spacing, container width (or diameter), depth etc. Adjustment of exposure conditions is important because it has an effect. Also, since the depth of focus varies depending on the type of resist, for example, when using a UV exposure system, it is desirable to select the exposure time and UV output value according to the thickness and sensitivity of the resist.
  • the first resist layer 2 may be heat-treated.
  • the heat treatment of the first resist layer 2 will be described.
  • Heat treatment after exposure is known as annealing to correct the shape of the resist pattern.
  • a chemically amplified negative resist is mainly a two-component or three-component system force, and, for example, an epoxy group at the end of a chemical structure is ring-opened and subjected to a crosslinking reaction by light during exposure.
  • a heat treatment time of 100 m the crosslinking reaction proceeds in a few minutes under the condition of a set temperature of 100 ° C.
  • the heat treatment of the first resist layer 2 proceeds too much, it becomes difficult to form a pattern by dissolving the uncrosslinked portion in the subsequent development. If the resist thickness to be set is not 100 m or more, It is preferable to select as appropriate, for example, by shortening the heat treatment time or by performing only heat treatment of the second resist layer 4 later.
  • FIG. 1C shows the first resist 2 being developed.
  • the method for developing the first resist layer 2 is not limited in any way.
  • a spin type, dip type or spray type developing device can be used.
  • a developer suitable for the first resist layer 2 is used.
  • an alkaline solution can be used.
  • FIG. 1D shows the substrate 1 etched.
  • the substrate 1 is etched through the developed first resist layer 2.
  • Etching of the substrate 1 is not limited at all.
  • etching can be performed using a wet etching apparatus or a dry etching apparatus.
  • the substrate 1 where the first resist layer 2 is removed by the development is etched, and a pattern can be formed on the substrate 1.
  • a concave portion is formed at the exposed portion of the substrate 1.
  • the exposed portion of the substrate 1 is etched, and a pattern corresponding to the pattern of the first resist layer 2 is formed on the substrate 1.
  • Etching is performed, for example, to a depth corresponding to a groove or depression formed in the microchannel array made of resin.
  • the first resist layer 2 is peeled off.
  • the resist stripping method is not limited at all.
  • a wet type resist stripping apparatus or a dry type ashing apparatus can be used.
  • the wet etching immersion etching, spray etching, or jet etching can be used.
  • the etchant for example, hydrofluoric acid or the like can be used.
  • an etching solution corresponding to the material of the substrate 1 can be used.
  • inductive coupling type reactive ion etching Induct lvely
  • High density plasma etching such as Coupled Plasma Reactive Ion Etching (ICP-RIE) can be used.
  • ICP-RIE Coupled Plasma Reactive Ion Etching
  • FIB focused ion beam
  • the ICP-RIE process forms a hole pattern in the photoresist applied on the silicon substrate surface by photolithographic process, and forms holes by etching with high density plasma of reactive ions using the photoresist as a mask.
  • the ICP-RIE method is capable of forming a large number of holes at a time in a short process, and the tip of the hole cannot be made as thin as the FIB process.
  • resist formation, development, and exposure steps are not required. That is, etching can be performed without forming a resist on the substrate.
  • FIG. 1E shows a state in which the second resist layer 4 is formed on the substrate 1.
  • the second resist layer 4 can be formed by the same method as the formation of the first resist layer 2 described in (i) above.
  • the second resist layer 4 is formed on the substrate 1 that has been etched. That is, the second resist layer 4 is formed on the substrate 1 on which the pattern is formed.
  • the second resist layer 4 is formed to a thickness that covers the entire substrate 1 having an uneven shape.
  • Alkali resistance can be expressed by setting the beta time to about 1.5 to 2.0 times the normal time.
  • the second resist layer 4 may be heat treated.
  • the heat treatment of the second resist layer 4 will be described.
  • the heat treatment of the second resist layer 4 is basically the same as the heat treatment of the first resist layer 2.
  • Chemical crosslinking proceeds by heat treatment, and alkali resistance is developed by increasing the crosslinking density. It is preferable that the heat treatment time for developing alkali resistance is appropriately selected according to the resist thickness, which is 1.1 to 2.0 times the normal range.
  • FIG. 1G shows a state in which the second resist layer 4 is developed.
