WO2021185087A1 - 检测芯片及其修饰方法 - Google Patents

检测芯片及其修饰方法 Download PDF

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Publication number
WO2021185087A1
WO2021185087A1 PCT/CN2021/078950 CN2021078950W WO2021185087A1 WO 2021185087 A1 WO2021185087 A1 WO 2021185087A1 CN 2021078950 W CN2021078950 W CN 2021078950W WO 2021185087 A1 WO2021185087 A1 WO 2021185087A1
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Prior art keywords
substrate
hydrophilic layer
spotting
detection chip
layer
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PCT/CN2021/078950
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English (en)
French (fr)
Inventor
殷雨丹
于静
刘浩男
刘祝凯
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京东方科技集团股份有限公司
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Priority to US17/631,461 priority Critical patent/US20220274106A1/en
Publication of WO2021185087A1 publication Critical patent/WO2021185087A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C23—COATING METALLIC MATERIAL; COATING MATERIAL WITH METALLIC MATERIAL; CHEMICAL SURFACE TREATMENT; DIFFUSION TREATMENT OF METALLIC MATERIAL; COATING BY VACUUM EVAPORATION, BY SPUTTERING, BY ION IMPLANTATION OR BY CHEMICAL VAPOUR DEPOSITION, IN GENERAL; INHIBITING CORROSION OF METALLIC MATERIAL OR INCRUSTATION IN GENERAL
    • C23C—COATING METALLIC MATERIAL; COATING MATERIAL WITH METALLIC MATERIAL; SURFACE TREATMENT OF METALLIC MATERIAL BY DIFFUSION INTO THE SURFACE, BY CHEMICAL CONVERSION OR SUBSTITUTION; COATING BY VACUUM EVAPORATION, BY SPUTTERING, BY ION IMPLANTATION OR BY CHEMICAL VAPOUR DEPOSITION, IN GENERAL
    • C23C16/00—Chemical coating by decomposition of gaseous compounds, without leaving reaction products of surface material in the coating, i.e. chemical vapour deposition [CVD] processes
    • C23C16/22—Chemical coating by decomposition of gaseous compounds, without leaving reaction products of surface material in the coating, i.e. chemical vapour deposition [CVD] processes characterised by the deposition of inorganic material, other than metallic material
    • C23C16/30—Deposition of compounds, mixtures or solid solutions, e.g. borides, carbides, nitrides
    • C23C16/40—Oxides
    • C23C16/401—Oxides containing silicon
    • 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
    • C—CHEMISTRY; METALLURGY
    • C23—COATING METALLIC MATERIAL; COATING MATERIAL WITH METALLIC MATERIAL; CHEMICAL SURFACE TREATMENT; DIFFUSION TREATMENT OF METALLIC MATERIAL; COATING BY VACUUM EVAPORATION, BY SPUTTERING, BY ION IMPLANTATION OR BY CHEMICAL VAPOUR DEPOSITION, IN GENERAL; INHIBITING CORROSION OF METALLIC MATERIAL OR INCRUSTATION IN GENERAL
    • C23C—COATING METALLIC MATERIAL; COATING MATERIAL WITH METALLIC MATERIAL; SURFACE TREATMENT OF METALLIC MATERIAL BY DIFFUSION INTO THE SURFACE, BY CHEMICAL CONVERSION OR SUBSTITUTION; COATING BY VACUUM EVAPORATION, BY SPUTTERING, BY ION IMPLANTATION OR BY CHEMICAL VAPOUR DEPOSITION, IN GENERAL
    • C23C16/00—Chemical coating by decomposition of gaseous compounds, without leaving reaction products of surface material in the coating, i.e. chemical vapour deposition [CVD] processes
    • C23C16/44—Chemical coating by decomposition of gaseous compounds, without leaving reaction products of surface material in the coating, i.e. chemical vapour deposition [CVD] processes characterised by the method of coating
    • C23C16/50—Chemical coating by decomposition of gaseous compounds, without leaving reaction products of surface material in the coating, i.e. chemical vapour deposition [CVD] processes characterised by the method of coating using electric discharges
    • C—CHEMISTRY; METALLURGY
    • C23—COATING METALLIC MATERIAL; COATING MATERIAL WITH METALLIC MATERIAL; CHEMICAL SURFACE TREATMENT; DIFFUSION TREATMENT OF METALLIC MATERIAL; COATING BY VACUUM EVAPORATION, BY SPUTTERING, BY ION IMPLANTATION OR BY CHEMICAL VAPOUR DEPOSITION, IN GENERAL; INHIBITING CORROSION OF METALLIC MATERIAL OR INCRUSTATION IN GENERAL
    • C23C—COATING METALLIC MATERIAL; COATING MATERIAL WITH METALLIC MATERIAL; SURFACE TREATMENT OF METALLIC MATERIAL BY DIFFUSION INTO THE SURFACE, BY CHEMICAL CONVERSION OR SUBSTITUTION; COATING BY VACUUM EVAPORATION, BY SPUTTERING, BY ION IMPLANTATION OR BY CHEMICAL VAPOUR DEPOSITION, IN GENERAL
    • C23C16/00—Chemical coating by decomposition of gaseous compounds, without leaving reaction products of surface material in the coating, i.e. chemical vapour deposition [CVD] processes
    • C23C16/56—After-treatment
    • 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
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2200/00—Solutions for specific problems relating to chemical or physical laboratory apparatus
    • B01L2200/06—Fluid handling related problems
    • B01L2200/0689—Sealing
    • 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
    • B01L2300/0809—Geometry, shape and general structure rectangular shaped
    • B01L2300/0819—Microarrays; Biochips
    • 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
    • B01L2300/16—Surface properties and coatings
    • B01L2300/161—Control and use of surface tension forces, e.g. hydrophobic, hydrophilic
    • 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
    • B01L2300/16—Surface properties and coatings
    • B01L2300/161—Control and use of surface tension forces, e.g. hydrophobic, hydrophilic
    • B01L2300/165—Specific details about hydrophobic, oleophobic surfaces
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2400/00—Moving or stopping fluids
    • B01L2400/08—Regulating or influencing the flow resistance
    • B01L2400/084—Passive control of flow resistance
    • B01L2400/086—Passive control of flow resistance using baffles or other fixed flow obstructions

Definitions

  • the present disclosure relates to the field of biomedical technology, in particular to a detection chip and a modification method thereof.
  • microfluidic chip originated from the Micro Total Analysis System ( ⁇ TAS) proposed by Manz and Widmer in the 1990s. Professor Manz successfully applied MEMS technology to the field of analytical chemistry, and soon realized high-speed capillary electrophoresis on microchips. The results were published in "Science” and other magazines. Since then, this field has quickly received attention from the academic community and has become the world today.
  • ⁇ TAS Micro Total Analysis System
  • Lab on a chip and Microfluidic Chip are different names that people have put forward in this field, and as the application of this subject expands from the initial analytical chemistry to multiple research and applications
  • the field, as well as researchers’ in-depth understanding of this subject microfluidic chips have become a general term for this field.
  • Biochip is a kind of chip technology. Its essence is to arrange a series of known recognition molecules in an orderly array on the surface of the substrate to combine or react with the tested substance, and then display and analyze it in a certain way. Obtain information such as the chemical molecular structure of the substance to be tested.
  • the application of biochips is very wide, and can be applied to the fields of molecular biology, biomedicine, and drug research and development. Compared with traditional detection methods, it has the characteristics of high throughput, high information content, speed, miniaturization, automation, and wide application.
  • An embodiment of the present disclosure provides a method for modifying a detection chip, including:
  • the hydrophilic layer having a hydroxyl-containing modification group formed on the surface is subjected to a surface epoxidation treatment to form an epoxy-containing modification group on the surface of the hydrophilic layer.
