WO2005113129A1 - Procede sol-gel de fonctionnalisation d'une surface d'un substrat solide - Google Patents
Procede sol-gel de fonctionnalisation d'une surface d'un substrat solide Download PDFInfo
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- WO2005113129A1 WO2005113129A1 PCT/FR2005/050317 FR2005050317W WO2005113129A1 WO 2005113129 A1 WO2005113129 A1 WO 2005113129A1 FR 2005050317 W FR2005050317 W FR 2005050317W WO 2005113129 A1 WO2005113129 A1 WO 2005113129A1
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y30/00—Nanotechnology for materials or surface science, e.g. nanocomposites
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- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
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- B01J19/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
- B01J19/0046—Sequential or parallel reactions, e.g. for the synthesis of polypeptides or polynucleotides; Apparatus and devices for combinatorial chemistry or for making molecular arrays
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B05—SPRAYING OR ATOMISING IN GENERAL; APPLYING FLUENT MATERIALS TO SURFACES, IN GENERAL
- B05D—PROCESSES FOR APPLYING FLUENT MATERIALS TO SURFACES, IN GENERAL
- B05D1/00—Processes for applying liquids or other fluent materials
- B05D1/18—Processes for applying liquids or other fluent materials performed by dipping
- B05D1/185—Processes for applying liquids or other fluent materials performed by dipping applying monomolecular layers
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- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y40/00—Manufacture or treatment of nanostructures
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- 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
- G01N33/54353—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals with ligand attached to the carrier via a chemical coupling agent
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- B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
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- B01J2219/00387—Applications using probes
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- B01J2219/00277—Apparatus
- B01J2219/00497—Features relating to the solid phase supports
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- B01J2219/00277—Apparatus
- B01J2219/00497—Features relating to the solid phase supports
- B01J2219/00527—Sheets
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- B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
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- B01J2219/00583—Features relative to the processes being carried out
- B01J2219/00596—Solid-phase processes
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- B—PERFORMING OPERATIONS; TRANSPORTING
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- B01J2219/00583—Features relative to the processes being carried out
- B01J2219/00603—Making arrays on substantially continuous surfaces
- B01J2219/00639—Making arrays on substantially continuous surfaces the compounds being trapped in or bound to a porous medium
- B01J2219/00641—Making arrays on substantially continuous surfaces the compounds being trapped in or bound to a porous medium the porous medium being continuous, e.g. porous oxide substrates
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
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- B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
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- B01J2219/00583—Features relative to the processes being carried out
- B01J2219/00603—Making arrays on substantially continuous surfaces
- B01J2219/00639—Making arrays on substantially continuous surfaces the compounds being trapped in or bound to a porous medium
- B01J2219/00644—Making arrays on substantially continuous surfaces the compounds being trapped in or bound to a porous medium the porous medium being present in discrete locations, e.g. gel pads
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- B01J2219/00603—Making arrays on substantially continuous surfaces
- B01J2219/00659—Two-dimensional arrays
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- B—PERFORMING OPERATIONS; TRANSPORTING
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- B01J2219/00583—Features relative to the processes being carried out
- B01J2219/00603—Making arrays on substantially continuous surfaces
- B01J2219/00677—Ex-situ synthesis followed by deposition on the substrate
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- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
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- B01J2219/0068—Means for controlling the apparatus of the process
- B01J2219/00686—Automatic
- B01J2219/00691—Automatic using robots
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
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- B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
- B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
- B01J2219/00718—Type of compounds synthesised
- B01J2219/0072—Organic compounds
- B01J2219/00722—Nucleotides
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
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- B—PERFORMING OPERATIONS; TRANSPORTING
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- B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
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- B01J2219/00718—Type of compounds synthesised
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- C—CHEMISTRY; METALLURGY
- C40—COMBINATORIAL TECHNOLOGY
- C40B—COMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES
- C40B40/00—Libraries per se, e.g. arrays, mixtures
- C40B40/04—Libraries containing only organic compounds
- C40B40/06—Libraries containing nucleotides or polynucleotides, or derivatives thereof
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- C—CHEMISTRY; METALLURGY
- C40—COMBINATORIAL TECHNOLOGY
- C40B—COMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES
- C40B40/00—Libraries per se, e.g. arrays, mixtures
- C40B40/04—Libraries containing only organic compounds
- C40B40/10—Libraries containing peptides or polypeptides, or derivatives thereof
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- C—CHEMISTRY; METALLURGY
- C40—COMBINATORIAL TECHNOLOGY
- C40B—COMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES
- C40B40/00—Libraries per se, e.g. arrays, mixtures
- C40B40/04—Libraries containing only organic compounds
- C40B40/12—Libraries containing saccharides or polysaccharides, or derivatives thereof
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- C—CHEMISTRY; METALLURGY
- C40—COMBINATORIAL TECHNOLOGY
- C40B—COMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES
- C40B60/00—Apparatus specially adapted for use in combinatorial chemistry or with libraries
- C40B60/14—Apparatus specially adapted for use in combinatorial chemistry or with libraries for creating libraries
Definitions
- the invention relates to a sol-gel process for functionalizing a surface of a solid substrate.
