WO2007141811A2 - processus d'élaboration d'un substrat semi-conducteur pour analyse biologique - Google Patents

processus d'élaboration d'un substrat semi-conducteur pour analyse biologique Download PDF

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Publication number
WO2007141811A2
WO2007141811A2 PCT/IT2006/000420 IT2006000420W WO2007141811A2 WO 2007141811 A2 WO2007141811 A2 WO 2007141811A2 IT 2006000420 W IT2006000420 W IT 2006000420W WO 2007141811 A2 WO2007141811 A2 WO 2007141811A2
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WO
WIPO (PCT)
Prior art keywords
process according
silane
nucleic acid
acid probes
group
Prior art date
Application number
PCT/IT2006/000420
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English (en)
Other versions
WO2007141811A3 (fr
Inventor
Andrea Frosini
Alessandra Fischetti
Original Assignee
Stmicroelectronics S.R.L.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Stmicroelectronics S.R.L. filed Critical Stmicroelectronics S.R.L.
Priority to PCT/IT2006/000420 priority Critical patent/WO2007141811A2/fr
Publication of WO2007141811A2 publication Critical patent/WO2007141811A2/fr
Publication of WO2007141811A3 publication Critical patent/WO2007141811A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6813—Hybridisation assays
    • C12Q1/6834—Enzymatic or biochemical coupling of nucleic acids to a solid phase
    • C12Q1/6837—Enzymatic or biochemical coupling of nucleic acids to a solid phase using probe arrays or probe chips
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6813—Hybridisation assays
    • C12Q1/6816—Hybridisation assays characterised by the detection means
    • C12Q1/6825—Nucleic acid detection involving sensors
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6813—Hybridisation assays
    • C12Q1/6834—Enzymatic or biochemical coupling of nucleic acids to a solid phase