  • the solution of an oxygen-containing compound is used to perform surface epoxidation treatment on the hydrophilic layer on which the hydroxyl-containing modification group is formed on the surface, specifically include:
  • the first substrate on which the hydroxyl-containing modification group is formed on the surface of the hydrophilic layer is placed in 0.5%-5% (v/v )
  • airtightly soak for 24h-72h at a temperature between room temperature and 70°C specifically including:
  • the surface activation treatment of the hydrophilic layer on the first substrate constituting the detection chip specifically includes:
  • the piranha solution is composed of concentrated sulfuric acid and 30% hydrogen peroxide, wherein , The volume ratio of the concentrated sulfuric acid to the 30% hydrogen peroxide is 1:3.
  • the first substrate is processed as follows:
  • the washed first substrate is ultrasonically cleaned in deionized water, and then dried with nitrogen for use.
  • the method before the surface activation treatment is performed on the hydrophilic layer on the first substrate constituting the detection chip, the method further includes:
  • the first substrate with the hydrophilic layer is ultrasonically cleaned with acetone, ethanol, and deionized water as a solution in sequence, and the first substrate after the final ultrasonic cleaning is blow-dried with nitrogen for use.
  • the method before the ultrasonic cleaning is performed on the first substrate with the hydrophilic layer using acetone as a solution, the method further includes:
  • the hydrophilic layer is formed on each spotting platform.
  • the forming the hydrophilic layer on each spotting platform specifically includes:
  • the silicon oxide layer is etched, and the silicon oxide layer covering the area where each spotting platform is located is retained to obtain the hydrophilic layer.
  • the embodiments of the present disclosure also provide a detection chip, including:
  • a spotting platform located on the first substrate
  • the hydrophilic layer is located on the first substrate and covers the spotting platform, and the surface of the hydrophilic layer has a carboxyl-containing modifying group; wherein,
  • the carboxyl-containing modification group is obtained by the above modification method provided in the embodiment of the present disclosure.
  • the above-mentioned detection chip provided by the embodiment of the present disclosure, it further includes:
  • a diversion dam is located on the first base, the diversion dam extends along the first path and is located between the adjacent spotting platforms;
  • the hydrophilic layer covers the diversion dam, and the part of the hydrophilic layer covering the diversion dam and the part covering the spotting platform are independent of each other.
  • the height of the diversion dam in the direction perpendicular to the first substrate is greater than the height of the spotting platform in the direction perpendicular to the first substrate.
  • the above-mentioned detection chip provided by the embodiment of the present disclosure, it further includes:
  • a hydrophobic layer, the hydrophobic layer is located on the first substrate, and the spotting platform and the diversion dam are both located on the hydrophobic layer.
  • the above-mentioned detection chip provided by the embodiment of the present disclosure, it further includes:
  • the second substrate is arranged opposite to the first substrate and is spaced apart from the first substrate to provide a detection space.
  • the first substrate and/or the second substrate is a glass substrate.
  • the above-mentioned detection chip provided by the embodiment of the present disclosure, it further includes:
  • the frame sealing glue is located between the first substrate and the second substrate and surrounds the diversion dam and the plurality of spotting platforms.
  • FIG. 1 is a flowchart of a modification method of a detection chip provided by an embodiment of the disclosure
  • FIG. 2a is a schematic plan view of a detection chip provided by an embodiment of the disclosure.
  • 2b is a schematic cross-sectional view of a detection chip provided by an embodiment of the disclosure.
  • Fig. 3 is a fluorescence image of antibody labeling using the detection chip provided in an embodiment of the present disclosure.
  • a compound film with epoxy groups or other groups that can be coupled with proteins is generally deposited or spin-coated on a glass substrate to realize the production of detection chips for subsequent protein coupling.
  • the glass substrate prepared by the melting process has many defects, resulting in poor adhesion of the above-mentioned compound film on the glass substrate, prone to fall off, which affects the efficiency of protein coupling.
  • the embodiments of the present disclosure provide a detection chip and a modification method thereof.
  • a modification method of a detection chip provided by an embodiment of the present disclosure, as shown in FIG. 1, includes the following steps:
  • the hydrophilic layer is generally made of silicon oxide SiO x material.
  • the surface activation treatment of the silicon oxide material can convert the silicon oxide on the surface of the hydrophilic layer into silanol groups, that is, form hydroxyl-containing modified groups on the surface of the hydrophilic layer. Group, as shown in reaction formula I.
  • the first substrate can be placed in an organic solution of 3-glycerylpropyltrimethoxysilane to form a modified group containing epoxy groups on the surface of the hydrophilic layer, as shown in Reaction Formula II.
  • a series of surface chemical reaction operations are performed on the surface of the detection chip, so that epoxy groups connected by chemical bonds are formed on the surface of the hydrophilic layer, which solves the problem that the detection chip in the related technology contains
  • the problem that the epoxy-based compound film is easy to fall off improves the subsequent protein coupling efficiency. It is suitable for microfluidic systems required for in vitro diagnosis, drug screening, cell culture, immunofluorescence detection, etc.
  • step S102 a solution of an oxygen-containing compound is used to perform surface epoxidation treatment on the hydrophilic layer on which a modification group containing a hydroxyl group is formed on the surface. This is done in the following ways:
  • the volume ratio (v/v) of 3-glycerylpropyltrimethoxysilane (GPTMS) in toluene can be 0.5%, 0.8%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5 %, 4%, 4.5%, 5%, etc.; toluene can be ultra-dry toluene; the soaking temperature is room temperature (generally around 25°C, such as 16°C ⁇ 18°C in winter, 24°C ⁇ 26°C in summer), 30°C , 35°C, 40°C, 45°C, 50°C, 55°C, 60°C, 65°C, 70°C; soaking time can be 24h, 30h, 36h, 40h, 48h, 60h, 72h, etc.
  • the first substrate with hydroxyl-containing modification groups formed on the surface of the hydrophilic layer can be vertically placed in the epoxidation fixture according to the fixture structure, and placed in the epoxy Inject 3% (v/v) 3-glyceryl propyltrimethoxysilane (GPTMS) in the ultra-dry toluene solution into the chemical fixture, and soak in a sealed solution at a temperature of 70° C. for 24 hours.
  • GTMS 3-glyceryl propyltrimethoxysilane
  • step S102 it is necessary to pour out the reaction solution, rinse the first substrate with deionized water at least twice, and then use deionized water to ultrasonically clean the first substrate for 5 minutes to remove the first substrate during the epoxidation process. An impurity contaminated on the substrate. Subsequently, the first substrate cleaned by nitrogen was blown dry and stored in a nitrogen atmosphere to complete the modification for subsequent use in protein coupling.
  • the surface activation treatment of the hydrophilic layer on the first substrate constituting the detection chip in step S101 can be specifically implemented in the following ways:
  • the stirring temperature in the water bath is 70°C, 72°C, 75°C, 80°C, 83°C, 85°C, 88°C, 90°C, etc.
  • the stirring time in the water bath is 12h, 15h, 18h, 20h, 21h, 24h, etc. .
  • step S101 it is necessary to pour the piranha solution and properly dispose of it, rinse the first substrate at least twice with deionized water, and then ultrasonically clean the first substrate with deionized water for 10 minutes to remove the activation process In the impurity contaminated on the surface of the first substrate, the first substrate is finally dried by nitrogen for use.
  • step S101 before performing surface activation treatment on the hydrophilic layer on the first substrate constituting the detection chip in step S101, the following steps may also be performed:
  • Acetone, ethanol, and deionized water are used as solutions to ultrasonically clean the first substrate with a hydrophilic layer, and nitrogen is used to dry the final ultrasonically cleaned first substrate for use.
  • the 0.5mm-thick master glass substrate is cut into a standard glass slide of 1in ⁇ 3in as the first substrate, and then loaded into the cleaning jig.
  • the pre-cleaning and cleaning process in turn include: ultrasonic cleaning with acetone for 10 minutes, ultrasonic cleaning with ethanol for 10 minutes, ultrasonic cleaning with deionized water for 10 minutes, and ultrasonic cleaning with deionized water for 10 minutes again. In this way, other impurities such as grease on the first substrate can be washed away. After the cleaning, the first substrate was dried with nitrogen for use.