- the technical field of the invention can be defined as that of the functionalization of a surface of a solid substrate with a view to providing this surface with chemical functions capable of reacting with chemical or biological molecules, in other words of functions chemicals capable of immobilizing, catching on, grafting biological or chemical molecules.
- the invention finds its application for example in the context of the preparation of chemical and biological sensors, in particular the production of DNA chips, oligonucleotides, sugars, peptides, and small organic molecules.
- the invention also finds its application in the preparation of fluidic microsystems requiring a functionalization of their walls.
- a functional layer that is to say a layer carrying chemical functions capable of to graft biological or chemical molecules.
- a functional layer that is to say a layer carrying chemical functions capable of to graft biological or chemical molecules.
- layers functional there are currently two types of layers functional, namely on the one hand the monomolecular layers and on the other hand the thick layers.
- Monomolecular layers are layers whose arrangement is controlled and which are also called self-assembled monolayers ("Self Assembled Monolayers" or "SAM" in English).
- These layers are generally obtained by a process involving the grafting of a silane in a slightly hydrated organic medium in order to avoid a high rate of hydrolysis of the silane leading to the formation of aggregates in solution and to thick unorganized layers.
- the process for preparing the monomolecular layers has the disadvantage of commonly using aggressive and / or toxic organic solvents such as aromatic solvents, alkanes, or chlorinated solvents.
- the preparation of such layers is described in particular in document FR-A-2 818 662.
- Thick layers are layers whose thickness is generally from a few nm to several microns, for example from 10 nm to 10 ⁇ m and their nature is more diverse.
- the thick layers can be prepared from organic polymers as described in document OA-01/67129; from mixtures of organic and inorganic organosilylated precursors; or from silsesquioxanes ("SSQ") comprising functional groups of amino type.
- SSQ silsesquioxanes
- the thick layers described in the prior art have several drawbacks.
- organic polymers such as nylon often present non-specific adsorption problems.
- Silsesquioxanes comprising an amino function do not directly allow the covalent attachment of biological molecules such as commercial oligonucleotides.
- the object of the invention is to provide a method for functionalizing a surface of a substrate which meets, among other things, the needs listed above.
- the object of the present invention is also to provide a method for functionalizing a surface of a substrate which does not have the drawbacks, defects, limitations and disadvantages of the methods of the prior art, which allows the substrate to be provided with a thick, uniform layer of controlled thickness and which meets the criteria and requirements indicated above.
- the support is a biochip and where the surface is used to graft biological molecules or probes, the support must guarantee that the signal obtained during fluorescence measurements for example after hybridization of the probes is of an order of magnitude sufficient .
- a sol-gel process for functionalizing a surface of a solid substrate, optionally cleaned and / or activated, in which the following steps are carried out: a) depositing on said surface, at room temperature, a solution in a mixture of water and a volatile organic solvent, miscible with water, of an acidic or basic catalyst, and of a silane or siloxane carrier at least one chemical function A allowing the immobilization of biological or chemical molecules and / or capable of being transformed into a chemical function A 'allowing the immobilization of biological or chemical molecules and at least one chemical function B d 'attachment capable of clinging chemically, or mechanically, to the surface; b) simultaneously with step a), and / or immediately after this step, the volatile organic solvent is evaporated, whereby the solution is transforms into a wet gel forming a thick gelled layer; then c) the thick gelled layer is dried, whereby a thick layer is obtained which is attached chemically
- the method according to the invention can be defined as a “sol-gel” type method which implements a specific solution of a specific silane or siloxane to functionalize a surface.
- a process for functionalizing a surface using such a solution of such a precursor is neither described nor suggested in the prior art.
- the method according to the invention meets the needs mentioned above, provides a solution to the problems of the methods of the prior art and remedies the drawbacks, defects, limitations and disadvantages of the methods of the prior art.
- the method according to the invention makes it possible to functionalize a support, whatever it is, quickly and uniformly, with reduced energy expenditure and at low cost.
- the method according to the invention uses a functional silane or siloxane solution in a mixture of water and a volatile organic solvent miscible with water, for example an alcohol such as ethanol or isopropanol, in presence of an acidic or basic catalyst.
- a functional silane or siloxane solution in a mixture of water and a volatile organic solvent miscible with water, for example an alcohol such as ethanol or isopropanol, in presence of an acidic or basic catalyst.
- organic solvents such as toluene, alkanes or chlorinated solvents, commonly used in the preparation of monomolecular layers. These solvents are generally more aggressive and / or toxic than the alcohols used in the sol-gel processes.
- the method according to the invention is compatible with many materials whose use was prohibited in the methods of the prior art such as plastics (for example plates to wells whose English name is MTP or "MicroTitration Plate"), resins (photosensitive and masking resins), glues (for example acrylic, epoxy, PU, ...), etc.