  • the development of the first resist layer 4 is basically the same as the development of the first resist layer 2.
  • different developing solutions may be used.
  • a predetermined developer corresponding to the resist used it is preferable to use a predetermined developer corresponding to the resist used.
  • Development conditions such as development time, development temperature, and developer concentration are preferably adjusted as appropriate according to the resist thickness and pattern shape. For example, if the development time is too long in order to obtain the required depth, it will become larger than a predetermined dimension, so it is preferable to set conditions appropriately.
  • the substrate 1 is exposed where the second resist layer 4 is removed by the development process.
  • the width (or diameter) of the surface may become wider than the width (or diameter) of the resist bottom in the development process. It is done.
  • the table For example, the sensitivity of the resist near the surface may be higher than that of the layer near the bottom. More specifically, BMR C-1000PM manufactured by Tokyo Ohka Kogyo Co., Ltd. can be used as a high-sensitivity resist, and PMER-N-CA3000PM manufactured by Tokyo Ohka Kogyo Co., Ltd. can be used as a low-sensitivity resist.
  • the sensitivity may be adjusted by changing the drying time of the resist. For example, when BMR C-1000PM manufactured by Tokyo Ohka Kogyo Co., Ltd. is used, when drying the resist after spin coating, the drying time for the first layer is 20 minutes at 110 ° C, and the drying time for the second layer is 110 ° C. By setting it to 40 minutes, the sensitivity of the second layer can be increased.
  • the resist type (negative type or positive type) used in resist coating is changed to use the flatness of the glass surface. And a method of polishing the surface of the structure.
  • the plurality of resist layers are exposed and developed at the same time, or after one resist layer is formed and exposed. Further, a resist layer can be formed and exposed, and the two resist layers can be developed simultaneously.
  • Etching of the substrate 1 and peeling of the second resist layer 4 will be described. Etching of the substrate 1 and peeling of the second resist layer 4 are basically the same as the etching and resist peeling shown in (V). Therefore, the substrate 1 is etched through the second resist layer 4. That is, a recess is formed in the exposed portion of the substrate 1. As a result, a pattern corresponding to the developed pattern of the second resist layer 4 can be formed on the substrate 1. Substrate 1 is etched to a depth corresponding to the grooves or depressions formed in the microchannel array
  • FIG. 1H shows a state where the second resist layer 4 is peeled off.
  • the structure 20 having an uneven pattern with a reverse pattern of the flow path formed in the resin microchannel array. That is, the pattern formed on the substrate 1 has a shape corresponding to the groove and Z or the depression formed on the first substrate of the resin microchannel array. Based on this structure 20, grooves and depressions corresponding to the flow paths of the resin microchannel array are made. A resin molded product having the following is produced.
  • the structure 20 may be polished according to its surface state. However, since there is a concern that dirt may adhere to the molded article, it is preferable to perform ultrasonic cleaning after polishing. Further, the structure 20 may be surface-treated with a release agent or the like in order to improve the surface state.
  • the inclination angle in the depth direction of the structure 20 is preferably 50 ° to 90 °, more preferably 60 ° to 87 °, in order to obtain a good yield without impairing the shape of the resin molded product. °. In order to increase the inclination angle of the structure 20 in the depth direction, it is preferable to use anisotropic etching.
  • the molded product forming step is a process of forming the resin molded product 9 using the structure 20 as a mold, as shown in FIG.
  • the method of forming the resin molded product 9 is not particularly limited, and examples thereof include injection molding, press molding, monomer cast molding, solvent cast molding, hot emboss molding, roll transfer method by extrusion molding, etc. From the viewpoint of mold transferability, injection molding is preferably used. Thereby, the uneven shape of the pattern of the structure 20 is transferred to the resin molded product 9.
  • This resin molded product 9 becomes the first substrate constituting the resin microchannel array. In other words, the resin molded product 9 is bonded to the second substrate as the first substrate.
  • both substrates are bonded so that the surface on which the pattern of the resin molded product 9 is formed is in contact with the second substrate. That is, the first substrate and the second substrate are bonded together, and the surface on which the pattern of the resin molded product 9 is formed faces the second substrate.