Definitions

  • the present invention relates to a process for preparing a semiconductor substrate for biological analysis, in particular in an integrated device.
  • Typical procedures for analyzing biological materials involve a variety of operations starting from raw material. These operations may include various degrees of cell purification, lysis, amplification or purification, and analysis of the resulting amplified or purified product.
  • these operations may include various degrees of cell purification, lysis, amplification or purification, and analysis of the resulting amplified or purified product.
  • DNA-based blood tests the samples are often purified by filtration, centrifugation or by electrophoresis so as to eliminate all the non- nucleated cells. Then, the remaining white blood cells are lysed using chemical, thermal or biochemical means in order to liberate the DNA to be analyzed.
  • the DNA is denatured by thermal, biochemical or chemical processes and amplified by an amplification reaction, such as PCR (polymerase chain reaction) , LCR
  • the amplification step allows the operator to avoid purification of the DNA being studied because the amplified product greatly exceeds the starting DNA in the sample.
  • RNA is usually copied into DNA (cDNA) and then the analysis proceeds as described for DNA.
  • the amplification product undergoes some type of analysis, usually based on sequence or size or some combination thereof.
  • the amplified DNA is passed over a plurality of detectors made up of individual oligonucleotides, hereinafter called probes, that are anchored, for example, on electrodes. If the amplified DNAs are complementary to the probes, stable bonds will be formed between them and the hybridized probes can be read using a wide variety of means, including optical, electrical, mechanical, magnetic or thermal means.
  • molecule purification is substituted for amplification and detection methods vary according to the molecule being detected.
  • a common diagnostic involves the detection of a specific protein by binding to its antibody or by a specific enzymatic reaction.
  • Lipids, carbohydrates, drugs and small molecules from biological fluids are processed in similar ways.
  • amplification and detection in integrated devices comprising a semiconductor support, for example a silicon substrate, generally including an amplification zone and a detection zone.
  • silicon substrates Due to their surface charge, silicon substrates can interact with amplified DNAs and nucleic acid probes. This interaction causes pollution of amplification and detection zones, and decreases the performance of subsequent analyses. Therefore it is commonly known to coat silicon substrates with a dielectric passivation layer for providing electrical insulation and protection against undesired chemical interactions between silicon reactive groups and the biological sample. In fact passivated substrates show reduced interaction with nucleic acid, thus improving the yield of the analyses.
  • the passivation is conducted with different techniques.
  • the passivation method that gives the best results is to form a silicon dioxide layer .
  • Another disadvantage of the known integrated devices is the need of superficial treatments specific for the amplification zone and the detection zone.
  • probes are grafted to the electrodes by means of a linker, for example pyrrole, that polymerizes on electrodes thanks to an electropolymerization process.
  • a linker for example pyrrole
  • the pollution of electrodes with passivation reactants can reduce the electro-polymerization, thus altering the grafting of probes.
  • the deposition of probes can pollute the amplification area, reducing the amplification results.
  • the integrated device comprises two separate chambers that must be subjected to different superficial treatments.
  • the amplification step is performed in the amplification chamber consisting of triangular or rectangular-shaped channels
  • the detection step is performed in the detection chamber comprising electrodes .
  • the aim of the present invention is to provide a process for treating silicon substrates that is free from the above described drawbacks.
  • the biological analysis comprises the steps of amplifying
  • An "integrated device” is defined as a single device wherein all sample processing and analysis steps can be performed without physical intervention by an operator, other than electronic control or programming of the analysis.
  • the process includes the step of forming a silicon dioxide surface on a semiconductor substrate to passivate the semiconductor substrate, thus reducing its reactivity to nucleic acid.