- the process according to invention is applicable to large areas of up to several m 2 and the thick layer deposited has a thickness generally in the range of a few tens (for example 2, 3, 4, 5, 10) from nanometers to a few tens (for example 2, 3, 4, 5, 10) of microns and this thickness is controlled very precisely, to within a few percent, in particular in order to be able to produce layers having optical properties.
- the deposition, the contacting of step a) is generally carried out using a liquid phase deposition technique known to those skilled in the art which is a simple, proven, and reliable technique.
- This liquid phase deposition technique can be chosen for example from centrifugation ("spin-coating” in English), dip-shrinkage (“dip- coating “in English), laminar flow coating", and its variants roller coating ("roller coating") and curtain coating ("curtain coating”), spraying ( “spray coating” in English), printing (“printing”) for example by implementing the technique of jet printing (“jet printing”), and pipetting ("spotting").
- process of the invention in step (a), and also generally in step (b) is generally carried out at room temperature, namely generally from 15 to 35 ° C., which is significantly lower than the neighboring temperature of 80 ° C. implemented during the deposition step of the processes for preparing layers of the "SAM" type.
- room temperature namely generally from 15 to 35 ° C., which is significantly lower than the neighboring temperature of 80 ° C. implemented during the deposition step of the processes for preparing layers of the "SAM" type.
- the energy consumption caused by the process é according to the invention is therefore significantly lower than that of the methods of the prior art, therefore the cost is also lower.
- the duration of the entire process of the invention is significantly shorter than that of the processes of the prior art.
- the total duration of steps a), b), c) of the process of the invention is generally less than or equal to 1 hour, for example it is 15 to 30 minutes. This is one of the advantages of the process of the invention that it can be carried out in a very short time, at least ten times shorter than the time of the process making it possible to prepare "SAM" type layers which is generally close to 16 hours. Furthermore, the duration of the contacting of the substrate with the solution during step a) does not influence the quality of the functionalization, unlike the methods of the prior art.
- this duration of deposition, of contacting is generally reduced to the minimum time necessary to spread the solution over the entire surface to be functionalized, this surface to be functionalized being able to correspond to the entire surface. of the substrate or only part of it. This duration depends mainly on the deposition technique chosen and the size and shape of the substrate.
- This duration is generally one or a few seconds (for example 2.5 to 10 seconds) for processes such as centrifugation, printing and pipetting to a few minutes (for example 2.5 to 10 minutes) for processes such as dip-shrinkage, laminar coating, and spraying.
- This duration is, in all cases, very shorter than the durations used in the prior art for comparable steps.
- the duration of step b) is generally less than or equal to 10 minutes, for example it is 1 to 5 minutes.
- This step b) is advantageously partially simultaneous with step a), that is to say that it begins while step a) is not yet completed, and that it still continues after the completion of step a), which saves additional time.
- the drying of the gelled layer carried out in step c) is generally a rapid drying of a duration generally less than or equal to 15 minutes, preferably of a duration of 1 to 10 minutes, for example 5 minutes.
- This drying is generally carried out at a moderate temperature, for example from 25 to 60 ° C.
- a step d ) baking or annealing at a higher temperature than the drying temperature can generally be from 70 to 200 ° C. and the duration of this annealing can range from one to a few minutes (for example 1, 2 or 5 minutes), to one hour.
- the annealing temperature can be easily chosen by a person skilled in the art depending on the substrate.
- the chemical function A is a reactive function with respect to the nucleophilic groups, such as an epoxy function. This type of function has the advantage of allowing direct attachment of biological and chemical molecules.
- said silane or siloxane corresponds to the following formula (I):
- Ri, R 2 and R 3 which are identical or different, represent a linear or branched alkyl group of 1 to 6 carbon atoms such as for example methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, or t-butyl; and Y represents a hydrocarbon chain such as a linear or branched alkyl chain of 1 to 20 carbon atoms in which one or more carbon atoms can be optionally replaced by an oxygen, sulfur or nitrogen atom.
- silane or siloxane of formula (I) is 5, 6-epoxyhexyltriethoxysilane (EHTEOS) available for example from ABCR under the reference SIE 4575.0.
- Other silanes or siloxanes are for example 2- (3, 4 epoxycyclohexyl) ethyl-trimethoxysilane, 2- (3, 4 epoxycyclohexyl) ethyltriethoxysilane, (3-glycidyloxypropyl) methyl-diethoxysilane, (3-glycidyloxypropyl) trimethoxysilane (GLYMO), (3-glycidoxypropyl) bis (trimethylsiloxy) methylsilane, (3-glycidoxypropyl) dimethylethoxysilane, (3-glycidoxypropyl) methyldimethoxysilane, (3-glycidoxypropyl) pentamethyldisiloxane.
- the catalyst can be an acid catalyst.
- the catalyst can be a basic catalyst.
- the basic catalyst is generally chosen from ammonia, and primary, secondary, tertiary and aromatic amines.
- the catalyst is a basic catalyst is selected from tri (alkyl Ci-C ⁇ 0) amines such as triethylamine (TEA).