  • the depressions and grooves formed in the resin molded product 9 become the flow path of the resin microchannel array. That is, the grooves and depressions formed in the resin molded product 9 according to the pattern of the structure 20 become the flow path of the resin microchannel array.
  • the resin molded product 9 is formed based on the structure 20 obtained by etching the substrate 1. That is, the groove and the depression are formed based on a pattern obtained by etching the substrate 1. Therefore, it is possible to form a groove and a recess corresponding to the channel and the microchannel based on a pattern obtained by wet etching or dry etching.
  • grooves and depressions corresponding to flow paths and microchannels are formed on the basis of patterns obtained by wet etching. It is possible to form.
  • the grooves and depressions corresponding to the microchannels may be formed based on a pattern obtained by dry etching, and the grooves and depressions corresponding to the flow paths may be formed based on a pattern obtained by wet etching. Furthermore, it is possible to form grooves and depressions corresponding to the flow paths and the microchannels based on the pattern obtained by dry etching.
  • the material cost of the silicon substrate is high, and the processing cost is high because photolithography is performed for each piece, and the fine flow path for each piece There was a problem that the dimensional accuracy of the product varied.
  • the resin molded product 9 is formed by injection molding using the structure 20 with a predetermined size selected as a mold, the shape of the structure can be reproduced in the resin molded product 9 with a high transfer rate. is there.
  • the material cost can be lowered, the manufacturing method is suitable for cost reduction (mass production), and high dimensional accuracy is satisfied.
  • the transfer rate can be confirmed using an optical microscope, a scanning electron microscope (SEM), a transmission electron microscope (TEM), a CCD camera, or the like.
  • SEM scanning electron microscope
  • TEM transmission electron microscope
  • CCD camera CCD camera
  • the structure 20 When forming the resin molded product 9 by using the structure 20 as a mold, for example, by injection molding, 10,000 to 50,000 sheets of a single structure 20 and 200,000 in some cases Product 9 can be obtained, and the cost burden for producing the resin molded product 9 can be greatly eliminated. Also, the time required for one cycle of injection molding is extremely efficient in terms of productivity, which is as short as 5 to 30 seconds. Productivity can be further improved by using a molding die that can form a plurality of resin moldings 9 simultaneously in one injection molding cycle. In the above molding method, the structure 20 may be used as a mold, or the structure 20 may be set in a prepared mold and used.
  • the resin material used to form the resin molded article 9 is not particularly limited, but examples thereof include acrylic resin, polylactic acid, polydalicolic acid, styrene resin, and acrylic / styrene resin.
  • These fats and oils may be used as necessary in the form of lubricants, light stabilizers, heat stabilizers, antifogging agents, pigments, flame retardants, antistatic agents, mold release agents, antiblocking agents, ultraviolet absorbers, and acid additives.
  • lubricants light stabilizers, heat stabilizers, antifogging agents, pigments, flame retardants, antistatic agents, mold release agents, antiblocking agents, ultraviolet absorbers, and acid additives.
  • One type or two or more types of inhibitors can be contained.
  • the minimum flatness of the resin molded article 9 is preferably 1 ⁇ m or more from the viewpoint of easy reproduction on an industrial scale.
  • the maximum flatness of the resin molded product is preferably 200 m or less in view power that does not hinder the use of the resin molded product 9 bonded to another substrate or being overlapped.
  • the dimensional accuracy of the molded part of the resin molded product is preferably within a range of ⁇ 0.5 to 10% from the viewpoint of easy industrial reproduction.
  • the dimensional accuracy with respect to the thickness of the resin molded product 9 is preferably within the range of ⁇ 0.5 to 10% from the viewpoint of industrial reproducibility.
  • the thickness of the resin molded product 9 is not particularly specified, but it is preferably in the range of 0.2 to 10 mm in consideration of breakage during ejection, breakage during handling, deformation and distortion. .
  • the size of the resin molded product 9 is not particularly limited, but when forming a resist pattern by a lithography method, for example, when forming a resist layer by a spin coat method, medium force in the range of 400 mm can be collected. It is preferable to select appropriately according to the application.
  • Quantitative data Data can be obtained.