  • the following steps may be performed before ultrasonic cleaning is performed on the first substrate with the hydrophilic layer using acetone as a solution:
  • a hydrophilic layer is formed on each spotting platform.
  • the first substrate of the detection chip has a certain degree of hydrophobicity, and the solvent contained in the solution to be tested in the biological field is generally water. Therefore, the contact between the solution to be tested and the first substrate is not good, which is not conducive to the solution to be tested.
  • the markers in the detection solution are combined with the detection chip. Silicon oxide has hydrophilicity, so that the detection chip provided by the present disclosure can better achieve close contact with the solution to be detected, and improve the detection effect.
  • the above-mentioned forming a hydrophilic layer on each spotting platform can be specifically implemented in the following ways:
  • PECVD plasma-enhanced chemical vapor deposition
  • the silicon oxide layer is etched to retain the silicon oxide layer covering the area where each spotting platform is located to obtain a hydrophilic layer.
  • the hydrophilic layer made of silicon oxide formed by the above-mentioned method has the advantages of good film thickness uniformity, few pinholes in the film layer, and resistance to cracking, so that the contact effect between the solution to be tested and the test chip is better.
  • embodiments of the present disclosure also provide a detection chip, as shown in FIGS. 2a and 2b, including: a first substrate 201, a spotting platform 202 on the first substrate 201, and a covering spotting platform
  • the surface of the hydrophilic layer 203 has an amino group-containing modification group 203'; wherein the amino group-containing modification group is obtained by the above-mentioned modification method provided in the embodiment of the present disclosure.
  • FIG. 2a is a schematic plan view of a detection chip provided by some embodiments of the present disclosure
  • FIG. 2b is a schematic cross-sectional view of the detection chip shown in FIG. 2a.
  • the modification group 203' on the surface of the hydrophilic layer 203 is obtained by the above-mentioned modification method provided in the embodiments of the present disclosure, and the modification group 203' has an epoxy group, which can bind to the target antigen or antibody.
  • the lighter-colored area i.e., the lower part of the picture
  • the first substrate 201 plays a role of support, protection, etc., and may be a plastic substrate, a glass substrate, or a silicon substrate, and may also be other applicable substrates, which are not limited in the embodiments of the present disclosure.
  • the first substrate 201 is a transparent substrate (such as a glass substrate), so that light can pass through the transparent substrate without damage or with low loss, thereby improving the accuracy of subsequent optical inspections and reducing the need for additional optical inspection equipment. Require.
  • a plurality of spotting platforms 202 are located on the first substrate 201, and the spotting platforms 202 are used to provide attachment positions for target antigens or antibodies, for example.
  • the spotting platform 202 has a convex shape, so as to facilitate the binding or reaction of the target antigen or antibody attached to the spotting platform 202 with the marker in the solution to be detected flowing through the spotting platform 202.
  • the spotting platform 202 can also be in the shape of a groove or a plane, as long as it can ensure that the target antigen or antibody attached to the spotting platform 202 can interact with the target antigen or antibody flowing through the spotting platform 202.
  • the detection solution is in contact with and can bind to the marker in it.
  • the number of spotting platforms 202 is not limited, and can be any number, for example, depending on the type or concentration of the marker to be detected.
  • the detection chip may further include: a diversion dam 204 located on the first substrate 201, and the diversion dam 204 extends along the first path And it is located between adjacent spotting platforms 202; the hydrophilic layer 203 covers the diversion dam 204, and the part of the hydrophilic layer 203 covering the diversion dam 204 and the part covering the spotting platform 202 are independent of each other.
  • the diversion dam 204 is located on the first base 201, and the diversion dam 204 extends along the first path and is located between adjacent spotting platforms 202.
  • the diversion dam 204 affects the flow field in the internal space of the detection chip, thereby improving the uniformity of the flow velocity at the location of the different spotting platforms 202, improving the parallelism of the flow field along the first path, and improving the stability of the flow field, so that The solution to be detected can stably and uniformly flow through the area where the spotting platform 202 is located. Therefore, the marker in the solution to be detected can fully bind or react with the target antigen or antibody on the spotting platform 202, thereby helping to improve the accuracy and reliability of the immunological detection result.
  • the detection chip also has the characteristics of small size and high throughput.
  • the multiple spotting platforms 202 are arranged in multiple rows, and the first path extends along the row direction Z.
  • Diversion dams 204 are provided on both sides of each column of spotting platforms 202, and a plurality of diversion dams 204 are parallel to each other.
  • the first path is not limited to extending along the column direction Z, and can also extend in any other direction.
  • the first path may extend along a straight line or a curve, which may be determined according to the flow path and flow mode of the solution to be detected, which is not limited in the embodiment of the present disclosure.
  • the diversion dam 204 when the first path extends along a straight line, the diversion dam 204 also extends along a straight line; when the first path extends along a curve, the diversion dam 204 also extends along a curve.
  • the multiple spotting platforms 202 can be arranged in multiple rows along a straight line, or can be arranged in multiple groups along a curve, and the diversion dam 204 located between adjacent spotting platforms 202 is along the arrangement direction of the spotting platforms 202 Just extend it.
  • the diversion dams 204 can be provided on both sides of each column of spotting platforms 202, or only some columns of spotting platforms 202 can be provided with diversion dams 204. This It can be determined according to the flow field parallelism that needs to be achieved, which is not limited in the embodiment of the present disclosure.
  • the flow field has a better Parallelism. If the target antigen or antibody on a spotting platform 202 accidentally falls off, the target antigen or antibody that falls off will flow along the column direction Z, that is, it will flow in the area where the spotting platform 202 is located. It will affect other array spotting platforms 202, so that crosstalk between different detection sites (ie spotting platforms 202) can be avoided, and cross-contamination can be avoided.
  • the number of diversion dams 204 is not limited, and may be one or more.
  • the diversion dam 204 can be located between the two rows of spotting platforms 202, so that While reducing the number of diversion dams 204, the flow field has better parallelism.
  • the cross-sectional shape of the diversion dam 204 in the direction perpendicular to the first path may be a rectangle, a square, a trapezoid, a semicircle or other applicable shapes, such as a regular shape or an irregular shape.
  • the embodiment of the present disclosure does not limit this.
  • different cross-sectional shapes will have different effects on the flow field, so the cross-sectional shape of the diversion dam 204 can be determined according to the characteristics of the flow field.
  • both the diversion dam 204 and the spotting platform 202 can be made of photoresist, for example, a photoresist that can be etched by a thick film.
  • the diversion dam 204 and the spotting platform 202 may be formed in the same patterning process to simplify the production process.
  • the detection chip may further include: a hydrophobic layer 205 on the first substrate 201, and the spotting platform 202 and the diversion dam 204 are both located on the hydrophobic layer. 205 on.
  • a hydrophobic layer 205 By providing the hydrophobic layer 205, the solution to be tested can flow more easily in the detection chip, and the markers in the solution to be tested can not easily adhere to the first substrate 201, so as to avoid the markers in the solution to be tested from being wasted.
  • the material of the hydrophobic layer 205 is resin or silicon nitride.
  • the hydrophobic layer 205 can also be made of other suitable inorganic or organic materials, as long as it is ensured that the side of the hydrophobic layer 205 away from the first substrate 201 is hydrophobic.
  • the hydrophobic layer 205 can be directly prepared using a hydrophobic material.
  • the hydrophobic layer 205 may be made of a material that does not have hydrophobicity. In this case, it is necessary to perform a hydrophobic treatment on the surface of the hydrophobic layer 205 away from the first substrate 201, so that the hydrophobic layer 205 is away from the first substrate.
  • the surface of 201 is hydrophobic.
  • the material of the second substrate 206 may be the same as or different from the material of the first substrate 201, which is not limited in the embodiment of the present disclosure.
  • the second substrate 206 is a transparent substrate (for example, a glass substrate), so that light can pass through the transparent substrate without damage or with low loss, thereby improving the accuracy of subsequent optical inspections and reducing the need for additional optical inspection equipment. Require.