- the organic solvent miscible in the solution of step a) is an alcohol such as an aliphatic alcohol comprising from 1 to 12 carbon atoms, for example ethanol or isopropanol.
- the mass proportions of alcohol, such as ethanol, and of water in the mixture of water and alcohol are from 0.05% to 10% of water relative to the alcohol.
- the relative amounts of water, of silane or siloxane, such as EHTEOS, and of catalyst such as TEA defined by the parameters: ⁇ [ 2 0], perennial[catalyst] s
- the epoxy function allows direct attachment of chemical or biological molecules.
- said function A ′ is an aldehyde function.
- the solution can optionally be subjected to maturation.
- the invention further relates to a process for preparing a solid substrate comprising a surface on which are immobilized, grafted, chemical or biological molecules (generally called probes) in which a surface of a solid substrate is functionalized by the functionalization process as described above, then chemical or biological molecules are reacted, without washing the functionalized surface, with said chemical functions A or A ′ carried by the thick layer.
- said chemical or biological molecules are molecules comprising nucleophilic groups such as, for example, amine, hydroxyl, phenol, oxyamine, thiol functions, or their anionic derivatives.
- the probes can be immobilized on the functionalized surface: - by soaking the substrate in a solution containing the chemical or biological molecules to be immobilized; - By depositing a drop of this same solution on the substrate, this deposition can be done manually or by means of a deposition robot.
- the irreversible immobilization of biological or chemical molecules is carried out by the creation of a covalent bond during the nucleophilic attack reaction between the chemical function A or A 'and the nucleophilic group carried by the biological or chemical molecules to be immobilized.
- a second characteristic of the surfaces obtained, on which the chemical or biological molecules deposited by the process of the invention are immobilized is to give, surprisingly, very homogeneous "spots" and of smaller size than art. prior. This constitutes an advantage, because in fact, obtaining spots of smaller diameter makes it possible to increase the density of probes on the surface and therefore, makes it possible either to reduce the size of the device (with identical complexity), or to increase the number of probes deposited (on an equal surface).
- the invention further relates to the use of the thick layer obtained by the process described above, at the end of step c) (dried thick layer) or d) (cooked thick layer) as an optical layer.
- optical layer or layer with optical properties is generally meant a layer generally thick from a few tens to a few hundred nm, which has the main property of creating interference.
- This layer can be used alone or it can be used in a stack of several optical layers (for example from 2 to 30 layers), the layers of the stack can all be layers deposited by the method according to the invention (at the end of step c) or d)) or only certain of these layers can be layers deposited by the method of the invention.
- FIG. 1 is a graph which gives the fluorescence signal expressed in gray levels (NG) on 16 bits (65536 levels) for different functionalized surfaces on which were immobilized oligonucleotides which were then hybridized by a target marked by a fluorophore CY3.
- Bars B and D give the fluorescence signals of the pads for the epoxy and aldehyde surfaces respectively prepared with functionalization by the sol-gel process of the invention (examples 3 and 4) and bars A and C give the fluorescence signals for the epoxy and aldehyde surfaces respectively prepared with a functionalization by the process using a layer of the "SAM" type (comparative examples 1 and 2).
- - Figure 2 is a graph which gives the background noise of fluorescence expressed in gray levels (NG) on 16 bits (65536 levels) for various functionalized surfaces on which were immobilized oligonucleotides and which were then hybridized by a target marked with a CY3 fluorophore.
- Bars B and D give the background noise for the epoxy and aldehyde surfaces respectively prepared with functionalization by the sol-gel process of the invention (Examples 3 and 4) and bars A and C give the background noise for the surfaces respectively epoxide and aldehyde prepared with a functionalization by the process using a layer of the "SAM" type (comparative examples 1 and 2).
- FIG. 3 is a graph which gives the diameter D in micrometers (on the ordinate) of studs, spots, for a drop volume of 650 pL (picoliters), as well as the contact angle ( ⁇ in degrees) of the surface (on the abscissa) for various layers; * corresponds to a "SAM” type layer with epoxy functions, corresponds to a "sol-gel” type layer with epoxy functions, • corresponds to a "SAM” type layer with aldehyde functions, ⁇ corresponds to a type layer "sol-gel” with aldehyde functions.
- the following diagram 1 describes the functionalization method by the sol-gel route according to the invention as well as a conventional method ("Reference method") of the prior art in which the functionalization is carried out via the preparation of a self-assembled monomolecular layer (“SAM” layer).
- Reference method a method of the prior art in which the functionalization is carried out via the preparation of a self-assembled monomolecular layer (“SAM” layer).
- the solid substrate can be made of a material chosen from semiconductors such as silicon; organic polymers such as poly (methyl methacrylate) (PMMA), polycarbonate (PC), polystyrene (PS), polypropylene (PP) and poly (vinyl chloride) (PVC); metals such as gold, aluminum and silver; the glasses ; mineral oxides generally in layers such as Si0 2 , AI2O3, Zr0 2 , Ti0 2 , a 2 ⁇ 5 ; and composite materials comprising several of these materials.
