WO2012077324A1 - Biopuce et substrat de réseau utilisant celle-ci - Google Patents

Biopuce et substrat de réseau utilisant celle-ci Download PDF

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Publication number
WO2012077324A1
WO2012077324A1 PCT/JP2011/006784 JP2011006784W WO2012077324A1 WO 2012077324 A1 WO2012077324 A1 WO 2012077324A1 JP 2011006784 W JP2011006784 W JP 2011006784W WO 2012077324 A1 WO2012077324 A1 WO 2012077324A1
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Prior art keywords
base material
biochip
reaction
reaction part
substrate
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PCT/JP2011/006784
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English (en)
Japanese (ja)
Inventor
健樹 山本
中谷　将也
高橋　誠
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パナソニック株式会社
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Publication of WO2012077324A1 publication Critical patent/WO2012077324A1/fr

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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/543—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals
    • G01N33/54366—Apparatus specially adapted for solid-phase testing

Definitions

  • the present invention relates to a biochip such as a microfluidic chip and a cell culture chip, and an array substrate such as a DNA array, a protein array, and a sugar chain array using the same.
  • Biochips measure proteins, genes, low molecular weight signal molecules, and the like based on biological molecular recognition mechanisms. Focusing on selective specific binding such as receptors, ligands, aptamers, lectins, antigen-antibody reactions, and selective catalytic reactions such as enzymes, molecules are measured by monitoring using a predetermined device.
  • array substrates with biochips have been used for various analyzes such as gene analysis, SNPs (single nucleotide polymorphism) analysis, and interaction analysis between substances in the field of medicine and pharmacology such as drug development and clinical diagnosis. It has been.
  • a reaction field region is provided in advance on the surface of the substrate, and a target detection substance is fixed to each reaction field region, and then a sample solution is dropped. Then, the interaction between the detection substance and the target substance contained in the sample is advanced, and the analysis is performed by detecting the degree of the interaction based on the fluorescence intensity or the like.
  • a substrate used for such a purpose is called an array substrate.
  • the surface area is increased by providing a biochip having a reaction part such as a fibrous or porous membrane in the reaction field region.
  • the biochip when the thermal expansion coefficient is different between the base material and the reaction part formed on the base material surface, the biochip warps and the adhesion between the base material and the reaction part is low.
  • the reaction part may peel off.
  • the biochip may warp due to a difference in thermal expansion coefficient between silicon and silicon oxide. That is, since silicon has a larger thermal expansion coefficient than silicon oxide, a warp that raises the center of the silicon base material may occur and the reaction part may peel from the base material.
  • the reaction part is warped, so that the detection accuracy in the measurement of the array substrate using these biochips may be lowered.
  • the spot diameter formed when droplets are dropped on a biochip provided in each reaction unit is uniform.
  • the droplets dropped on the biochip during measurement spread widely and the spot diameter becomes non-uniform.
  • the detection sensitivity may decrease, or the accurate concentration may not be determined.
  • liquid droplets are mixed not in the target biochip but in an adjacent biochip, making accurate measurement difficult.
  • the spot diameter is not uniform, accurate analysis cannot be performed, and as a result, the detection accuracy of the array substrate may be lowered.
  • the biochip of the present invention includes a base material, a fibrous reaction part provided on the surface of the base material, and a boundary part that divides the reaction part into a plurality of parts.
  • FIG. 1 is a perspective view of an array substrate according to an embodiment of the present invention.
  • 2 is a cross-sectional view taken along the line 2-2 of the array substrate in FIG.
  • FIG. 3 is a cross-sectional view of the biochip in the embodiment of the present invention.
  • FIG. 4 is a top view of the biochip in the embodiment of the present invention.
  • FIG. 5 is a cross-sectional view of another biochip in the embodiment of the present invention.
  • FIG. 6 is a top view of another biochip in the embodiment of the present invention.
  • FIG. 7 is a cross-sectional view of another biochip in the embodiment of the present invention.
  • FIG. 8 is a top view of another biochip in the embodiment of the present invention.
  • FIG. 1 is a perspective view of an array substrate according to an embodiment of the present invention.