  • a plurality of spotting platforms 202 are located in the detection area 001, and the plurality of spotting platforms 202 are arranged in multiple rows, and the injection port 207 and the sample outlet 207' are distributed along the column direction Z on both sides of the detection area 001 (for example, located The upper and lower sides in the figure).
  • the solution to be tested can be injected into the sample inlet 207 through a microsyringe pump or a pipette, and flows out of the sample outlet 207' after flowing through the multiple spotting platforms 202 along the column direction Z.
  • the sample inlet 207 and the sample outlet 207' are symmetrically or centrally distributed along the Z axis in the column direction on both sides of the detection area 001, so that the parallelism and stability of the flow field can be further improved.
  • the embodiment of the present disclosure is not limited to this, and the sample inlet 207 and the sample outlet 207' may also be distributed asymmetrically, which may be determined according to the characteristics of the flow field and actual requirements.
  • the sample inlet 207 and the sample outlet 207' are provided on the second substrate 206.
  • the injection port 207 may be a through hole that penetrates the second substrate 206, and the shape of the through hole on a cross-section parallel to the second substrate 206 may be any suitable shape such as a circle, a rectangle, a square, etc. shape.
  • the sample outlet 207' can also be a through hole penetrating the second substrate 206, and the shape of the sample outlet 207' on a cross-section parallel to the second substrate 206 can be the same as or different from the shape of the sample inlet 207.
  • FIG. 2b only schematically shows the arrangement of the injection port 207 on the second substrate 206, but the relative position of the injection port 207 and the spotting platform 202 is not affected by the situation shown in FIG. 2b. limit.
  • the detection chip may further include: a frame sealant 208 located between the first substrate 201 and the second substrate 206, and the frame sealant 208 serves as a support
  • the components surround a diversion dam 204 and a plurality of spotting platforms 202.
  • the first substrate 201, the second substrate 206, and the sealant 208 jointly define the flow space of the solution to be detected.
  • spacers can be mixed in the sealant 208, so that the spacing between the first substrate 201 and the second substrate 206 can be controlled by the spacers, and the compression strength of the detection chip can be enhanced.
  • the height h2 can better adjust the parallelism of the flow field.
  • the height h1 of the diversion dam 204 is 30% to 60% of the distance h0 between the first substrate 201 and the second substrate 206, for example, 40% or 50%.
  • the distance h0 between the first substrate 201 and the second substrate 206 is 100 microns
  • the height h1 of the diversion dam 204 is 50 microns
  • the height h2 of the spotting platform 202 is 3 microns
  • the heights of h1 and h2 are The difference is large, and the parallelism of the flow field can be better adjusted.
  • the radius of the semicircle may be greater than or equal to the first substrate 110
  • the distance h0 from the second substrate 206 is half.
  • the height h1 can not only guide the height of the flow dam 204 itself, but also guide the sum of the heights of the flow dam 204 and the hydrophilic layer 203.
  • the height h2 can refer to the point-like platform.
  • the height of 202 itself can also refer to the sum of the height of the spot-like platform 202 and the hydrophilic layer 203.
  • the target antigen or antibody is first attached to the spotting platform 202 before the first substrate 201 and the second substrate 206 are paired.
  • a liquid containing a target antigen or antibody can be dropped on the spotting platform 202.
  • the target antigen or antibody can be attached to the spotting platform 202 by binding to the modifying group 203'.
  • the first substrate 201 and the second substrate 206 are aligned with the frame sealing glue 208.
  • the solution to be tested is injected from the sample inlet 207, so that the solution to be tested flows through the detection area 001 and flows out from the sample outlet 207'.
  • the marker in the solution to be detected flows through the spotting platform 202, it will bind or react with the target antigen or antibody attached to the spotting platform 202.
  • a bovine serum albumin (BSA) solution can be injected into the detection chip to clean the internal space of the detection chip, thereby reducing the adsorption of the solution to be detected in the internal space of the detection chip except the spotting platform 202. , Thereby improving the accuracy of subsequent detection.
  • optical detection equipment is used to perform optical detection on the detection chip to obtain immunological detection results.
  • a positioning component 209 may be further included.
  • the positioning component 209 is used to cooperate with a separately provided optical detection device to achieve the Positioning, so as to facilitate the optical detection equipment to perform optical detection on the detection chip.
  • the positioning member 209 is disposed on the first substrate 201 and is covered by the hydrophobic layer 205.
  • the positioning member 209 may be made of a metal material, such as molybdenum (Mo), or may be made of an opaque insulating material, which is not limited in the embodiment of the present disclosure.
  • the optical positioning device of the optical detection device when positioning is performed, emits light for positioning. If the detection chip is located at a preset position, since the positioning component 209 does not transmit light, the sensor set at the corresponding position detects The received light intensity is very small or zero, so that it can be determined that the detection chip is located at a preset position to achieve positioning.
  • optical detection equipment can be used to perform optical detection and signal reading on specific locations.
  • the specific site is a certain spotting platform(s) 202 on which the target antigen or antibody is attached.
  • the positioning component 209 is located outside the detection area 001, for example, further outside the liquid flow space formed by the first substrate 201, the second substrate 206 and the sealant 208, so as to avoid affecting the optical detection.
  • a plurality of positioning components 209 are arranged on one side of the detection chip and close to the edge of the detection chip. By providing a plurality of positioning members 209, the positioning accuracy can be improved.
  • the location of the positioning component 209 can be determined according to actual needs, for example, it can be set on any side, any two sides, around or other suitable positions of the detection chip. It depends on the positioning method of the optical inspection equipment.
  • the number of positioning components 209 is also not limited, and can be any number, which can be determined according to actual requirements.
  • an embodiment of the present disclosure also provides a reaction system, including: the above-mentioned detection chip provided by the embodiment of the present disclosure. Since the principle of the reaction system to solve the problem is similar to the principle of the above detection chip to solve the problem, the implementation of the reaction system provided in the embodiment of the present invention can refer to the implementation of the detection chip provided in the embodiment of the present invention, and the repetition will not be omitted. Go into details.
  • the hydrophilic layer of the detection chip is activated to form a hydroxyl-containing modification group on the surface of the hydrophilic layer;
  • the compound solution performs surface epoxidation treatment on the hydrophilic layer to form high-density epoxy-containing modified groups on the surface of the hydrophilic layer.
  • the above-mentioned series of surface chemical reactions cause the surface of the hydrophilic layer to generate epoxy groups connected by chemical bonds, which solves the problem that the epoxy-containing compound film on the detection chip is easy to fall off in the related technology, and improves the subsequent protein Coupling efficiency.
  • the above-mentioned modification method provided by the present disclosure is based on a glass substrate, which not only facilitates mass production, but also effectively reduces the cost.
  • the operation flow of the above modification method provided by the present disclosure is relatively simple, which facilitates the improvement of efficiency.

