WO2007141811A2 - Process for preparing a semiconductor substrate for biological analysis - Google Patents
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- 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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- 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
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- 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
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- 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
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Abstract
A process for preparing a semiconductor substrate for biological analysis in an integrated device, the biological analysis comprising the steps of amplifying DNA and detecting amplified DNA in the same chamber, comprises the steps of a) forming a silicon dioxide surface on said semiconductor substrate b) treating said silicon dioxide surface with a silane; c) forming a silanized surface; d) grafting nucleic acid probes; e) treating said silanized surface with a deactivating agent and f) forming a deactivated substrate sequentially. Further the process can include the step of cleaning the silicon dioxide substrate before the step of treating said silicon dioxide surface with a silane and the step of reacting the terminal group of the silane with a cross-linker or alternatively the step of reacting the derivatized nucleic acid probes with a cross-linker, before the grafting step.
Description
PROCESS FOR PREPARING A SEMICONDUCTOR SUBSTRATE FOR BIOLOGICAL ANALYSIS
TECHNICAL FIELD The present invention relates to a process for preparing a semiconductor substrate for biological analysis, in particular in an integrated device. BACKGROUND ART
Typical procedures for analyzing biological materials, such as nucleic acid, 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. As an example, in 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.
Next, the DNA is denatured by thermal, biochemical or chemical processes and amplified by an amplification reaction, such as PCR (polymerase chain reaction) , LCR
(ligase chain reaction) , SDA (strand displacement amplification) , TMA (transcription-mediated
amplification) , RCA (rolling circle amplification) , and the like. 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.
The procedures are similar if RNA is to be analyzed, but more emphasis is placed on purification or other means to protect the labile RNA molecule. RNA is usually copied into DNA (cDNA) and then the analysis proceeds as described for DNA.
Finally, the amplification product undergoes some type of analysis, usually based on sequence or size or some combination thereof. In an analysis by hybridization, for example, 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.
Other biological molecules are analyzed in a similar way, but typically molecule purification is substituted for amplification and detection methods vary according to the molecule being detected. For
example, 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.
It is known to perform both amplification and detection in integrated devices comprising a semiconductor support, for example a silicon substrate, generally including an amplification zone and a detection zone.
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. In particular, the passivation method that gives the best results is to form a silicon dioxide
layer .
Nevertheless, though the reactivity of passivated silicon substrates towards biological molecules is lower than the silicon as such, experimental tests proved that passivated silicon substrates still show a residual reactivity, which can alter the results of subsequent analyses.
Therefore it is well known to those skilled in the art to treat passivated silicon substrates in the amplification zone with further treatments, such as deposition of silanes, in order to further reduce the reactivity of the silicon substrate. Disadvantageously, although these treatments show good results, none of them provides a significant increase in yield as compared to the silicon dioxide alone.
Another disadvantage of the known integrated devices is the need of superficial treatments specific for the amplification zone and the detection zone.
In particular, while the passivation treatments are essential in the amplification zone, they can interfere with the deposition of probes in the detection zone. Generally, probes are grafted to the electrodes by means of a linker, for example pyrrole, that polymerizes on electrodes thanks to an electropolymerization process. The pollution of
electrodes with passivation reactants can reduce the electro-polymerization, thus altering the grafting of probes. In the same way, the deposition of probes can pollute the amplification area, reducing the amplification results.
Therefore, in order to avoid pollution, the integrated device comprises two separate chambers that must be subjected to different superficial treatments. In particular, the amplification step is performed in the amplification chamber consisting of triangular or rectangular-shaped channels, and the detection step is performed in the detection chamber comprising electrodes .
DISCLOSURE OF INVENTION The aim of the present invention is to provide a process for treating silicon substrates that is free from the above described drawbacks.
In particular, it would be desirable to find a process for treating semiconductor substrates to reduce interactions between nucleic acid and the semiconductor substrate, thus improving analytical results and allowing repeated biological analyses on the same semiconductor substrate.
According to the present invention, there is provided a process according to claim 1.
According to an aspect of the present invention, in the process for preparing a semiconductor substrate for biological analysis in an integrated device, the biological analysis comprises the steps of amplifying
DNA and detecting amplified DNA in the same chamber.
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.
Subsequently, the silicon dioxide surface undergoes cleaning to remove insoluble organic contaminants and metal residues from the silicon dioxide surface. Preferably the cleaning solution comprises water, ammonium hydroxide and hydrogen peroxide.
More preferably the relative quantity of water, ammonium hydroxide and hydrogen peroxide is 5:1:1.
After cleaning, the silicon dioxide surface is treated with a silane in order to form a silanized
surface .
Preferably the silane has a terminal group able to react with a nucleic acid probe.
More preferably the silane is selected from the group consisting of amino-terminated silane, mercapto- terminated silane, epoxy-terminated silane.
Even more preferably amino-terminated silane is (3- aminopropyl) trimethoxysilane (3-APTES) , the mercapto- terminated silane is (3-mercaptopropyl) trimethoxysilane (3-MPTS) and the epoxy-terminated silane is (3- glicydoxypropyl) trimethoxysilane (GPS) .
After the step of forming a silanized surface, the nucleic acid probes are grafted to the terminal groups of the silane. Preferably 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. Among the physical 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.