  • 2 is a cross-sectional view taken along the line 2-2 of the array substrate in FIG.
  • FIG. 3 is a cross-sectional view of the biochip in the embodiment of
  • FIG. 9 is a cross-sectional view of another array substrate in the embodiment of the present invention.
  • FIG. 10 is a cross-sectional view of another biochip in the embodiment of the present invention.
  • FIG. 11 is a cross-sectional view of another biochip in the embodiment of the present invention.
  • FIG. 12 is a cross-sectional view of another biochip in the embodiment of the present invention.
  • FIG. 1 is a perspective view of an array substrate according to an embodiment of the present invention.
  • 2 is a cross-sectional view taken along the line 2-2 of the array substrate in FIG.
  • FIG. 3 is a cross-sectional view of the biochip in the embodiment of the present invention.
  • FIG. 4 is a top view of the biochip in the embodiment of the present invention.
  • the array substrate 1 has a plate 2 made of a resin in which a plurality of depressions are formed, and a substantially square biochip 3 embedded in the depressions.
  • the biochip 3 has a base material 4 made of silicon and a reaction portion 5 formed on the surface of the base material 4.
  • the reaction part 5 is comprised from several fiber 5a, and the fiber 5a and the base material 4 are joined directly.
  • the fiber 5a is mainly composed of silicon oxide.
  • direct bonding refers to a state in which the reaction part 5 is directly formed on the base material 4 and atoms or molecules constituting the base material 4 and the reaction part 5 are directly bonded. And molecules are covalently bonded.
  • silicon atoms on the surface of the substrate 4 and silicon atoms in the fiber 5a are covalently bonded through oxygen atoms.
  • no adhesive or the like is used on the bonding surface between the base material 4 and the reaction part 5, and no material other than atoms or molecules constituting the base material 4 and the reaction part 5 is included.
  • the base material 4 is a silicon substrate formed of single crystal silicon.
  • silicon substrate formed of single crystal silicon.
  • polycrystalline silicon, silicon oxide, quartz, borosilicate glass, amorphous silicon, or the like can be used for the substrate 4.
  • the reaction part 5 is made of, for example, a fiber 5a mainly composed of silicon oxide, and preferably composed of a fiber 5a mainly composed of amorphous silicon dioxide.
  • the thickness of the fiber 5a used as the reaction part 5 is about 0.01 ⁇ m to 1 ⁇ m.
  • the fibers 5a may be densely formed so as to be intertwined with each other, or may be formed by mixing those branched in a free direction. Since the fibers 5a are entangled with each other to form a film, the reaction portion 5 is firmly bonded to the base material 4. Further, even when the fiber 5 a has a plurality of branches, the reaction portion 5 is firmly bonded to the base material 4. Alternatively, the plurality of fibers 5a may be oriented in the same direction. However, it is desirable that the plurality of fibers 5a are formed in various directions because the reaction part 5 and the base material 4 are firmly bonded to each other when the fibers 5a are entangled with each other.
  • the container raw material is heated and softened by nanoimprinting, and the shape of the mold is transferred to the container raw material by pressing a mold on which the protrusions and the shape defining the culture surface are pressed.
  • this embodiment is preferable because the reaction portion 5 that is thinner and has a larger surface area than the conventional transfer can be formed.
  • the biochip 3 includes a base material 4, a fibrous reaction part 5 provided on the surface of the base material 4, and a boundary part 6 that divides the reaction part 5 into a plurality of parts. . That is, the reaction part 5 of the biochip 3 is divided into a plurality of parts via the boundary part 6 on the surface of the substrate 4 made of silicon. As shown in FIG. 4, a plurality of reaction units 5 are provided on one biochip 3. Preferably, a plurality of boundary portions 6 are formed vertically and horizontally, and the reaction portions 5 are formed in a lattice shape so as to be parallel to the depressions of the array substrate 1.
  • boundary part 6 should just be formed in at least one place of the biochip 3, curvature can be further suppressed by forming the boundary part 6 in multiple places.
  • the shape of the lattice divided by the boundary portion 6 is generally a square, but is not necessarily a square.