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Abstract

一种检测芯片及其修饰方法。检测芯片的亲水层表面活化处理，以使亲水层表面形成含羟基的修饰基团；之后采用含氧基化合物的溶液对亲水层进行表面环氧化处理，在亲水层的表面形成含环氧基的修饰基团。

Description

检测芯片及其修饰方法
相关申请的交叉引用
本公开要求在2020年03月19日提交中国专利局、申请号为202010197439.3、申请名称为“一种检测芯片、其修饰方法及反应系统”的中国专利申请的优先权，其全部内容通过引用结合在本公开中。
技术领域
本公开涉及生物医学技术领域，尤其涉及一种检测芯片及其修饰方法。
背景技术
微流控芯片这一名词最初源于20世纪90年代Manz与Widmer提出微全分析系统(μTAS)。Manz教授成功的把MEMS技术运用到分析化学领域，并在不久后在微芯片上实现了高速毛细管电泳，成果发表在《Science》等杂志上，从此这一领域迅速受到学界重视，并成为当今世界上最前沿的科技领域之一。芯片实验室(Lab on a chip)和微流控芯片(Microfluidic Chip)都是人们对这一领域提出的不同名称，而随着这一学科的应用从最初的分析化学拓展到多个研究与应用领域，以及研究者对这一学科的深入理解，微流控芯片已经成为对这一领域的统称。
生物芯片是一种芯片技术，其实质就是在基片表面上有序地点阵排列一系列已知的识别分子，使之与被测物质结合或反应，再以一定的方法进行显示和分析，最后得出被测物质的化学分子结构等信息。生物芯片应用十分广泛，可以应用于分子生物学、生物医学、药物的研究和开发等领域。与传统的检测方法相比，具有高通量、高信息量、快速、微型化、自动化、用途广等特点。
发明内容
本公开实施例提供的一种检测芯片的修饰方法，包括：
对构成检测芯片的第一基底上的亲水层进行表面活化处理，在所述亲水层的表面形成含羟基的修饰基团；所述亲水层覆盖位于所述第一基底上的点样平台；
采用含氧基化合物的溶液，对表面形成有含羟基的修饰基团的所述亲水层进行表面环氧化处理，在所述亲水层的表面形成含环氧基的修饰基团。
可选地，在本公开实施例提供的上述修饰方法中，所述采用含氧基化合物的溶液，对表面形成有含羟基的修饰基团的所述亲水层进行表面环氧化处理，具体包括：
将所述亲水层表面形成有含羟基的修饰基团的所述第一基底放入0.5％-5％(v/v)3-甘油丙基三甲氧基硅烷的甲苯溶液中，在室温至70℃的温度条件下密闭浸泡24h-72h。
可选地，在本公开实施例提供的上述修饰方法中，所述将所述亲水层表面形成有含羟基的修饰基团的所述第一基底放入0.5％-5％(v/v)3-甘油丙基三甲氧基硅烷的甲苯溶液中，在室温至70℃的温度条件下密闭浸泡24h-72h，具体包括：
将所述亲水层表面形成有含羟基的修饰基团的所述第一基底放入3％(v/v)3-甘油丙基三甲氧基硅烷的甲苯溶液中，在70℃下密闭浸泡24h。
可选地，在本公开实施例提供的上述修饰方法中，所述对构成检测芯片的第一基底上的亲水层进行表面活化处理，具体包括：
将具有所述亲水层的所述第一基底放入食人鱼溶液中，在70℃-90℃的温度条件下浸泡12h-24h；所述食人鱼溶液由浓硫酸和30％双氧水构成，其中，所述浓硫酸与所述30％双氧水的体积比为1:3。
可选地，在本公开实施例提供的上述修饰方法中，在所述表面活化处理和所述表面环氧化处理之后，均对所述第一基底进行如下处理：
采用去离子水对所述第一基底冲洗至少两遍；
将冲洗后的所述第一基底在去离子水中超声清洗处理后，氮气吹干备用。
可选地，在本公开实施例提供的上述修饰方法中，在对构成检测芯片的第一基底上的亲水层进行表面活化处理之前，还包括：
依次采用丙酮、乙醇、去离子水作为溶液对具有所述亲水层的所述第一基底进行超声清洗，并采用氮气对最终超声清洗后的所述第一基底吹干备用。可选地，在本公开实施例提供的上述修饰方法中，在所述采用丙酮作为溶液对具有所述亲水层的所述第一基底进行超声清洗之前，还包括：
在所述第一基底上形成多个点样平台；
在各所述点样平台上分别形成所述亲水层。
可选地，在本公开实施例提供的上述修饰方法中，所述在各所述点样平台上分别形成所述亲水层，具体包括：
采用等离子体增强化学的气相沉积法，在390℃的温度条件下，在各所述点样平台所在层上沉积一层厚度为300nm的氧化硅层；
并对所述氧化硅层进行刻蚀，保留覆盖各所述点样平台所在区域的氧化硅层，得到所述亲水层。
另一方面，本公开实施例还提供了一种检测芯片，包括：
第一基底；
点样平台，位于所述第一基底上；
亲水层，位于所述第一基底上且覆盖所述点样平台，所述亲水层的表面具有含羧基的修饰基团；其中，
所述含羧基的修饰基团采用本公开实施例提供的上述修饰方法获得。
可选地，在本公开实施例提供的上述检测芯片中，还包括：
导流坝，位于所述第一基底上，所述导流坝沿第一路径延伸且位于相邻的所述点样平台之间；
所述亲水层覆盖所述导流坝，且所述亲水层覆盖所述导流坝的部分与覆盖所述点样平台的部分相互独立。
可选地，在本公开实施例提供的上述检测芯片中，所述导流坝沿垂直于 所述第一基底方向的高度大于所述点样平台沿垂直于所述第一基底方向的高度。
可选地，在本公开实施例提供的上述检测芯片中，还包括：
疏水层，所述疏水层位于所述第一基底上，所述点样平台和所述导流坝均位于所述疏水层上。
可选地，在本公开实施例提供的上述检测芯片中，还包括：
第二基底，所述第二基底与所述第一基底相对设置，且与所述第一基底间隔开以提供检测空间。
可选地，在本公开实施例提供的上述检测芯片中，所述第一基底和/或所述第二基底为玻璃基底。
可选地，在本公开实施例提供的上述检测芯片中，还包括：
封框胶，所述封框胶位于所述第一基底和所述第二基底之间，且围绕所述导流坝和所述多个点样平台。
附图说明
图1为本公开实施例提供的检测芯片的修饰方法的流程图；
图2a为本公开实施例提供的检测芯片的平面示意图；
图2b为本公开实施例提供的检测芯片的剖面示意图；
图3为采用本公开实施例提供的检测芯片进行抗体标记的荧光图像。
具体实施方式
为使本公开实施例的目的、技术方案和优点更加清楚，下面将结合本公开实施例的附图，对本公开实施例的技术方案进行清楚、完整地描述。显然，所描述的实施例是本公开的一部分实施例，而不是全部的实施例。基于所描述的本公开实施例，本领域普通技术人员在无需创造性劳动的前提下所获得的所有其它实施例，都属于本公开保护的范围。
需要注意的是，下述实施例中所用的材料、试剂等，如无特殊说明，均 可从商业途径得到。附图中各图形的尺寸和形状不反映真实比例，目的只是示意说明本公开内容。并且自始至终相同或类似的标号表示相同或类似的元件或具有相同或类似功能的元件。
相关技术中，一般在玻璃基底上沉积或旋涂具备环氧基或其他包含可与蛋白偶联的基团的化合物薄膜，实现检测芯片的制作，以用于后续蛋白偶联。然而，熔融工艺制备的玻璃基底具有诸多缺陷，致使上述化合物薄膜在玻璃基底上的附着性较差，易发生脱落，影响蛋白偶联效率。
针对相关技术中存在的上述问题，本公开实施例提供了一种检测芯片及其修饰方法。
具体地，本公开实施例提供的一种检测芯片的修饰方法，如图1所示，包括以下步骤：
S101、对构成检测芯片的第一基底上的亲水层进行表面活化处理，在亲水层的表面形成含羟基的修饰基团；亲水层覆盖位于第一基底上的点样平台。
具体地，亲水层一般采用氧化硅SiO x材料制作，对氧化硅材料进行表面活化处理，可以使亲水层表面的氧化硅转化为硅羟基，即在亲水层表面形成含羟基的修饰基团，如反应式I所示。
Figure PCTCN2021078950-appb-000001