  • the silicon dioxide surface undergoes cleaning to remove insoluble organic contaminants and metal residues from the silicon dioxide surface.
  • the cleaning solution comprises water, ammonium hydroxide and hydrogen peroxide.
  • the relative quantity of water, ammonium hydroxide and hydrogen peroxide is 5:1:1.
  • the silicon dioxide surface is treated with a silane in order to form a silanized surface .
  • the silane has a terminal group able to react with a nucleic acid probe.
  • the silane is selected from the group consisting of amino-terminated silane, mercapto- terminated silane, epoxy-terminated silane.
  • amino-terminated silane is (3- aminopropyl) trimethoxysilane (3-APTES)
  • the mercapto- terminated silane is (3-mercaptopropyl) trimethoxysilane (3-MPTS)
  • the epoxy-terminated silane is (3- glicydoxypropyl) trimethoxysilane (GPS) .
  • the nucleic acid probes are grafted to the terminal groups of the silane.
  • the probes are DNA probes.
  • the grafting of the probes to the silane can be performed, for example, by deposition with piezo or contact systems and can be achieved by taking advantage of different physical or chemical methods.
  • UV radiation may be advantageously used, in particular, if a 3-APTES has been used during the silanization.
  • This grafting method involves the creation of radicals that induce interchain cross-linking between the silane and the probes.
  • the probes can be grafted to the silane through the formation of covalent bonds.
  • the probes are preferably derivatized to form derivatized probes. More preferably the probes are derivatized with a linker.
  • the linker includes a functional group selected from the group consisting of NH 2 , SH, OH.
  • a linker including an NH 2 group can be used and, in particular, if a GPS has been used during the silanization, the terminal epoxy ring can be opened and thus react with an NH 2 group in order to form a covalent amine bond, according to the following reaction:
  • the derivatized probe can be bound to the terminal group of the silane through a cross-linker.
  • the process includes the step of reacting the terminal group of the silane with a cross-linker or alternatively the step of reacting the derivatized probes with a cross-linker, before the step of grafting probes .
  • the cross-linker is selected from the group consisting of succinic anhydride, 1, 4-phenylene diisothiocyanate, 1, 4-phenylene diisocyanate, dithiobispyridine, 1, 1' -dithiobispiperidine, 2,2'- dithiobis (5-nitropyridine) .
  • a cross-linker such as, for example, 1, 4-phenylene diisocyanate can be advantageously used, according to the following reactions, if a 3-APTES has been used during the silanization; alternatively, a cross-linker such as dithiobispyridine can be used if a
  • the final step is to treat the silanized surface to which probes have been grafted with a deactivating agent in order to deactivate the remaining free terminal groups of the silane, thus preventing further reaction between the nucleic acid and the silanized surface.
  • the deactivating agent is preferably able to react with said terminal groups of said silane. More preferably the deactivating agent is a molecule containing a NH 2 group or an oxidizing agent. Even more preferably it is selected from the group consisting of BSA, salmon sperm DNA, Denhardt's solution, ⁇ -amino alkanes, ⁇ -amino carboxylic acids, ⁇ - amino alcohols.
  • the deactivating agent is BSA.
  • the deactivating agent is hydrogen peroxide .
  • FIG. 1 is a simplified block diagram of a biochemical analysis apparatus including a microreactor
  • FIG. 2 is a top plan view, with parts removed, of a microreactor having a substrate prepared according to the present invention
  • FIG. 3 is a cross section through the microreactor of Figure 2, taken along the line III-III of Figure 3.
  • the following example describes a process for preparing a semiconductor substrate for biological analysis according to the present invention comprising the step of cleaning a semiconductor substrate on which a silicon dioxide surface is formed.
  • the silicon dioxide surface is cleaned using an RCA solution, which is prepared by mixing 625 mL of distillated water, 125 mL of ammonium hydroxide and 125 mL of hydrogen peroxide and then heating the solution at 75 0 C. Subsequently, the silicon dioxide surface is soaked in the cleaning solution at 60 0 C for 1 minute and then rinsed with water three times. Finally the silicon dioxide surface is dried at 80 0 C for 30 minutes .
  • an RCA solution which is prepared by mixing 625 mL of distillated water, 125 mL of ammonium hydroxide and 125 mL of hydrogen peroxide and then heating the solution at 75 0 C. Subsequently, the silicon dioxide surface is soaked in the cleaning solution at 60 0 C for 1 minute and then rinsed with water three times. Finally the silicon dioxide surface is dried at 80 0 C for 30 minutes .