  • the size of the minimum side of the lattice is preferably several ⁇ m or more.
  • a mask is formed with a resist at a position where the boundary portion 6 is formed.
  • a catalyst layer or the like is selectively formed on the surface of the base material 4 other than the portion provided with the resist mask, that is, the boundary portion 6, thereby forming the fiber 5a as the reaction portion 5.
  • the fiber 5a is formed by sputtering and heat-treating a metal catalyst layer on the surface of the base material 4 other than the boundary portion 6. By using these methods, it is possible to selectively form the fiber 5a mainly composed of amorphous silicon dioxide using silicon constituting the base material 4 only at a desired position.
  • the biochip warps and the adhesion between the substrate and the reaction part is low. Separation may occur.
  • a fiber made of silicon oxide is provided on a substrate made of silicon by direct bonding, the biochip may warp due to a difference in thermal expansion coefficient between silicon and silicon oxide.
  • the plurality of fibers are not protrusions but film-like objects, and the fibers are entangled one by one, and the film-like substance and the substrate are directly joined.
  • the spot diameter of the sample solution dropped on the biochip 3 during the measurement using the array substrate 1 is not captured and is captured on the reaction part 5 of the biochip 3. Therefore, it is possible to reliably cause an interaction without lowering the detection sensitivity. Furthermore, by suppressing warpage, the dropped sample solution is not erroneously mixed into the adjacent biochip 3 instead of the target biochip 3. Therefore, the spot diameter and the concentration of the sample solution on each biochip 3 become uniform. Therefore, the analysis accuracy becomes accurate and the array substrate 1 with high detection accuracy can be obtained.
  • the fiber 5a mainly composed of silicon oxide when used as the reaction part 5, the fluorescence intensity due to the material of the reaction part 5 is lowered, and the generation of noise can be suppressed. Furthermore, since the fiber 5a mainly composed of silicon oxide is a chemically stable material, it can be subjected to various surface treatments. Further, the surface area per unit area can be increased by the fiber 5a mainly composed of silicon oxide, and the detection accuracy can be improved.
  • the biochip 3 is less warped and can be prevented from peeling by annealing in an NF 3 atmosphere while maintaining a high temperature. . This is because the Si—O—Si bond is cut in the oxide film, the SiO 2 lattice becomes open, and the compressive stress is relaxed. At this time, fluorine (F) remains in the fiber 5a.
  • the biochip 3 that is less likely to warp and suppresses peeling is obtained. Since the fiber 5a before the application of corona discharge is in a state where compressive stress is applied, the refractive index measurable with an ellipsometer or the like is about 1.472. However, when corona discharge is applied, the lattice is relaxed and the refractive index is about 1.46. In addition to the corona discharge, the same effect can be obtained by performing similar treatment using plasma.
  • the silicon (111) as the base material 4 and forming the fiber 5a using a part of the base material 4 as a raw material, it is possible to provide the biochip 3 that is less likely to warp and suppresses peeling. This is because the stress of silicon oxide depends on the crystal orientation, and the stress is the smallest when silicon (111) is used as the substrate 4.
  • the biochip 3 which is less warped and suppresses peeling can be obtained.
  • the warp magnitude of the substrate 4 follows the Stoney equation. That is, the warp of the substrate 4 increases as the thickness of the reaction portion 5 increases. In order to prevent the reaction part 5 from being peeled off, it is better to reduce the film thickness of the reaction part 5, and it is preferable that the film thickness is about 30 ⁇ m.
  • FIG. 5 is a cross-sectional view of the biochip 13 in the embodiment of the present invention.
  • FIG. 6 is a top view of the biochip 13 in the embodiment of the present invention.
  • a protrusion 7 is formed at the boundary portion 6.
  • FIGS. 5 and 6 by etching the surface of the base material 4, projections 7 are formed in a lattice shape as the boundary portion 6, and the reaction portion 5 is provided in a region where the projections 7 are not formed. Even if it exists, there exists an effect similar to the case of FIG. 3, FIG. Furthermore, if the protrusion 7 has a reverse taper shape, the effect is higher.