- the surface of the solid substrate which it is desired to functionalize will optionally be cleaned and / or activated to allow the covalent or mechanical attachment of the layer to the substrate. This cleaning and / or activation can be done according to the protocols described below.
- the purpose of cleaning is to remove organic and / or inorganic contaminants that could prevent the effectiveness of the functionalization.
- the cleaning process used depends on the nature of the substrate and is chosen from the physical, chemical or mechanical processes known to those skilled in the art.
- the cleaning method can be chosen from immersion in an organic solvent and / or detergent cleaning and / or acid pickling assisted by ultrasound; these cleanings being optionally followed by rinsing with tap water, then rinsing with deionized water; these rinses being optionally followed by drying by "lift-out", by an alcohol spray, by a jet of compressed air, with hot air, or by infrared rays.
- Cleaning can also be cleaning with ultraviolet rays.
- the purpose of activation is to activate the surface in order to make it more reactive during the functionalization step.
- the activation method used depends on the nature of the substrate and can easily be chosen by a person skilled in the art from known activation methods. For example, for glass or oxide surfaces, in particular in the case of silicon substrates covered with an oxide layer, chemical activation of the surface makes it possible to confer hydroxyl groups on it.
- the purpose of activation is to create the maximum number of OH sites, the surface oxide molecules, for example of surface SiO 2, thus give, for example, SiOH.
- This activation can be carried out under basic conditions, for example using sodium hydroxide or of potassium hydroxide, for example in the case of the Brown process where an extended stay of the surface is carried out in the soda, or by a detergent cycle followed by an abundant rinsing with EDI then by drying.
- the activation of the glass or oxide surface can also be carried out by controlled attack with an inorganic acid such as HF or by the Piranha process (mixture H2O2 / H2SO4), or by means of hydrochloric acid, sulfochromic acid or d 'sulfo-oxygenated acid, buffered or not, this attack being followed by abundant rinsing with deionized water and drying.
- Activation of any surface can also be achieved by an oxygen plasma which creates free radicals.
- the surface can be activated by controlled cleaning with an inorganic acid such as HF or by the Piranha process (mixture H2O2 / H2SO4), this attack being followed by abundant rinsing with water and drying.
- Activation can also be achieved by an oxygen plasma.
- silicon no chemical activation is necessary, because the grip is mainly mechanical.
- the diversity of the compositions makes prefer a mode of activation of the plasma type, for example by an oxygen plasma or a low pressure plasma or an air plasma, although the chemical processes of detergents type work if they are optimized for each material.
- the substrate can have any shape but it is generally a flat substrate and the functionalized surface is then generally the upper free surface of said substrate. However, the two faces of the same substrate can be functionalized simultaneously or separately by the same function or by different functions.
- the substrate can be structured or unstructured. According to the invention, a solution of a suitable siloxane or silane is first prepared.
- This silane or siloxane can for example correspond to the formula (I) given above.
- This silane or siloxane can more generally be chosen from the epoxy-functional silanes or siloxanes of the following table:
- the silane or siloxane solution is a solution in a mixture of alcohol and water, preferably ethanol and water and it generally contains a catalyst such as triethylamine
- T (where r xl represents the molar concentration of the species x) which are such that O ⁇ ⁇ 100 and O ⁇ T ⁇ 100, the preferred values have already been mentioned above.
- This solution is deposited on the substrate, possibly after maturation.
- the term “maturation” or maturation is a term commonly used in the field of deposition by the sol-gel route and is clear to those skilled in the art in this field of technology.
- “maturation” is generally meant that the solution is stored under special conditions for a period allowing the hydrolysis and condensation reactions to proceed until an ideal advancement for, on the one hand, the cohesion of the deposited layer then on the surface, and on the other hand, for grafting said layer to the substrate.
- the ripening generally comprises, a storage of the solution in a closed container, protected from air and possibly from humidity, for example generally under an inert atmosphere, static (that is to say without agitation) or with gentle stirring, at a temperature generally between 15 ° and 60 °, for a period generally from one to a few hour (s) (for example 2, 5 or 10 hours) to one or a few weeks (for example 2, 5 or 10 weeks).
- the maturing time depends mainly on the storage temperature and the parameters H and T defined above and can be easily determined by a person skilled in the art.
- a ripening is preferably carried out, for example at least 3 days at 22 ° C. with stirring.
- the solution obtained can be defined as a liquid hydrolyzed silane solution, it is this solution which is used. contact with the surface of the substrate, deposited thereon.
- the deposition can be carried out by any suitable liquid phase deposition process known to a person skilled in the art such as, and in a non-exhaustive manner: centrifugal coating ("spin coating”), dip-coating (“dip coating”), laminar coating (“laminar flow coating” or “meniscus coating”), and its variants roller coating (“roller coating”) and curtain coating (“curtain coating”), printing (“printing” for example “ink jet printing “), pipetting (“ spotting "), or spray coating.