  • the optical system used include a fluorescence microscope, a laser microscope, and a laser scanner. Fluorescent substances can be used to fluorescently color each blood cell or liquid component, or the fluorescence intensity emitted from each blood cell can be identified, thereby distinguishing between different types of blood cells and between blood cells and the surrounding fluid. It becomes extremely easy. Increased measurement points! ], And in order to perform aggregate evaluation of measurement data, it is preferable to apply a system program using a computer.
  • the flow of the blood sample makes it possible to measure the migration of specific blood cells by only the difference in the concentration of the physiologically active substance. That is, by providing a difference in the concentration of the physiologically active substance instead of the hydrostatic pressure difference between the inlet side and the outlet side of the channel, only blood cells that can recognize the difference in the concentration of the physiologically active substance migrate into the channel. come. By measuring the number and transit time, blood can be measured.
  • a blood measurement can also be performed by performing a blood measurement on a blood sample after exposure to a physiologically active substance.
  • the detection method based on the surface plasmon resonance (SPR) phenomenon is a method in which light is incident on a plate made of a thin film such as gold by vapor deposition or the like, and the change in dielectric constant on the surface of the thin film is regarded as a change in reflected light intensity. It detects with high sensitivity.
  • SPR surface plasmon resonance
  • the activity of leukocytes immobilized in a fine flow path for example, by depositing a thin film such as gold on a microchannel array made of resin, a resin microchannel array, or a laminated substrate by vapor deposition or the like. Is detected by the change in the dielectric constant on the surface of the thin film (change in the intensity of reflected light), and converted into an electrical signal and amplified. It is possible to accurately calculate the difference in activity for each specimen.
  • the surface plasmon resonance sensor has been miniaturized by semiconductor processing technology, and it is possible to perform measurement in which a depression or a minute flow path part is specified.
  • a sensor that electrochemically detects the amount of electrical displacement is possible.
  • a FET sensor can be mentioned.
  • the Ion Sensitive FET sensor covers the surface of the Si chip with a SiO 2 -Si N film and changes the potential caused by the chemical species adsorbed on the surface.
  • Detection with a FET sensor can also be expected in blood measurement using a microchannel array made of greaves.
  • an FET sensor and an electrode are fixed on an overlapping substrate, and for example, the activity of leukocytes fixed in a fine flow path is detected by a change in potential of the electrode surface, and electrical amplification is performed. . Differences in activity by specimen can be accurately quantified.
  • a method of aligning each substrate a method is used in which a concave and convex pattern is formed on the front and back surfaces of the substrate so that the substrates are in close contact with each other with good positional accuracy, and the outer edge of the substrate is fixed with a jig.
  • There are a method of fixing a method of fixing using a positioning pin in a through hole, a method of observing and adjusting a position using a CCD power camera and a laser-type optical device.
  • the FET sensor has been miniaturized by semiconductor processing technology, and it is also possible to perform measurements that specify the indentation and minute flow path parts. By making the resin microchannel array disposable and repeatedly using the overlapping substrate, the cost of testing can be reduced.
  • Detection with an ultrasonic sensor can also be expected in blood measurement using a microchannel array made of resin.
  • a microchannel array made of resin.
  • an ultrasonic sensor and an electrode are fixed on an overlapping substrate, The activity of the immobilized leukocytes is detected as a weak frequency change width, and it is converted into an electric signal and amplified. It is possible to accurately calculate the difference in activity for each specimen.
  • Ultrasonic sensors are being miniaturized by semiconductor processing technology, and measurements can be made with specific areas of depressions and fine channels. By making the resin microchannel array disposable and repeatedly using the overlapping substrate, the cost of testing can be reduced.
  • the substrate 1 is processed by etching to form the structure 20 as a mold.
  • the manufacturing method according to the present invention is not limited to this.
  • the structure 20 may be manufactured by processing the substrate 1 by mechanical cutting. That is, a pattern corresponding to a groove or a depression is formed on the substrate 1 by precision machine cutting. Thereby, the structure 20 having the same shape as described above is formed.
  • a resin molded product 9 is formed.
  • This resin molded product 9 becomes the first substrate constituting the resin microchannel array.
  • the resin molded product 9 that becomes the first substrate is manufactured based on the structure 20 manufactured by mechanical cutting. Using this resin molded product 9 as a first substrate, a resin microchannel array is manufactured.
  • a microchannel array made of resin can be manufactured with high productivity.