  • the height of the protrusion 7 is preferably lower than the height of the reaction portion 5.
  • the micro liquid sample needs to be applied as close as possible to the reaction unit 5 in order to apply the micro liquid sample to a target position. If the height of the protrusion 7 is lower than the height of the reaction part 5, there is no possibility that the micropump pipette or the like interferes with the protrusion 7. For this reason, since it can be applied close to the reaction unit 5, the positional accuracy of the micro liquid sample is increased, and measurement with high accuracy is possible.
  • a solution containing a specific biological material such as protein or DNA may be used, and it may be used to apply both a detection substance and a target substance.
  • the height of the protrusion 7 may be higher than the height of the reaction part 5.
  • several different types of biomaterials may be applied as detection substances to different portions of the reaction unit 5 and a sample containing the target substance may be dropped onto the several types of detection substances.
  • a sample containing several different target substances may be dropped.
  • the detection substance is applied to the entire depth of the reaction unit 5. Therefore, the amount of the solution containing the detection substance may be required so that the reaction unit 5 is sufficiently immersed.
  • the protrusion 7 can prevent mixing of several kinds of detection substances. As a result, even a minute region of about several ⁇ m 2 can be measured with high accuracy.
  • the amount of the solution enough to immerse the reaction part 5 may be necessary. Also in this case, the projection 7 can prevent mixing of several kinds of target substances.
  • FIG. 7 is a cross-sectional view of the biochip 23 in the embodiment of the present invention.
  • FIG. 8 is a top view of the biochip 23 in the embodiment of the present invention.
  • the boundary portion is a recess provided in the base material.
  • the surface of the base material 4 is etched to form the recesses 8 in a lattice shape as the boundary portions 6, and the reaction portion 5 is provided in a region where the recesses 8 are not formed. Even if it exists, there exists an effect similar to the case of FIG. 3, FIG.
  • a layer (not shown) of a material different from that of the base material 4 may be provided on the upper surface or side surface of the projection 7 or the side surface or bottom surface of the recess 8.
  • a layer made of a material different from that of the base material 4 is applicable to the case where the components included are completely matched, even when the characteristics such as density, resistivity, refractive index, and crystal orientation are different.
  • the layer made of a material different from the base material 4 is a layer whose main component coincides with that of the base material 4.
  • the base material 4 is silicon, silicon oxide, silicon nitride, or the like is desirable.
  • the reaction part 5 is formed of a fiber.
  • the porosity is large, such as a porous film or a nanotube, and has a large specific surface area of, for example, several m 2 / g, the same effect can be obtained. be able to.
  • the reaction part 5 is made of an inorganic material. By configuring the reaction part 5 with an inorganic material, it is possible to obtain the reaction part 5 having excellent heat resistance and chemical resistance.
  • the fiber 5a is directly bonded to the base material 4, but may not be directly bonded. However, since each of the plurality of fibers 5a is directly bonded to the substrate 4 and the stress applied to the reaction part 5 is dispersed, the separation of the fibers 5a from the substrate 4 can be further suppressed, so that the fibers 5a are directly bonded. It is desirable.
  • the plate 2 made of resin is used.
  • a plate made of the same material as the base 4 may be used as the plate 2, and the base 4 is integrated with the plate 2. Also good. By doing so, the man-hour in a manufacturing process can be reduced.
  • the array substrate 20 may have a structure in which the plate 22 has through holes 24 in an array shape, and the biochips 3, 13, and 23 are embedded in the through holes 24.
  • the protrusion 26 may be provided on the lower surface of the plate 22 of the through hole 24, and the biochips 3, 13, and 23 may be inserted and installed so as to contact the protrusion 26.
  • the biochips 3, 13, and 23 can be easily positioned, and the heights of the biochips 3, 13, and 23 can be made uniform.
  • each biochip 3, 13, 23 on the surface of the plate 2 or the plate 22 using an adhesive agent may adhere each biochip 3, 13, 23 on the surface of the plate 2 or the plate 22 using an adhesive agent.
  • the biochips 3, 13, and 23 of the present embodiment are desirable to store in an environment where there is no moisture or in an environment where there is little moisture until it is actually used after being manufactured.