S102、采用含氧基化合物的溶液，对表面形成有含羟基的修饰基团的亲水层进行表面环氧化处理，在亲水层的表面形成含环氧基的修饰基团。
具体地，可以将第一基底置于3-甘油丙基三甲氧基硅烷的有机溶液中，在亲水层表面形成含有环氧基的修饰基团，如反应式II所示。
Figure PCTCN2021078950-appb-000002
在本公开实施例提供的上述修饰方法中，在检测芯片表面上进行了一系列表面化学反应操作，使得亲水层表面生成了通过化学键连接的环氧基，解决了相关技术中检测芯片上包含环氧基的化合物薄膜易脱落的问题，提高了后续蛋白偶联效率。适用于体外诊断、药性筛选、细胞培养、免疫荧光检测等所需的微流控体系。
可选地，在本公开实施例提供的上述修饰方法中，步骤S102采用含氧基化合物的溶液，对表面形成有含羟基的修饰基团的亲水层进行表面环氧化处理，具体可以通过以下方式进行实现：
将亲水层表面形成有含羟基的修饰基团的第一基底按照夹具构造竖直放入环氧化夹具中，并在该环氧化夹具中注入0.5％-5％(v/v)3-甘油丙基三甲氧基硅烷(GPTMS)的甲苯溶液中，在室温至70℃的温度条件下密闭浸泡24h-72h。
具体地，3-甘油丙基三甲氧基硅烷(GPTMS)在甲苯中的体积比(v/v)可以为0.5％、0.8％、1％、1.5％、2％、2.5％、3％、3.5％、4％、4.5％、5％等；甲苯可选用超干甲苯；浸泡温度为室温(一般来说在25℃左右，例如冬季16℃～18℃，夏季24℃～26℃)、30℃、35℃、40℃、45℃、50℃、55℃、60℃、65℃、70℃；浸泡时间可以为24h、30h、36h、40h、48h、60h、72h等。
较佳地，为取得较好的环氧化效果，可将亲水层表面形成有含羟基的修饰基团的第一基底按照夹具构造竖直放入环氧化夹具中，并在该环氧化夹具中注入3％(v/v)3-甘油丙基三甲氧基硅烷(GPTMS)的超干甲苯溶液中，在70℃的温度条件下密闭浸泡24h。
可选地，在执行上述步骤S102后，还需要倒掉反应液，采用去离子水冲洗至少两遍第一基底，再采用去离子水对第一基底超声清洗5min，去除环氧 化过程中第一基底上沾染的杂质。随后采用氮气吹干超声清洗的第一基底，并将其保存在氮气氛围中，完成修饰，以备后续用于蛋白偶联。
可选地，在本公开实施例提供的上述修饰方法中，步骤S101构成检测芯片的第一基底上的亲水层进行表面活化处理，具体可以通过以下方式进行实现：
将具有亲水层的第一基底按照夹具构造竖直放入活化夹具中，现场配制食人鱼溶液(浓硫酸：30％双氧水＝1:3)，无需冷却，缓慢倒入上述活化夹具中，在70℃-90℃的条件下水浴搅拌12h-24h。
具体地，水浴搅拌的温度为70℃、72℃、75℃、80℃、83℃、85℃、88℃、90℃等，水浴搅拌的时间为12h、15h、18h、20h、21h、24h等。
可选地，在执行上述步骤S101后，还需要倒掉食人鱼溶液并妥善处理，采用去离子水冲洗至少两遍第一基底，再采用去离子水对第一基底超声清洗10min，去除活化过程中沾染在第一基底表面的杂质，最后氮气吹干第一基底备用。
可选地，在本公开实施例提供的上述修饰方法中，在执形步骤S101对构成检测芯片的第一基底上的亲水层进行表面活化处理之前，还可以执行以下步骤：
依次采用丙酮、乙醇、去离子水作为溶液对具有亲水层的第一基底进行超声清洗，并采用氮气对最终超声清洗后的第一基底吹干备用。
具体地，在母版玻璃基底上制作亲水层等膜层后，在将0.5mm厚度的母版玻璃基底切割成1in×3in标准载玻片大小后作为第一基底，装入清洗夹具中进行预清洗，清洗工艺流程依次包括：采用丙酮超声清洗10min，采用乙醇超声清洗10min，采用去离子水超声清洗10min，再次采用去离子水超声清洗10min。这样可以将第一基底的油脂等其他杂质清洗掉。清洗结束后，氮气吹干第一基底备用。
可选地，在本公开实施例提供的上述修饰方法中，在采用丙酮作为溶液对具有亲水层的第一基底进行超声清洗之前，还可以执行以下步骤：
在第一基底上形成多个点样平台；
在各点样平台上分别形成亲水层。
相关技术中，检测芯片的第一基底具有一定程度的疏水性，而生物领域的待检测溶液所含溶剂一般为水，因此，待检测溶液与第一基底之间的接触不好，不利于待检测溶液中的标志物与检测芯片进行结合。氧化硅具有亲水性，使得本公开提供的检测芯片可以更好地实现与待检测溶液的紧密接触，提升检测效果。
可选地，在本公开实施例提供的上述修饰方法中，上述在各点样平台上分别形成亲水层，具体可以通过以下方式进行实现：
采用等离子体增强化学的气相沉积法(PECVD)，在390℃的温度条件下，在各点样平台所在层上沉积一层厚度为300nm的氧化硅层；
并对氧化硅层进行刻蚀，保留覆盖各点样平台所在区域的氧化硅层，得到亲水层。
采用上述方法所形成氧化硅材质的亲水层，具有膜厚均一性好、膜层针孔少、不易龟裂等优点，使得待检测溶液与检测芯片的接触效果更好。
值得注意的是，上述修饰过程中出现的时间和温度等参数仅是举例说明，并不作为限定条件。
基于同一发明构思，本公开实施例还提供了一种检测芯片，如图2a和图2b所示，包括：第一基底201，位于第一基底201上的点样平台202，以及覆盖点样平台202的亲水层203，亲水层203的表面具有含氨基的修饰基团203’；其中，含氨基的修饰基团采用本公开实施例提供的上述修饰方法获得。
图2a为本公开一些实施例提供的一种检测芯片的平面示意图，图2b为如图2a所示的检测芯片的剖面示意图。
具体地，在亲水层203表面的修饰基团203’采用本公开实施例提供的上述修饰方法获得，修饰基团203’上具有环氧基，该环氧基可与目标抗原或抗体结合。具体地，在图3中，颜色较浅的区域(即图片中下半部分)示出了荧光标记的抗体与修饰基团203’中环氧基之间连接效率的测试结果。结果证 明：本公开提供的检测芯片表面较高的环氧基接枝密度，致使在其与抗体等蛋白结合时，表现出超高的蛋白偶联效率和超低的非特异性吸附。
具体地，第一基底201起支撑、保护等作用，可以为塑料基底、玻璃基底或硅基底，也可以为其他适用的基底，本公开的实施例对此不作限制。例如，当采用玻璃基底时，成本较低；当采用硅基底时，性能较好。例如，第一基底201为透明基底(例如玻璃基底)，以使光线可以无损或损耗较低地穿过该透明基底，从而可以提高后续光学检测的准确性，降低对另行提供的光学检测设备的要求。
具体地，多个点样平台202位于第一基底201上，点样平台202例如用于为目标抗原或抗体提供附着位置。例如，在一些示例中，点样平台202为凸台形状，从而便于附着在其上的目标抗原或抗体与流过点样平台202的待检测溶液中的标志物结合或反应。当然，本公开的实施例不限于此，点样平台202也可以为凹槽形状或者平面形状，只要能保证附着在点样平台202上的目标抗原或抗体能够与流过点样平台202的待检测溶液接触并能与其中的标志物结合即可。需要说明的是，本公开的实施例中，点样平台202的数量不受限制，可以为任意个数，例如根据需要检测的标志物的种类或浓度而定。
可选地，在本公开实施例提供的上述检测芯片中，如图2a和图2b所示，还可以包括：位于第一基底201上的导流坝204，导流坝204沿第一路径延伸且位于相邻的点样平台202之间；亲水层203覆盖导流坝204，且亲水层203覆盖导流坝204的部分与覆盖点样平台202的部分相互独立。
具体地，导流坝204位于第一基底201上，导流坝204沿第一路径延伸且位于相邻的点样平台202之间。导流坝204对检测芯片的内部空间的流场产生影响，从而可以提高不同点样平台202所在位置的流速均一性，提高流场沿第一路径的平行性，提高流场的稳定性，使得待检测溶液能够稳定均匀地流过点样平台202所在的区域。因此，待检测溶液中的标志物能够与点样平台202上的目标抗原或抗体充分结合或反应，从而有助于提高免疫检测结果的准确度和可靠度。并且，该检测芯片还具有体积小、高通量等特点。