- Some of these deposition methods make it possible to coat large areas, for example from a few hundred cm 2 to a few m 2 , which constitutes one of the advantages of the method of the invention. Certain others of these methods make it possible to produce localized deposits, for example of a few nm 2 to a few mm 2 , which constitutes another advantage of the method according to the invention. Other techniques can be highly automated and reach high rates (centrifugation, printing, spotting) which constitutes another advantage of the process of the invention.
- the deposition is generally carried out at room temperature: that is to say at a temperature generally of 15 to 35 ° C, preferably of 20 to 25 ° C, for example 23 ° C.
- the deposit is generally made in a few seconds to a few minutes, and the solution deposited on the surface in contact with it for a sufficient time, for example less than 10 minutes, to form a thick gelled layer covalently attached to the surface (step b)).
- the formation of the thick layer (step b) takes place simultaneously (for example in part) in step a) or immediately after step a).
- a final drying is carried out between 25 and 60 ° C for a few minutes for example for a period of less than 15 minutes, then the layer is optionally annealed at a temperature generally between 70 ° C and 200 ° C.
- the thick layer is bonded to the surface via -Si-O- bonds.
- This layer carries the free chemical functions which are the epoxide functions (EP) shown in diagram 1 and which allow the attachment, immobilization, grafting, of chemical or biological molecules.
- thick layer within the meaning of the invention generally means a layer of a few nanometers to several microns, for example from 10 nm to 10 ⁇ m, for example from 50 nm to 1 ⁇ m, for example 100 nm, as opposed to self-assembled monomolecular layers which generally have a thickness of a few Angstroms to a few nm.
- the layer obtained is a uniform layer (without irregularities) even over a large area.
- the thickness homogeneity is typically ⁇ 3%.
- the layer also has very low absorption and diffusion losses (k ⁇ 2.10 "3 ) and its refractive index is close to 1.47 in the visible. This layer can therefore be used for its optical properties, alone or as a layer part of a stack of optical layers.
- the process according to the invention which could be defined for example as a process of silanization by sol-gel route in hydroalcoholic medium, is compared to a process according to l prior art in which the silanization is carried out by preparing a layer of the "SAM" type.
- a solution of the same siloxane namely EHTEOS
- EHTEOS is applied to the surface, but in an organic solvent such than toluene and in the presence of a catalyst chosen from organic bases such as for example triethylamine (TEA) or diisopropylethylamine (DIEA).
- TAA triethylamine
- DIEA diisopropylethylamine
- SAM self-assembled monomolecular layer
- the functionalized surface namely the surface provided with the "SAM” layer or the thick layer, both carrying functions allowing the immobilization of chemical or biological molecules, one then proceeds to the immobilization, to the attachment, to the grafting of chemical or biological molecules.
- the function carried by the layer being generally a function such as the epoxide function which is reactive with respect to nucleophilic groups
- the chemical or biological molecule to be immobilized therefore generally comprises a nucleophilic group such as an amino group, thiol, oxyamine , hydroxyl or phenol or the conjugate base of these groups.
- the chemical molecule is generally chosen according to the envisaged application, for example it may be a chiral, achiral, linear, cyclic or heterocyclic molecule.
- the biological molecule is generally chosen from proteins, DNA, oligonucleotides, peptides, and oligosaccharides. If the chemical or biological molecule does not carry a nucleophilic group, it can be modified to give it one. In scheme 1, the immobilized molecule is thus an oligonucleotide modified with an NH 2 group.
- the grafting, the immobilization of the biological or chemical molecules is done very simply, for example by putting the molecule in solution in an adequate medium, such as an aqueous buffer, and by depositing it on the functionalized surface, for example manually or by l using a "spotting" robot provided with piezoelectric type heads (without contact with the surface) or with "pin” or “pin and ring” type (contact with the surface).
- a surface is finally obtained on which are grafted, attached, immobilized chemical or biological molecules: in diagram 1 of the oligonucleotides are thus immobilized via an amino-type bond (CN).
- the functions carried by the thick layer or the "SAM" layer into other functions allowing the immobilization of chemical or biological molecules.
- These functions are preferably also reactive functions with respect to the nucleophilic groups.
- the epoxide functions can be transformed into aldehyde functions by first opening the epoxide cycle in aqueous HC1 medium to give a diol, and then carrying out an oxidative cleavage, for example with NaI0 4 .
- the immobilization of chemical or biological molecules on the layer provided with aldehyde groups is done for example by bringing the chemical or biological molecule comprising a nucleophilic group into contact with the functionalized surface by aldehydes.
- nucleophilic group is an NH2 group as in scheme 1 with oligo-NH2
- a reduction is then carried out for example by NaBH.
- EXAMPLE 1 in this example, by the “sol-gel” method according to the invention, a thick layer with a thickness close to 100 nm is prepared comprising epoxy functions on a cleaned glass substrate (commercial float glass slide) and primed by pickling in soda (Brown process).
- a solution of 5,6-epoxyhexyltriethoxysilane (EHTEOS) in ethanol is deposited on said substrate in the presence of triethylamine (TEA) and water.
- TAA triethylamine
- EHTEOS is 2.5%.