  • the flow path of the microchannel array made of resin can be precisely manufactured, blood measurement can be performed efficiently. Therefore, a microcapsule array made of resin suitable for blood measurement can be produced.
  • the material of the substrate 1 on which the machine cutting is performed is not particularly limited. For example, resin, metal, glass and the like can be used.
  • a metal structure may be formed by attaching metal to the structure 20 described above. That is, a metal structure is formed based on the structure 20 manufactured by etching or machine cutting. A resin molded product can be formed using this metal structure as a mold (stamper). This metal structure manufacturing process will be described.
  • the metal structure forming step is to deposit a metal along the pattern obtained in the structure forming step, and form an uneven surface of the metal structure along the pattern of the structure 20, thereby obtaining a metal structure. It is about.
  • the structure 20 is manufactured by the manufacturing process shown in FIGS. To do. Then, as shown in FIG. 2B, a conductive film 7 is attached to the pattern forming surface of the structure 20. Thereby, the conductive film 7 is formed according to the pattern of the structure 20.
  • the method for forming the conductive film 7 is not particularly limited, but preferably vapor deposition, sputtering, or the like can be used. Examples of the conductive material used for the conductive film 7 include gold, silver, platinum, copper, and aluminum.
  • the conductive film 7 is deposited on the upper surface of the pattern formed on the substrate 1 and the entire side surface of the pattern.
  • a metal structure 8 is formed by depositing metal along the pattern by plating.
  • the method for depositing the metal is not particularly limited, and examples thereof include electrolytic plating and electroless plating.
  • the metal used is not particularly limited, nickel, a nickel-cobalt alloy, copper, and gold can be used. Nickel is preferably used from the viewpoint of economy and durability. Thereby, the uneven shape of the pattern of the structure 20 is transferred to the metal structure 8.
  • the metal structure 8 is formed based on the structure 20 formed by etching or mechanical cutting, and the resin molded product 9 is formed using the metal structure 8 as a mold. That is, the structure 20 is produced as a master disk of the metal structure 8 that becomes the mold of the resin molded product 9. As a result, the metal structure 8 serving as the mold of the resin molded article 9 that is not subjected to treatment such as exposure and etching can be manufactured. That is, by repeatedly depositing the conductive film 7 and forming the metal structure 8 for one structure 20, a large number of metal structures 8 can be produced. Therefore, productivity can be improved.
  • the pattern shape of the structure 20 is the reverse of the metal structure 8 pattern shape, that is, the same shape as the pattern shape of the resin molded product 9.
  • the metal structure 8 may be polished according to the surface state thereof. However, since there is a concern that dirt may adhere to the molded article, it is preferable to perform ultrasonic cleaning after polishing. Further, the metal structure 8 may be surface-treated with a release agent or the like in order to improve the surface condition. It should be noted that the inclination angle in the depth direction of the metal structure 8 is preferably 50 ° to 90 °, more preferably 60 ° to 90 ° in order to obtain a good yield without impairing the shape of the resin molded product. 87 °. The metal structure 8 deposited by plating is separated from the resist pattern force. [0137] The molded product forming step using the metal structure 8 will be described in more detail. As shown in FIG.
  • the molded product forming step is a process of forming the resin molded product 9 using the metal structure 8 as a mold.
  • the method of forming the resin molded product 9 is not particularly limited, and examples thereof include injection molding, press molding, monomer cast molding, solvent cast molding, hot emboss molding, roll transfer method by extrusion molding, and the like. From the viewpoint of transferability, injection molding is preferably used.
  • the uneven pattern formed on the metal structure 8 is transferred to the resin molded product 9. Therefore, the same effect as when the resin molded product 9 is formed using the structure 20 can be obtained. That is, the resin molded article 9 produced based on the metal structure 8 is used as the first substrate of the resin microchannel array. Then, a microfabricated microchannel is produced using the resin molded product 9. This makes it possible to manufacture the microchannel array made of resin with high productivity. Furthermore, since the flow path of the micro-channel array made of resin can be precisely produced, blood measurement can be performed efficiently. Therefore, a microcapsule array made of resin suitable for blood measurement can be produced.
  • the structure 20 can be manufactured by another method.