例如，在一些示例中，如图2a所示，多个点样平台202排列为多列，第一路径沿列方向Z延伸。每列点样平台202的两侧均设置有导流坝204，且多个导流坝204彼此平行。当待检测溶液沿列方向Z流过多个点样平台202时，在导流坝204的作用下，待检测溶液流动所形成的流场沿列方向Z的平行性得到提高，使得待检测溶液能够稳定均匀地沿列方向Z流动。
需要说明的是，本公开的实施例中，第一路径不限于沿列方向Z延伸，也可以沿其他任意的方向延伸。并且，第一路径可以沿直线延伸，也可以沿曲线延伸，这可以根据待检测溶液的流动路径和流动方式而定，本公开的实施例对此不作限制。例如，当第一路径沿直线延伸时，导流坝204也沿直线延伸；当第一路径沿曲线延伸时，导流坝204也沿曲线延伸。相应地，多个点样平台202可以沿直线排列为多列，也可以沿曲线排列为多组，位于相邻的点样平台202之间的导流坝204沿着点样平台202的排列方向延伸即可。
需要说明的是，本公开的实施例中，可以在每列点样平台202的两侧设置导流坝204，也可以仅在某些列点样平台202的两侧设置导流坝204，这可以根据需要达到的流场平行性而定，本公开的实施例对此不作限制。
例如，当每列点样平台202的两侧均设置有导流坝204时(例如，点样平台202和导流坝204设置为如图2a所示的情形时)，流场具有较好的平行性。若某个点样平台202上的目标抗原或抗体意外脱落，该脱落的目标抗原或抗体会沿着列方向Z流动，也即是，在该列点样平台202所在的区域内流动，因此不会影响其他列点样平台202，从而可以避免不同检测位点(即点样平台202)之间的串扰，避免交叉污染。
例如，导流坝204的数量不受限制，可以为一个或多个。例如，在一些示例中，若多个点样平台202仅排列为两列，则可以仅设置一个导流坝204，且使该导流坝204位于两列点样平台202之间，从而可以在减少导流坝204数量的同时使流场具有较好的平行性。
例如，导流坝204在垂直于第一路径(例如列方向Z)的方向上的截面形状可以为矩形、正方形、梯形、半圆形或其他适用的形状，例如可以为规则 形状或不规则形状，本公开的实施例对此不作限制。例如，不同的截面形状会对流场产生不同程度的影响，因此可以根据流场的特点确定导流坝204的截面形状。
例如，导流坝204和点样平台202均可以采用光刻胶制备，该光刻胶例如为可厚膜刻蚀的光刻胶。例如，在一些示例中，可以在同一个构图工艺中形成导流坝204和点样平台202，以简化生产工艺。
可选地，在本公开实施例提供的上述检测芯片中，如图2b所示，还可以包括：位于第一基底201上的疏水层205，点样平台202和导流坝204均位于疏水层205上。通过设置疏水层205，可以使待检测溶液在检测芯片中更容易流动，并且可以使待检测溶液中的标志物不易附着在第一基底201上，以避免待检测溶液中的标志物被浪费。
例如，疏水层205的材料为树脂或硅氮化物。当然，疏水层205也可以采用其他合适的无机或有机材料制备，只要保证疏水层205远离第一基底201的一侧具有疏水性即可。例如，疏水层205可以采用疏水性材料直接制备。又例如，疏水层205可以采用不具有疏水性的材料制备，在这种情况下，需要在该疏水层205远离第一基底201的表面进行疏水化处理，从而使该疏水层205远离第一基底201的表面具有疏水性。
可选地，在本公开实施例提供的上述检测芯片中，如图2b所示，还可以包括：与第一基底201相对设置的第二基底206，且第二基底206与第一基底201间隔开以提供检测空间(即液体流动空间)。第二基底206的材料可以与第一基底201的材料相同或不同，本公开的实施例对此不作限制。例如，第二基底206为透明基底(例如玻璃基底)，以使光线可以无损或损耗较低地穿过该透明基底，从而可以提高后续光学检测的准确性，降低对另行提供的光学检测设备的要求。
可选地，在本公开实施例提供的上述检测芯片中，如图2a所示，还可以包括进样口207、出样口207’和检测区域001。例如，多个点样平台202位于检测区域001中，多个点样平台202排列为多列，进样口207和出样口207’ 沿列方向Z分布在检测区域001的两侧(例如位于图中的上下侧)。例如，待检测溶液可以通过微量注射泵或通过移液枪注射到进样口207，在沿着列方向Z流经多个点样平台202之后，从出样口207’流出。例如，进样口207和出样口207’沿列方向Z轴对称或中心对称分布在检测区域001的两侧，从而可以进一步提高流场的平行性和稳定性。当然，本公开的实施例不限于此，进样口207和出样口207’也可以呈不对称分布，这可以根据流场的特性和实际需求而定。
具体地，进样口207和出样口207’设置在第二基底206上。例如，如图2b所示，进样口207可以为贯穿第二基底206的通孔，该通孔在平行于第二基底206的截面上的形状可以为圆形、矩形、正方形等任意适用的形状。类似地，出样口207’也可以为贯穿第二基底206的通孔，且出样口207’在平行于第二基底206的截面上的形状可以与进样口207的形状相同或不同。需要说明的是，图2b仅示意性地示出进样口207在第二基底206上的设置方式，但进样口207和点样平台202的相对位置并不受图2b所示的情形的限制。
可选地，在本公开实施例提供的上述检测芯片中，如图2b所示，还可以包括：位于第一基底201和第二基底206之间的封框胶208，封框胶208作为支撑部件围绕导流坝204和多个点样平台202。具体地，第一基底201、第二基底206和封框胶208共同限定待检测溶液的流动空间。例如，在一些示例中，可以在封框胶208中混合隔垫物，从而可以通过隔垫物控制第一基底201和第二基底206之间的间距，并且加强该检测芯片的抗压强度。
可选地，在本公开实施例提供的上述检测芯片中，如图2b所示，导流坝204沿垂直于第一基底201方向的高度h1大于点样平台202沿垂直于第一基底201方向的高度h2，从而可以更好地起到调节流场平行性的作用。具体地，导流坝204的高度h1为第一基底201与第二基底206之间的距离h0的30％至60％，例如为40％或50％。例如，在一些示例中，第一基底201与第二基底206的距离h0为100微米，导流坝204的高度h1为50微米，点样平台202的高度h2为3微米，h1和h2的高度差异较大，可以更好地调节流场的平行 性。例如，在一些示例中，当导流坝204在垂直于第一路径的方向(例如列方向Z)上的截面形状为半圆形时，该半圆形的半径可以大于或等于第一基板110与第二基底206之间的距离h0的一半。
需要说明的是，本公开的实施例中，高度h1既可以指导流坝204自身的高度，又可以指导流坝204和亲水层203的高度之和，同样地，高度h2既可以指点样平台202自身的高度，又可以指点样平台202和亲水层203的高度之和。
具体地，在使用本公开实施例提供的上述检测芯片时，首先在第一基底201和第二基底206对盒之前，使目标抗原或抗体附着在点样平台202上。例如，可以将包含目标抗原或抗体的液体滴在点样平台202上，由于存在修饰基团203’，因此目标抗原或抗体与修饰基团203’结合，从而可以附着在点样平台202上。然后，采用封框胶208将第一基底201和第二基底206对盒。接着，从进样口207注入待检测溶液，使待检测溶液流过检测区域001，并从出样口207’流出。待检测溶液中的标志物在流经点样平台202时，会与附着在点样平台202上的目标抗原或抗体结合或反应。然后，可以将例如牛血清白蛋白(BSA)溶液注入该检测芯片，以对检测芯片的内部空间进行清洗，从而减少检测芯片的内部空间中除点样平台202之外的部分对待检测溶液的吸附，进而提高后续检测的准确性。最后，采用光学检测设备对该检测芯片进行光学检测，从而得到免疫检测结果。