- the ratio of the mass concentrations of H 2 0 and EtOH is 0.18% (H 2 0 / EtOH).
- the solution was matured for at least 3 days at 22 ° C with gentle stirring.
- the deposit is made at room temperature by centrifugation at a speed of 200 to 3000 rpm, for example 700 rpm to give a wet layer.
- the contact time between the substrate and the liquid solution is from 1 to a few seconds (for example 1 to 10 seconds).
- the contact time between the substrate and the wet layer is 5 minutes ( drying of the layer with the substrate still in rotation). This gives a thick gelled layer on the substrate with a thickness of about 140 nm carrying epoxy functions.
- the densified layer grafted to the substrate After drying for 5 minutes under an IR lamp and cooking for 1 to a few minutes (for example 5 or 10 minutes) up to 30 minutes at a temperature between 80 ° C and 150 ° C, the densified layer grafted to the substrate has a thickness close to 100 nm + 5 nm and a refractive index close to 1.47 (it is quarter wave around 595 nm).
- EXAMPLE 2 a thick layer with a thickness of approximately 100 nm comprising aldehyde functions is prepared on a glass substrate (commercial float glass slide) by the "sol-gel" method according to the invention.
- the substrate provided with a thick layer carrying epoxy functions, prepared as in Example 1 is treated with an aqueous solution of HCl (stay at room temperature for 3 hours in an aqueous solution at 0.2 N and then three successive rinses in 1 deionized water, then drying (by air jet or centrifugation) in order to open the epoxide cycles and form diols, then an oxidative cleavage of said diol is carried out with NaI0 (stirring for 1 hour at room temperature, rinsing for 5 minutes in deionized water then drying by centrifugation) to obtain the aldehyde type functions.
- EXAMPLE 3 An NH 2 modified oligonucleotide (20 mothers) is deposited and immobilized on the supports prepared in Example 1. The deposition is carried out in an aqueous solution (Na 2 HP0 0.3 M) by a robot of the Piezo type. The oligonucleotide probes obtained were hybridized by a complementary target marked with a fluorophore CY3. The fluorescence measurements are carried out with an Axon Genepix scanner.
- EXAMPLE 4 The same procedure is repeated as in Example 3 but with the supports prepared in Example 2 and a support is obtained on which modified oligonucleotides are immobilized.
- COMPARATIVE EXAMPLE 1 a monomolecular layer is prepared, the arrangement of which is controlled ("SAM" layer) and which comprises epoxy functions, on a substrate by the following process:
- the support glass slide or silica
- the support is cleaned and activated in basic medium (NaOH / EtOH / deionized water in the proportions 1 g / 4 mL / 3 mL) then rinsed with deionized water (5 min) then dried at 80 ° C.
- the support thus cleaned and activated (hydroxyl functions on the surface) is then functionalized at 80 ° C.
- FIGS. 1 and 2 The results of the fluorescence measurements are given in FIGS. 1 and 2.
- FIG. 1 gives the fluorescence signal expressed in gray levels (NG) on 16 bits (65536 levels) for the various hybridized probes obtained in Examples 3, 4 according to the invention (B and D) and Comparative Examples 1 and 2 (A and C).
- FIG. 2 gives the background noise of the substrate for the samples of Examples 3, 4 (B and D) and Comparative Examples 1 and 2 (A and C).
- Epoxy and aldehyde type surfaces provide a signal of the same order of magnitude. This signal is slightly weaker on the surfaces obtained by the sol-gel route according to the method according to the invention (B and D in FIG. 1): the signal of the sol-gel layers is less than 30% for the epoxy and 20% for aldehyde surfaces.
- the background noise is improved on the surfaces obtained by the sol-gel route according to the method according to the invention (B and D in FIG. 2), which in particular makes it possible to increase the signal / noise ratio (sensitivity).
- the diameter of this spot depends mainly on the contact angle of the surface: the higher this angle, the more hydrophobic the surface and the greater the diameter of a spot of an aqueous solution is weak.
- the diameter of the spots obtained by the "sol-gel" route according to FIG. 3 is less than that obtained by the "SAM" route (FIG. 3).
- spots is 650 pL (picoliters).
- SAM semometric Adenosine A
- the spots obtained have a diameter of 170 and 200 microns respectively.
- the values of the contact angles for the epoxy and aldehyde type layers are close (respectively 65 and 66 °). We therefore expect to obtain a spot diameter between 180-190 microns.
- the spots obtained on the "sol-gel” layers have a diameter of 90 and 110 microns respectively for the epoxy and aldehyde layers.
- This thick layer of perfectly controlled thickness can, among other things, be used as an optical layer alone or as part of a stack, for example a Bragg mirror.
- This mirror is characterized by optical layers whose thickness is equal to the emission wavelength divided by 4 times the refractive index of the layer at this wavelength.
- a description of the preparation of this type of mirror by sol-gel route is given in document FR-A-2 818 378 (OA-02/48691).