  • the pattern of the structure 20 can be formed by a resist pattern formed on the substrate 1. That is, a resist layer is formed on the substrate 1, and this resist layer is exposed, heat-treated, and developed to form a resist pattern.
  • the substrate 1 with this resist pattern becomes the structure 20.
  • the conductive film 7 is formed on the resist pattern remaining on the substrate 1 in the same manner as shown in FIG. 2B.
  • the metal structure 8 is formed by a plating method, similar to the process shown in FIG. 2C.
  • the metal structure 8 is transferred with the concavo-convex shape of the resist pattern formed on the substrate 1. Using this metal structure 8 as a mold, a resin molded product 9 is formed in the same manner as shown in FIG.
  • the resist pattern can be formed by the same process as that for the first resist layer 2 and the second resist layer 4.
  • the flatness of the resin microchannel array obtained in the molded product forming step is determined in the step of forming a resist on the substrate 1. That is, the flatness at the time when the resist layer is formed on the substrate 1 is reflected in the flatness of the structure, and thus the microchannel array made of resin. Two or more resist patterns can be displayed simultaneously. Please image.
  • the structure 20 or the metal structure 8 can be manufactured by combining two or more of the above methods. That is, the structure 20 or the metal structure 8 can be manufactured by combining two or more of the etching of the substrate 1, mechanical cutting, and resist pattern formation.
  • the structure 20 may be formed by etching the substrate after machining by mechanical cutting.
  • the structure 20 may be formed by performing mechanical cutting after etching the substrate. Then, using this structure 20 as a mold, a resin molded product is directly produced.
  • a metal structure 8 is formed in accordance with the structure 20, and a resin molded article 9 is produced using the metal structure 8 as a mold.
  • the metal structure 8 as a mold, the same effect as when the structure 8 is manufactured as a mold can be obtained.
  • a microchannel array made of resin may be manufactured using a metal structure obtained by further attaching metal as a mold. That is, the second metal structure is formed on the pattern formed in the metal structure 8. The second metal structure and the metal structure 8 are separated, and the second metal structure is used as a mold. In this case, the second metal structure has a reverse pattern of the metal structure 8. Since the second metal structure can be repeatedly produced by the metal structure 8, the productivity can be improved.
  • etching or mechanical cutting may be performed on the substrate 1 on which the resist pattern is formed.
  • the surface force of the resist pattern is also etched or machined on the substrate 1 and / or the resist pattern. That is, force may be applied to the substrate 1 by etching or mechanical cutting from above the resist pattern. As a result, a desired uneven shape can be formed on the surface of the substrate.
  • the metal structure 8 manufactured in the above process may be processed by wet etching or mechanical cutting.
  • the structure 20 is produced by etching the substrate, machining, or forming a resist pattern.
  • a resist pattern is formed on the metal structure 8 formed based on the structure 20, and the metal structure 8 is etched.
  • this metal structure 8 is machined. Thereby, the metal structure 8 is processed, and a desired pattern corresponding to the depression and / or groove can be formed.
  • This processing Using the formed metal structure 8 as a mold, a microchannel array made of resin is produced.
  • a metal structure obtained by further attaching metal may be used as a mold to manufacture a microchannel array made of resin. Even with these manufacturing methods, the same effects as described above can be obtained.
  • the formation of the pattern may be repeated three or more times to produce the structure 20 or the metal structure 8 having an uneven shape of three or more steps.
  • the shape of the resin microchannel array that can be produced by the above process will be described.
  • the outer shape is 16 mm wide x 8 mm long, with a thickness of 1. Omm.
  • a through hole with a diameter of 1.6 mm can be created with an inlet at the left end and an outlet at the right end.
  • the number of the wall portions that define the recesses can be 15, and one groove can have a shape of 340 fine grooves, for a total of 5100.
  • Figure 3 shows the outline drawing.
  • Fig. 3A is a top view of a microchannel array made of resin
  • Fig. 3B is a sectional view thereof.
  • This resin microchannel array is configured by superimposing a first substrate 10 and a second substrate 16.
  • the first substrate 10 is provided with a recess 13.
  • the depression 13 has a rectangular depression 131 formed in the vicinity of one end portion and a rectangular depression 132 formed in the vicinity of the other end portion.