可选地，在本公开实施例提供的上述检测芯片中，如图2a和图2b所示，还可以包括定位部件209，定位部件209用于与另行提供的光学检测设备配合以实现检测芯片的定位，从而便于光学检测设备对检测芯片进行光学检测。例如，定位部件209设置在第一基底201上，且被疏水层205覆盖。定位部件209可以采用金属材料制备，例如钼(Mo)，也可以采用不透光的绝缘材料制备，本公开的实施例对此不作限制。
例如，在一些示例中，进行定位时，光学检测设备的光学定位器件发出用于定位的光，若检测芯片位于预设的位置，由于定位部件209不透光，因 此设置在相应位置的传感器检测到的光强很小或者为零，从而可以判断该检测芯片位于预设的位置，以实现定位。定位完成后，可以采用光学检测设备对特定位点进行光学检测及信号读取。例如，该特定位点为某个或某些点样平台202，其上附着有目标抗原或抗体。
具体地，定位部件209位于检测区域001之外，例如进一步位于第一基底201、第二基底206和封框胶208形成的液体流动空间之外，以避免影响光学检测。例如，在一些示例中，如图2a所示，多个定位部件209设置在检测芯片的一侧且靠近检测芯片的边缘。通过设置多个定位部件209，可以提高定位精度。当然，本公开的实施例不限于此，定位部件209的设置位置可以根据实际需求而定，例如可以设置在检测芯片的任意一侧、任意两侧、四周或其他合适的位置，这可以根据与之配合的光学检测设备的定位方式而定。定位部件209的数量也不受限制，可以为任意数量，这可以根据实际需求而定。
基于同一发明构思，本公开实施例还提供了一种反应系统，包括：本公开实施例提供的上述检测芯片。由于该反应系统解决问题的原理与上述检测芯片解决问题的原理相似，因此，本发明实施例提供的该反应系统的实施可以参见本发明实施例提供的上述检测芯片的实施，重复之处不再赘述。
综合上述描述可知，在本公开实施例提供的上述检测芯片及其修饰方法中，通过对检测芯片的亲水层活化处理，使得亲水层表面形成含羟基的修饰基团；之后采用含氧基化合物的溶液，对亲水层进行表面环氧化处理，在亲水层的表面形成了高密度含环氧基的修饰基团。也就是说，上述一系列表面化学反应，使得亲水层表面生成了通过化学键连接的环氧基，解决了相关技术中检测芯片上包含环氧基的化合物薄膜易脱落的问题，提高了后续蛋白偶联效率。适用于体外诊断、药性筛选、细胞培养、免疫荧光检测等所需的微流控体系。另外，本公开提供的上述修饰方法是基于玻璃基底进行的，既便于量产，又有效降低了成本。此外，由上述描述可见，本公开提供的上述修饰方法操作流程相对简易，便于提高效率。
需要说明的是，本公开通过上述实施例来说明本公开的工艺方法，但本 公开并不局限于上述工艺步骤，即不意味着本公开必须依赖上述工艺步骤才能实施。所属技术领域的技术人员应该明了，对本公开的任何改进，对本公开所选用原料的等效替换及辅助成分的添加、具体方式的选择等，均落在本公开的保护范围和公开范围之内。

Claims (15)

  1. 一种检测芯片的修饰方法，其中，包括：
    对构成检测芯片的第一基底上的亲水层进行表面活化处理，在所述亲水层的表面形成含羟基的修饰基团；所述亲水层覆盖位于所述第一基底上的点样平台；
    采用含氧基化合物的溶液，对表面形成有含羟基的修饰基团的所述亲水层进行表面环氧化处理，在所述亲水层的表面形成含环氧基的修饰基团。
  2. 如权利要求1所述的修饰方法，其中，所述采用含氧基化合物的溶液，对表面形成有含羟基的修饰基团的所述亲水层进行表面环氧化处理，具体包括：
    将所述亲水层表面形成有含羟基的修饰基团的所述第一基底放入0.5％-5％(v/v)3-甘油丙基三甲氧基硅烷的甲苯溶液中，在室温至70℃的温度条件下密闭浸泡24h-72h。
  3. 如权利要求2所述的修饰方法，其中，所述将所述亲水层表面形成有含羟基的修饰基团的所述第一基底放入0.5％-5％(v/v)3-甘油丙基三甲氧基硅烷的甲苯溶液中，在室温至70℃的温度条件下密闭浸泡24h-72h，具体包括：
    将所述亲水层表面形成有含羟基的修饰基团的所述第一基底放入3％(v/v)3-甘油丙基三甲氧基硅烷的甲苯溶液中，在70℃下密闭浸泡24h。
  4. 如权利要求1所述的修饰方法，其中，所述对构成检测芯片的第一基底上的亲水层进行表面活化处理，具体包括：
    将具有所述亲水层的所述第一基底放入食人鱼溶液中，在70℃-90℃的温度条件下浸泡12h-24h；所述食人鱼溶液由浓硫酸和30％双氧水构成，其中，所述浓硫酸与所述30％双氧水的体积比为1:3。
  5. 如权利要求1-4任一项所述的修饰方法，其中，在所述表面活化处理和所述表面环氧化处理之后，均对所述第一基底进行如下处理：
    采用去离子水对所述第一基底冲洗至少两遍；
    将冲洗后的所述第一基底在去离子水中超声清洗处理后，氮气吹干备用。
  6. 如权利要求1-4任一项所述的修饰方法，其中，在对构成检测芯片的第一基底上的亲水层进行表面活化处理之前，还包括：
    依次采用丙酮、乙醇、去离子水作为溶液对具有所述亲水层的所述第一基底进行超声清洗，并采用氮气对最终超声清洗后的所述第一基底吹干备用。
  7. 如权利要求6所述的修饰方法，其中，在所述采用丙酮作为溶液对具有所述亲水层的所述第一基底进行超声清洗之前，还包括：
    在所述第一基底上形成多个点样平台；
    在各所述点样平台上分别形成所述亲水层。
  8. 如权利要求7所述的修饰方法，其中，所述在各所述点样平台上分别形成所述亲水层，具体包括：
    采用等离子体增强化学的气相沉积法，在390℃的温度条件下，在各所述点样平台所在层上沉积一层厚度为300nm的氧化硅层；
    并对所述氧化硅层进行刻蚀，保留覆盖各所述点样平台所在区域的氧化硅层，得到所述亲水层。
  9. 一种检测芯片，其中，包括：
    第一基底；
    点样平台，位于所述第一基底上；
    亲水层，位于所述第一基底上且覆盖所述点样平台，所述亲水层的表面具有含羧基的修饰基团；其中，
    所述含羧基的修饰基团采用如权利要求1-8任一项所述的修饰方法获得。
  10. 如权利要求9所述的检测芯片，其中，还包括：
    导流坝，位于所述第一基底上，所述导流坝沿第一路径延伸且位于相邻的所述点样平台之间；
    所述亲水层覆盖所述导流坝，且所述亲水层覆盖所述导流坝的部分与覆盖所述点样平台的部分相互独立。
  11. 如权利要求10所述的检测芯片，其中，所述导流坝沿垂直于所述第 一基底方向的高度大于所述点样平台沿垂直于所述第一基底方向的高度。
  12. 如权利要求10所述的检测芯片，其中，还包括：
    疏水层，所述疏水层位于所述第一基底上，所述点样平台和所述导流坝均位于所述疏水层上。
  13. 如权利要求10-12任一项所述的检测芯片，其中，还包括：
    第二基底，所述第二基底与所述第一基底相对设置，且与所述第一基底间隔开以提供检测空间。
  14. 如权利要求13所述的检测芯片，其中，所述第一基底和/或所述第二基底为玻璃基底。
  15. 如权利要求13所述的检测芯片，其中，还包括：
    封框胶，所述封框胶位于所述第一基底和所述第二基底之间，且围绕所述导流坝和所述多个点样平台。
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