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Abstract
Description
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EP05762681A EP1744828A1 (fr) | 2004-05-12 | 2005-05-12 | Procede sol-gel de fonctionnalisation d'une surface d'un substrat solide |
JP2007512306A JP4827835B2 (ja) | 2004-05-12 | 2005-05-12 | 固体基板の表面の官能基化のためのゾル−ゲル法 |
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FR0450917 | 2004-05-12 | ||
FR0450917A FR2870143B1 (fr) | 2004-05-12 | 2004-05-12 | Procede sol-gel de fonctionnalisation d'une surface d'un substrat solide. |
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EP (1) | EP1744828A1 (fr) |
JP (1) | JP4827835B2 (fr) |
CN (1) | CN100512947C (fr) |
FR (1) | FR2870143B1 (fr) |
WO (1) | WO2005113129A1 (fr) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
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JP2008136916A (ja) * | 2006-11-30 | 2008-06-19 | Nagoya Institute Of Technology | 基材表面修飾方法 |
JP2008170238A (ja) * | 2007-01-10 | 2008-07-24 | Sumitomo Bakelite Co Ltd | バイオチップ用基板の製造方法 |
Families Citing this family (5)
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WO2011010610A1 (fr) * | 2009-07-21 | 2011-01-27 | 国立大学法人北海道大学 | Précurseur de catalyseur, son procédé de production, son procédé dutilisation et réacteur qui lutilise |
CN101831503B (zh) * | 2010-05-21 | 2013-07-24 | 北京欧凯纳斯科技有限公司 | 一种乙烯基修饰的基因芯片、其制备方法及应用 |
CN101831504B (zh) * | 2010-05-21 | 2012-12-12 | 北京欧凯纳斯科技有限公司 | 一种炔基修饰的基因芯片、其制备方法及应用 |
CN112322469B (zh) * | 2017-11-10 | 2022-01-04 | 深圳市真迈生物科技有限公司 | 芯片及其制备方法 |
CN111333759A (zh) * | 2020-02-26 | 2020-06-26 | 青岛科技大学 | 一种固体基底表面两性离子聚合物图案的制备方法 |
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US5254904A (en) * | 1991-05-21 | 1993-10-19 | U.S. Philips Corporation | Antireflective coating layer in particular for a cathode ray tube |
EP1167462A1 (fr) * | 1999-01-11 | 2002-01-02 | Showa Denko K K | Preparation cosmetique, particules d'oxyde metallique enrobees d'un sol de silice rendues hydrophobes en surface, oxyde metallique revetu de sol de silice et procedes de production |
US20020028506A1 (en) * | 2000-09-04 | 2002-03-07 | Chih-Wei Ho | High-density functional slide and preparation method thereof |
US20020085954A1 (en) * | 1993-11-01 | 2002-07-04 | Nanogen, Inc. | Inorganic permeation layer for micro-electric device |
US6503850B1 (en) * | 1997-04-17 | 2003-01-07 | Alliedsignal Inc. | Process for producing nanoporous dielectric films at high pH |
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2004
- 2004-05-12 FR FR0450917A patent/FR2870143B1/fr not_active Expired - Lifetime
-
2005
- 2005-05-12 JP JP2007512306A patent/JP4827835B2/ja not_active Expired - Fee Related
- 2005-05-12 WO PCT/FR2005/050317 patent/WO2005113129A1/fr active Search and Examination
- 2005-05-12 EP EP05762681A patent/EP1744828A1/fr not_active Withdrawn
- 2005-05-12 CN CNB2005800223738A patent/CN100512947C/zh not_active Expired - Fee Related
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US5254904A (en) * | 1991-05-21 | 1993-10-19 | U.S. Philips Corporation | Antireflective coating layer in particular for a cathode ray tube |
US20020085954A1 (en) * | 1993-11-01 | 2002-07-04 | Nanogen, Inc. | Inorganic permeation layer for micro-electric device |
US6503850B1 (en) * | 1997-04-17 | 2003-01-07 | Alliedsignal Inc. | Process for producing nanoporous dielectric films at high pH |
EP1167462A1 (fr) * | 1999-01-11 | 2002-01-02 | Showa Denko K K | Preparation cosmetique, particules d'oxyde metallique enrobees d'un sol de silice rendues hydrophobes en surface, oxyde metallique revetu de sol de silice et procedes de production |
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JP2008136916A (ja) * | 2006-11-30 | 2008-06-19 | Nagoya Institute Of Technology | 基材表面修飾方法 |
JP2008170238A (ja) * | 2007-01-10 | 2008-07-24 | Sumitomo Bakelite Co Ltd | バイオチップ用基板の製造方法 |
Also Published As
Publication number | Publication date |
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FR2870143A1 (fr) | 2005-11-18 |
FR2870143B1 (fr) | 2006-07-14 |
EP1744828A1 (fr) | 2007-01-24 |
JP4827835B2 (ja) | 2011-11-30 |
CN101010133A (zh) | 2007-08-01 |
JP2008515610A (ja) | 2008-05-15 |
CN100512947C (zh) | 2009-07-15 |
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