  • the change in stress of the fiber 5a that is the reaction part 5 can be reduced, and the long-term stability of the biochips 3, 13, and 23 is improved.
  • the amount of water contained in the stored fiber 5a is reduced.
  • the amount of water contained in the fiber 5a can be quantified by using an analysis such as TDS.
  • the biochips 3, 13, and 23 are enclosed in a package.
  • the package for example, aluminum, polydimethylsiloxane (PDMS), polypropylene, polycarbonate, polyolefin, polyethylene, polystyrene, polyamide, polymethyl methacrylate (PMMA), cyclic polyolefin resin, or the like can be used.
  • materials that adsorb moisture include silica gel, zeolite, lithium chloride, triethylene glycol, and a moisture getter agent.
  • the inside of the package may be filled with a gas not containing moisture.
  • the gas not containing moisture is preferably an inert gas such as N 2 or Ar, but it does not cause alteration of the biochips 3, 13 and 23 even with a gas such as O 2. As long as the is lowered. Further, air or gas compressed and compressed may be enclosed. In this case, since the moisture (saturated water vapor amount) that can be contained in the air is reduced, it is possible to enclose with a reduced moisture content.
  • the biochips 3, 13, and 23 have been described as examples using the array substrate 1.
  • the present invention is not limited to this, and may be used as a microfluidic chip or a cell culture chip.
  • the reaction part 5 was used as a reaction field, you may use as an ion exchange adsorbent, a filter material, a gas sensor, and an electrode besides using it as a reaction field.
  • the ion exchange adsorbent is used for purification of waste water (adsorption of heavy metal ions), adsorption of various gases, auxiliary agent for oxygen scavenger, dehydration of industrial gas, adsorption separation of by-product gas, and the like.
  • waste water adsorption of heavy metal ions
  • auxiliary agent for oxygen scavenger auxiliary agent for oxygen scavenger
  • dehydration of industrial gas adsorption separation of by-product gas, and the like.
  • a device using an ion exchange adsorbent can be formed by embedding the reaction part 5 in a microfluidic chip, or by forming a flow channel groove in the substrate 4 and forming the reaction part 5 on the bottom surface of the groove. . If the reaction part 5 formed in the microfluidic chip is warped, the fluid resistance increases or the fluid becomes difficult to pass uniformly. By dividing the reaction part 5 by the boundary part 6, warpage of the microfluidic chip can be reduced. Thereby, it is possible to perform highly reliable processing by reducing fluid resistance and allowing fluid to pass uniformly. Moreover, when it is necessary to seal the base material 4, joining may become difficult by the curvature of the base material 4, and the reliability of joining improves by reducing curvature by this structure.
  • the fiber 5a extracts only a specific substance from the solution, it can be used for various filter materials such as a separation filter, an analysis filter, and a sterilization filter. By configuring the filter material with the fiber 5a, higher separation efficiency can be obtained.
  • a filter material it is desirable to form the reaction part 5 in the flow channel device.
  • a device having a filter can be formed by embedding a biochip having the reaction part 5 in the flow channel device.
  • the flow channel device can be a flat plate or a capillary type.
  • a channel groove is formed in the base material 4, the reaction part 5 is formed in the bottom surface of the groove, a channel groove is formed in the base material 4, and a through hole that penetrates the base material 4 is formed in the bottom surface of the channel groove
  • a flow path device can be formed also by forming the reaction part 5 in the upper surface of a through-hole.
  • the direction in which the sample solution flows may be parallel or perpendicular to the surface where the reaction part 5 and the substrate 4 are joined.
  • the reaction part 5 in the flow path device is warped, the fluid resistance increases or the fluid becomes difficult to pass uniformly.
  • the warpage of the flow path device can be reduced. Thereby, it is possible to perform highly reliable processing by reducing fluid resistance and allowing fluid to pass uniformly.
  • joining may become difficult by the curvature of the base material 4, and reliability improves by reducing a curvature by this structure.
  • the reaction part 5 can also be used as a detection material for a gas sensor.
  • SnO 2 , ZnO, ZrO 2 , Y—ZrO 2 (yttrium-stabilized zirconia) or the like is used as a detection material for a gas sensor.