  • a plurality of elongated depressions 1311 and 1321 are provided from the respective depressions 131 and 132 toward the center. In the long recess, the recesses 1311 extending from the recesses 131 and the recesses 1321 extending from the recesses 132 are alternately arranged.
  • a wall portion 14 is formed between adjacent recesses.
  • the wall portion 14 is provided with a large number of minute grooves that do not separate completely adjacent recesses 1311 and 1321. In this example, 340 microgrooves are provided per wall 14.
  • a minute groove communicating with the depressions 1311 and 1321 serves as a flow path.
  • the first substrate 10 is provided with an inlet 11 through which physiological saline, a blood sample, and a reagent are introduced.
  • the inflow port 11 is a through hole provided in the recess 131 of the first substrate 10.
  • An outlet 12 is provided at a position away from the inlet 11.
  • the outflow port 12 is also a through hole provided in the recess 132 of the first substrate 10.
  • the inlet 11 and the outlet 12 are both cylindrical holes with a diameter of 1.6 mm.
  • the second substrate 10 has a second surface on the side where the recess 13 is provided.
  • the substrate 16 is overlaid, and a space is formed between the recess 13 and the minute groove and the second substrate 16.
  • a blood sample or the like flows into the inflow port 11, it flows from the space of the recess 131 to the elongated recess 1311. Then, the blood sample or the like passes through the minute groove provided between the depression 1311 and the depression 1321, and flows into the depression 1321. Observe white blood cells, platelets, etc. contained in blood samples that pass through these microgrooves. A blood sample or the like that has flowed into the recess 132 from the recess 1321 flows out from the outlet 12.
  • FIG. 4 is an enlarged top view of a P portion and a Q portion in FIG. 4A.
  • FIG. 5B is an enlarged top view of a P portion and a Q portion in FIG. 5A.
  • the present invention is used, for example, in a blood test container and method.

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Abstract

L'invention concerne un procédé de fabrication d’une matrice de micro-canaux de résine convenant à la santé, au diagnostic et au traitement de maladies, et un procédé de prise de sang. L'invention concerne en particulier un procédé de fabrication d’une matrice de micro-canaux de résine caractérisée en ce qu’un espace formé par les évidements et les rainures sert de canal au niveau d’une portion de jonction ou de contact à pression d’un premier substrat, caractérisée en ce qu’une pluralité d'évidements ayant chacun une entrée au niveau au moins d'une extrémité et une pluralité d’évidements ayant chacun une sortie au niveau au moins de l'autre extrémité sont disposés et que des micro-rainures interconnectant les évidements sont pratiquées dans des portions murales coupant les évidements, et d'un second substrat, et la largeur et la profondeur des rainures sont respectivement comprises dans la fourchette de 1 à 50 µm, et le rapport de la largeur et de la profondeur du canal est compris dans la fourchette de 1:10-10:1. Une structure (20) ayant un motif correspondant aux évidements et/ou aux rainures s’obtient par attaque chimique d’un substrat (1) et un premier substrat est formé sur la base de la structure (20).
PCT/JP2006/318349 2005-09-16 2006-09-15 Procédé de fabrication de matrice de micro-canaux de résine et procédé de prise de sang employant ladite matrice WO2007032467A1 (fr)

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JP2005270042A JP4753672B2 (ja) 2005-09-16 2005-09-16 樹脂製マイクロチャネルアレイの製造方法及びこれを用いた血液測定方法
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WO2014038420A1 (fr) * 2012-09-07 2014-03-13 東京エレクトロン株式会社 Procédé de traitement de substrat, support d'informations informatique et système de traitement de substrat
JP2017104095A (ja) * 2015-11-26 2017-06-15 学校法人獨協学園獨協医科大学 白血球の活性化度の測定装置及び測定方法
CN107305214A (zh) * 2016-04-22 2017-10-31 清华大学 一种硬质微流体芯片的制作方法

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JP5137007B2 (ja) * 2007-11-14 2013-02-06 ローム株式会社 マイクロチップ
WO2011010569A1 (fr) * 2009-07-24 2011-01-27 コニカミノルタオプト株式会社 Puce et dispositif de mesure de la vitesse
JP5490492B2 (ja) * 2009-10-30 2014-05-14 学校法人立命館 血漿分離器及び血液分析装置
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