  • the silicon dioxide surface is silanized using a GPS solution 10% v/v in anhydrous toluene at 35 0 C for 8 hours . Subsequently the silanized surface is rinsed with anhydrous toluene three times vigorously.
  • the surface is cured at 120 0 C for 30 minutes.
  • the following step is to graft DNA probes.
  • a printing buffer solution is prepared, composed of 150 mM Na 3 PO 4 (pH 8.5). Oligonucleotide probes with 5'- C6-NH 2 linker are resuspended at 100 ⁇ m.
  • the printing buffer solution containing the oligonucleotide probes is spotted on the silanized surface with piezo systems. .Subsequently the spotted silanized surface is kept in a humid atmosphere overnight at 25 0 C.
  • silanized surface is treated with a solution of deactivating agent containing BSA 1%, Sodium Dodecylsulfate (SDS) 0.1% and Saline Sodium Citrate (SSC) 5x.
  • deactivating agent containing BSA 1%, Sodium Dodecylsulfate (SDS) 0.1% and Saline Sodium Citrate (SSC) 5x.
  • a biochemical analysis apparatus 1 comprises a reader 2, including a processing unit 3, a power source 4 controlled by the processing unit 3, and a microreactor 5.
  • the microreactor 5 is mounted on a board 7, which is removably inserted in a driver device 8 of the reader 2, for selective coupling to the processing unit 3 and to the power source 4.
  • the board 7 is also provided with contacts 9.
  • the driver device 8 also includes a cooling element 6, e.g. a Peltier module, which is controlled by the processing unit 3 and is coupled to the microreactor 5 when the board 7 is loaded in the driver device 8.
  • the microreactor 5 comprises a body 10, having a recess wherein a reaction chamber 11 is formed. Moreover a microarray 15 of DNA probes 16 is housed in the reaction chamber 11.
  • the body 10 includes a substrate 12, of a thermally conductive material, such as undoped silicon.
  • a surface 13 of the substrate 12 is prepared as above explained for biological analysis, and defines the bottom of the reaction chamber 11.
  • DNA probes 16 are anchored to the surface 12.
  • a structural layer 14, e.g. of glass, is bonded to the surface 13 of the substrate 12 by a glue layer 17 and has a through opening that laterally delimits the reaction chamber 11.
  • Heaters 18 and a temperature sensor 19 are formed on the surface 13 of the substrate 12.
  • the heaters 18 are incorporated in the glue layer 17 and are sy ⁇ tmetr ⁇ cally arranged around the reaction chamber 11, so as to favor a substantially even temperature distribution therein; the temperature sensor 19 is preferably arranged in the reaction chamber 1.
  • the heaters 18 and the temperature sensor 19 are electrically insulated from the substrate 12, because the preparation thereof involves forming a silicon dioxide surface. However, due to the small thickness of the silicon dioxide, the heaters 18 and the temperature sensor 19 are thermally coupled to the substrate 12. Moreover, the heaters 18 and the temperature sensor 19 are electrically coupled to respective pads 20 over conductive lines 21, for connection with contacts 9 (here not shown) .
  • the microarray 15 includes a plurality of DNA probes 16, which are formed by single DNA filaments grafted to the passivation layer 17 at respective predetermined locations thereof. Known measures are taken in the fabrication of the microarray 15 to prevent that the DNA probes 16 may be duplicated during DNA amplification processes to be carried out in the reaction chamber 11. For example (figure 3a), ends 3' of the DNA probes 16 are grafted to the passivation layer 17, whereas ends 5' are free.
  • DNA probes 16 could be grafted by their 5' end, and inhibition of extension by polymerase could be achieved by using 3' end capped derivatives (for example 3' -methylated) .
  • the reaction chamber 11 is closed by a cap layer 26 (not shown in figure 2), glued on the wall layer 14.
  • the cap layer 26, e.g. of glass, is pervious to visible radiation.
  • Inlets 27 are also provided in the cap layer 26, which are accessible from outside the microreactor 5 and are fluidly coupled to the reaction chamber 11 via microchannels 29.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Zoology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Wood Science & Technology (AREA)
  • Analytical Chemistry (AREA)
  • Microbiology (AREA)
  • Physics & Mathematics (AREA)
  • Molecular Biology (AREA)
  • Immunology (AREA)
  • Biotechnology (AREA)
  • Biophysics (AREA)
  • Biochemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Engineering & Computer Science (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
  • Apparatus Associated With Microorganisms And Enzymes (AREA)