  • SnO 2 and ZnO a change in electrical resistance caused by gas adsorption and reaction on the surface of the oxide semiconductor (the surface of the detection material) is detected.
  • ZrO 2 or Y—ZrO 2 a gas sensor is formed by forming a battery with an ion conductor and detecting an electromotive force due to gas with a detection material.
  • the detection part is airtight.
  • a base material with other joining materials (for example, sealing material).
  • the detection material is formed in a space formed by the base material and the bonding material.
  • the substrate is warped by using the fiber 5a as the detection material, it becomes difficult to join the bonding material.
  • the bonding stability is increased. As a result, the reliability of the gas sensor can be improved.
  • the reaction part 5 can be used as an electrode of a battery.
  • electrodes made of different materials such as aluminum and cobalt
  • ions in the electrolyte solution move between the electrodes, and a battery for taking out current can do.
  • the electrode material of the battery LiMn 2 O 4 , LiFePO 4 , LiCoO 2 , LiNiO 2 , LixMeyO 2 or the like is used as the positive electrode.
  • As the negative electrode Li, Si, SiO, Sn—Me, Si—Me, C, HC, Li 4 Ti 5 O 12 , La 3 Co 2 Sn 7 or the like is used.
  • the distance between the electrodes is a factor that determines the ion movement time.
  • the distance between the electrodes is preferably as small as possible.
  • the internal resistance of the battery becomes unstable when the distance between the electrodes changes due to warpage of the base material and the electrodes. Also, if the substrate and the electrode have a large warp, the risk of causing a short circuit between the electrodes increases. By dividing the reaction part 5 by the boundary part 6, it is possible to reduce the warpage of the base material and the electrode. Thereby, a highly reliable battery can be formed.
  • FIGS. 3 and 4 are denoted by the same reference numerals, and detailed description thereof is omitted.
  • the difference from FIGS. 3 and 4 is that the uneven portion 16 exists on the surface of the base material 14, and a plurality of reaction portions 15 are directly bonded to the surface of the base material 14.
  • FIG. 10 is a cross-sectional view of the biochip 33 in the embodiment of the present invention.
  • the biochip 33 includes a base material 14 made of a silicon layer having a concavo-convex portion 16 on the surface of the base material 14, and a reaction portion 15 made up of a plurality of fibers 15a mainly composed of silicon oxide. The surface to which the fiber 15a on the surface of the substrate 14 is fixed and the fiber 15a are directly joined.
  • the reaction unit 15 is made of, for example, a fiber 15a mainly composed of silicon oxide, and is preferably composed of a fiber 15a mainly composed of amorphous silicon dioxide.
  • An uneven portion 16 is formed on the surface of the base material 14 made of silicon by sandblasting.
  • a layer that generates the uneven portion 16 may be used as the surface of the base material 14.
  • polysilicon may be formed at a temperature of 580 ° C. to 600 ° C. using a CVD method.
  • a catalyst layer (not shown) is applied to the surface of the substrate 14 and the silicon layer is used as a raw material, whereby the fiber 15a as the reaction part 15 can be formed.
  • the manufacturing method is not limited to this, and it is only necessary that the uneven portion 16 finally exists on the surface of the substrate 14.
  • a method may be used in which a silicon layer and a catalyst are applied to a silicon oxide layer where the concavo-convex portion 16 is present, and the fiber 15a is formed until the silicon layer is consumed using the silicon layer as a raw material. As a result, the fiber 15a is directly bonded to the surface of the silicon oxide layer where the uneven portion 16 exists.
  • the reaction part 15 provided on the biochip 33 it is possible to prevent the reaction part 15 provided on the biochip 33 from being peeled off and improve the detection accuracy of the array substrate using the biochip 33. That is, the presence of a layer that generates the concavo-convex portion 16 on the surface of the base material 14 causes an anchor effect between the surface of the base material 14 and the fiber 15a. As a result, the reaction part 15 is difficult to peel off from the base material 14.
  • FIG. 11 is a cross-sectional view of the biochip 43 in the embodiment of the present invention.