Abstract

L'invention concerne un processus d'élaboration d'un substrat semi-conducteur pour analyse biologique dans un dispositif intégré, l'analyse biologique comprenant les phases consistant à amplifier l'ADN et à détecter l'ADN amplifié dans la même chambre, qui comprend les phases consistant à a) former une surface de dioxyde de silicium sur ledit substrat semi-conducteur ; b) traiter ladite surface de dioxyde de silicium avec un silane ; c) former une surface silanisée ; d) greffer des sondes d'acide nucléique ; e) traiter ladite surface silanée avec un agent de désactivation et f) former un substrat désactivé de manière séquentielle. De plus le processus peut comprendre la phase consistant à nettoyer le substrat de dioxyde de silicium avant la phase de traitement de ladite surface de dioxyde de silicium avec un silane et la phase consistant à mettre en réaction le groupe terminal du silane avec un agent réticulant ou en variante la phase consistant à mettre en réaction les sondes d'acide nucléique dérivées avec un agent réticulant, avant la phase de greffe.
PCT/IT2006/000420 2006-06-06 2006-06-06 processus d'élaboration d'un substrat semi-conducteur pour analyse biologique WO2007141811A2 (fr)

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PCT/IT2006/000420 WO2007141811A2 (fr) 2006-06-06 2006-06-06 processus d'élaboration d'un substrat semi-conducteur pour analyse biologique

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009151407A2 (fr) 2008-06-14 2009-12-17 Veredus Laboratories Pte Ltd Séquences de la grippe

Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1990005910A1 (fr) * 1988-11-14 1990-05-31 I Stat Corp Biocapteurs entierement microfabriques et procede de production et utilisation de ces capteurs
US5688642A (en) * 1994-12-01 1997-11-18 The United States Of America As Represented By The Secretary Of The Navy Selective attachment of nucleic acid molecules to patterned self-assembled surfaces
US5919523A (en) * 1995-04-27 1999-07-06 Affymetrix, Inc. Derivatization of solid supports and methods for oligomer synthesis
WO2001012846A1 (fr) * 1999-08-16 2001-02-22 Pamgene B.V. Preparation de supports d'oxydes metalliques charges de biomolecules
US6387626B1 (en) * 1997-06-06 2002-05-14 Orchid Biosciences, Inc. Covalent attachment of unmodified nucleic acids to silanized solid phase surfaces
WO2003040700A1 (fr) * 2001-11-08 2003-05-15 Ciphergen Biosystems, Inc. Puce a surface hydrophobe
WO2004001506A2 (fr) * 2002-06-20 2003-12-31 Affymetrix, Inc. Revetements antireflet pour synthese photolithographique a haute resolution d'arrangements adn
EP1413352A1 (fr) * 2002-10-21 2004-04-28 Agilent Technologies Inc. (a Delaware Corporation) Liaison à un assemblage de matrices chimiques comportant couches métalliques
WO2005005039A1 (fr) * 2003-06-30 2005-01-20 Agilent Technologies, Inc. Procede de production de microreseaux de ligands
WO2005029042A2 (fr) * 2003-09-23 2005-03-31 Massachusetts Institute Of Technology Fabrication et emballage de detecteurs de microcanaux suspendus

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6284465B1 (en) * 1999-04-15 2001-09-04 Agilent Technologies, Inc. Apparatus, systems and method for locating nucleic acids bound to surfaces

Patent Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1990005910A1 (fr) * 1988-11-14 1990-05-31 I Stat Corp Biocapteurs entierement microfabriques et procede de production et utilisation de ces capteurs
US5688642A (en) * 1994-12-01 1997-11-18 The United States Of America As Represented By The Secretary Of The Navy Selective attachment of nucleic acid molecules to patterned self-assembled surfaces
US5919523A (en) * 1995-04-27 1999-07-06 Affymetrix, Inc. Derivatization of solid supports and methods for oligomer synthesis
US6387626B1 (en) * 1997-06-06 2002-05-14 Orchid Biosciences, Inc. Covalent attachment of unmodified nucleic acids to silanized solid phase surfaces
WO2001012846A1 (fr) * 1999-08-16 2001-02-22 Pamgene B.V. Preparation de supports d'oxydes metalliques charges de biomolecules
WO2003040700A1 (fr) * 2001-11-08 2003-05-15 Ciphergen Biosystems, Inc. Puce a surface hydrophobe
WO2004001506A2 (fr) * 2002-06-20 2003-12-31 Affymetrix, Inc. Revetements antireflet pour synthese photolithographique a haute resolution d'arrangements adn
EP1413352A1 (fr) * 2002-10-21 2004-04-28 Agilent Technologies Inc. (a Delaware Corporation) Liaison à un assemblage de matrices chimiques comportant couches métalliques
WO2005005039A1 (fr) * 2003-06-30 2005-01-20 Agilent Technologies, Inc. Procede de production de microreseaux de ligands
WO2005029042A2 (fr) * 2003-09-23 2005-03-31 Massachusetts Institute Of Technology Fabrication et emballage de detecteurs de microcanaux suspendus

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009151407A2 (fr) 2008-06-14 2009-12-17 Veredus Laboratories Pte Ltd Séquences de la grippe

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