  • the base material surface 17 where the base material 14 and the fiber 15a are joined is composed of the silicon oxide layer 17a, and the silicon oxide layer 17a and the fiber 15a which is the reaction part 15 are joined directly.
  • the surface to be bonded to the reaction portion 15 is formed of the same material as that of the reaction portion 15.
  • the contact point between the surface of the base material 14 and the fiber 15a can be a surface contact instead of a point contact, peeling of the fiber 15a from the base material 14 can be reduced.
  • the fiber 15a mainly composed of silicon oxide is not directly bonded to the silicon layers having different thermal expansion coefficients, and the main component is directly bonded to the same silicon oxide layer 17a. Therefore, the stress concerning the reaction part 15 can be reduced and peeling and a curvature can be suppressed.
  • FIG. 3 and 4 are denoted by the same reference numerals, and detailed description thereof is omitted.
  • FIG. 12 is a cross-sectional view of the biochip 53 in the embodiment of the present invention. As shown in FIG. 12, the base material 14 has the entire base material surface 17 formed of the same material as the reaction part 15.
  • a silicon oxide layer 17a is further formed on the entire surface 17 of the substrate, and the silicon oxide layer 17a and the fiber 15a that is the reaction portion 15 are directly bonded.
  • the silicon oxide layer 17a equivalent to the material of the fiber 15a is formed as the base material surface 17. That is, the entire surface of the silicon substrate 14 is coated with the silicon oxide layer 17a.
  • the silicon oxide layer 17 a is isotropically formed on the base material 14. Therefore, the curvature of the base material 14 caused by the silicon oxide layer 17a can be reduced.
  • the silicon oxide layer 17a may be formed not on the entire surface of the base material 14 but on the surface facing the reaction portion 15, but the substrate 14 is warped when formed on the entire surface of the base material 14. Further reduction can be achieved.
  • a CVD method, a sputtering method, a CSD method, thermal oxidation, and the like can be given.
  • the thermal oxidation method does not require an expensive vacuum apparatus, and can process a plurality of substrates at once by a simple method, which is desirable from the viewpoint of productivity.
  • the base material 14 is placed in a quartz tube, the furnace is heated to 900 ° C. to 1150 ° C., oxygen gas and hydrogen gas are fed in a ratio of 1: 2, and water vapor (H 2 O near the inlet of the furnace).
  • oxygen gas is fed from the gas inlet, and the silicon layer on the surface of the substrate 14 made of silicon is oxidized to form a silicon oxide layer 17a, or oxidation in an atmosphere to which halogen such as HCl or Cl 2 is added. Can also be used.
  • the formed silicon oxide layer 17a is formed by a CVD method or by thermal oxidation can be confirmed by measuring its refractive index or density.
  • the silicon oxide layer formed by the CVD method has a refractive index of about 1.46
  • the silicon oxide layer formed by thermal oxidation has a refractive index of about 1.48.
  • This refractive index is a value measured by ellipsometry using a He-Ne laser having a wavelength of 632.8 nm.
  • the density of the silicon oxide layer 17a can be analyzed from the etching rate of buffered hydrofluoric acid (BHF) because it is difficult to directly measure the density.
  • BHF buffered hydrofluoric acid
  • the etching rate of the silicon oxide layer by the CVD method is about 20 ⁇ / min, and the silicon oxide by the thermal oxidation is about 6.8 to 7 .3 ⁇ / min.
  • the biochips 3, 13, 23, 33 are formed at 1000 ° C. to 1100 ° C. in the first process, and the second By raising the temperature to 1200 ° C. or higher, which is equal to or higher than the softening temperature of the fiber 15 a in this step, the portion of the fiber 15 a fixed to the base material 14 is thermally melted and fused to the base material 14. As a result, the contact area between the surface of the base material 14 and the reaction portion 15 can be further increased. Therefore, peeling of the reaction part 15 from the base material 14 can be reduced. At this time, the fiber 15a is not necessarily formed at a temperature of 1200 ° C. or higher.
  • the material of the reaction unit 15 is doped with an inorganic substance such as boron (B) or phosphorus (P).
  • an inorganic substance such as boron (B) or phosphorus (P).
  • B boron
  • P phosphorus
  • the softening temperature is relatively high at 1160 ° C., but phosphorus-doped PSG (phosphosilicate glass) has a softening point of around 1000 ° C., BSG (borosilicate glass) and BPSG (Boron phosphorous).
  • the softening point of Silicon Glass is about 900 ° C. and the softening temperature is low. Therefore, by doping B or P into the fiber 15a, the temperature at which the fiber 15a is melted can be lowered, and the productivity is improved.
  • the biochips shown in FIGS. 3 to 8 and 10 to 12 are used as cell culture chips.
  • cell culture chips have been used for medical purposes for cell transplantation, and have been used in culture techniques for transplanting skin and transplanting small amounts of cells into complex organs such as the cornea, teeth, bones, and organs. Has been.
  • a chip in which a container made of glass or resin is coated with a material having high affinity with cells is used.
  • cells can be cultured on a surface that has affinity for the cells, but because of the strong adhesion between the cultured cells and the cell culture chip, the cells can be detached from the cell culture chip. It can be difficult.
  • the cultured cells are physically damaged by mechanical peeling, and the membrane proteins on the cell surface are destroyed by peeling by chemical treatment using an enzyme such as trypsin. In some cases, the rate of colonization in the cell tissue may decrease.
  • cells can be cultured on the reaction unit 5.
  • an appropriate gap can be formed below the cultured cells, so that the cultured cells can be peeled off more efficiently than before. Furthermore, since nutrients and wastes are more efficiently transported by the voids, the culture efficiency can be further improved.
  • the culture solution can be stably held by using the biochip of the present embodiment.
  • biochip of the present invention and an array substrate using the same are used for biochips such as microfluidic chips and cell culture chips, and array substrates such as DNA arrays, protein arrays, and sugar chain arrays.

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Abstract

L'invention concerne une biopuce qui comprend un substrat; une section de réaction fibreuse disposée sur la surface du substrat; et une section de bordure qui divise la section de réaction en une pluralité de parties. La déformation de la biopuce peut ainsi être évitée.
PCT/JP2011/006784 2010-12-07 2011-12-05 Biopuce et substrat de réseau utilisant celle-ci WO2012077324A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2017504183A (ja) * 2013-12-19 2017-02-02 イルミナ インコーポレイテッド ナノパターン化表面を含む基材およびその調製方法

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Publication number Priority date Publication date Assignee Title
JP2007212446A (ja) * 2006-01-12 2007-08-23 Toray Ind Inc 選択結合性物質固定化担体
JP2007298521A (ja) * 2006-05-02 2007-11-15 Samsung Electronics Co Ltd 多機能オリゴマープローブアレイおよびその製造方法
JP2008020412A (ja) * 2006-07-14 2008-01-31 Sony Corp バイオアッセイ用基板、及び、バイオアッセイ方法
WO2010004695A1 (fr) * 2008-07-09 2010-01-14 パナソニック株式会社 Séquenceur

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Publication number Priority date Publication date Assignee Title
JP2007212446A (ja) * 2006-01-12 2007-08-23 Toray Ind Inc 選択結合性物質固定化担体
JP2007298521A (ja) * 2006-05-02 2007-11-15 Samsung Electronics Co Ltd 多機能オリゴマープローブアレイおよびその製造方法
JP2008020412A (ja) * 2006-07-14 2008-01-31 Sony Corp バイオアッセイ用基板、及び、バイオアッセイ方法
WO2010004695A1 (fr) * 2008-07-09 2010-01-14 パナソニック株式会社 Séquenceur

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2017504183A (ja) * 2013-12-19 2017-02-02 イルミナ インコーポレイテッド ナノパターン化表面を含む基材およびその調製方法
US10682829B2 (en) 2013-12-19 2020-06-16 Illumina, Inc. Substrates comprising nano-patterning surfaces and methods of preparing thereof
US11110683B2 (en) 2013-12-19 2021-09-07 Illumina, Inc. Substrates comprising nano-patterning surfaces and methods of preparing thereof

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