Among the chemical methods the probes can be grafted to the silane through the formation of covalent bonds.
For this purpose, the probes are preferably derivatized to form derivatized probes. More preferably the probes are derivatized with a linker.
Preferably the linker includes a functional group selected from the group consisting of NH2, SH, OH.
The presence of one of these functional groups on the probe allows the reaction with the terminal group brought from the silane and therefore the formation of covalent bonds . Preferably a linker including an NH2 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 NH2 group in order to form a covalent amine bond, according to the following reaction:
Alternatively, according to the present invention, the derivatized probe can be bound to the terminal group of the silane through a cross-linker. In this case 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 . Preferably 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) . In particular, 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
3-MPTS has been used during the silanization. A) 3-MPTS
B) 3-APTES
The final step, according to the process of the present invention, 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 NH2 group or an oxidizing agent. Even more preferably it is selected from the group consisting of BSA, salmon sperm DNA, Denhardt's solution, ω-amino alkanes, ω-amino carboxylic acids, ω- amino alcohols.
Even more preferably the deactivating agent is BSA. Alternatively, the deactivating agent is hydrogen peroxide .
BRIEF DESCRIPTION OF THE DRAWINGS
For a better understanding of the present invention a preferred embodiment thereof is now described, purely by way of a non-limiting example, with reference to the enclosed drawings, wherein:
- Figure 1 is a simplified block diagram of a biochemical analysis apparatus including a microreactor; - Figure 2 is a top plan view, with parts removed,
of a microreactor having a substrate prepared according to the present invention; and
- Figure 3 is a cross section through the microreactor of Figure 2, taken along the line III-III of Figure 3.
BEST MODE FOR CARRYING OUT THE INVENTION Example 1
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 750C. Subsequently, the silicon dioxide surface is soaked in the cleaning solution at 600C for 1 minute and then rinsed with water three times. Finally the silicon dioxide surface is dried at 800C for 30 minutes .
The silicon dioxide surface is silanized using a GPS solution 10% v/v in anhydrous toluene at 350C for 8 hours .
Subsequently the silanized surface is rinsed with anhydrous toluene three times vigorously.
After this step the surface is cured at 1200C for 30 minutes. The following step is to graft DNA probes.
A printing buffer solution is prepared, composed of 150 mM Na3PO4 (pH 8.5). Oligonucleotide probes with 5'- C6-NH2 linker are resuspended at 100 μm.
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 250C.
Subsequently the silanized surface is treated with a solution of deactivating agent containing BSA 1%, Sodium Dodecylsulfate (SDS) 0.1% and Saline Sodium Citrate (SSC) 5x.
Lastly the semiconductor substrate is rinsed in water three times and dried under N2. With reference to figure 1, 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. To this end, 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.
As illustrated in figures 2 and 3, 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
syπtmetr±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) . When the board 7 is loaded into the driver device 8 (figure 1) , the power source 4 is connected to the heaters 18 for delivering electrical power and the temperature sensor 19 is connected to the processing unit 3 for providing a temperature signal Sτ. 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. Since polymerase always starts sequence reconstruction from end 3' and toward end 5' (and not vice versa) duplication of probes is prevented. Moreover, 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.
Claims
1. A process for preparing a semiconductor substrate for biological analysis in an integrated device, said biological analysis comprising the steps of amplifying DNA and detecting amplified DNA, said process comprising the step of: forming a silicon dioxide surface on said semiconductor substrate; characterized by the steps of: - treating said silicon dioxide surface with a silane; - grafting nucleic acid probes to said silane;
treating said silanized surface with a deactivating agent.
2. A process according to claim 1, wherein said steps of amplifying DNA and detecting amplified DNA are conducted in a same chamber.
3. A process according to claims 1 or 2, wherein said silane has a terminal group able to react with a nucleic acid probe.
4. A process according to any of claims 1 to 3, wherein said silane is selected from the group consisting of amino-terminated silane, mercapto- terminated silane, epoxy-terminated silane.
5. A process according to claim 4, wherein said amino-terminated silane is (3-aminopropyl) trimethoxysilane (3-APTES) .
6. A process according to claim 4, wherein said mercapto-terminated silane is (3-mercaptopropyl) trimethoxysilane (3-MPTS) .
7. A process according to claim 4, wherein said epoxy-terminated silane is (3-glicydoxypropyl) - trimethoxysilane (GPS) .
8. A process according to any of claims 1 to 7, wherein said nucleic acid probes are DNA probes.
9. A process according to claim 8, wherein said nucleic acid probes are derivatized to form derivatized nucleic acid probes.
10. A process according to claim 9, wherein said nucleic acid probes are derivatized with a linker.
11. A process according to claim 10, wherein said linker includes a functional group selected from the group consisting of NH?, SH, OH.
12. A process according to any of claims 1 to 11, wherein said deactivating agent is able to react with said terminal groups of said silane.
13. A process according to claim 12, wherein said deactivating agent is a molecule containing a NH2 group or an oxidizing agent.
14. A process according to claims 12 or 13, wherein said molecule containing a NHa group is selected from the group consisting of BSA, salmon sperm DNA, Denhardt' s solution, amino-terminated alkanes, amino- terminated carboxylic acids, amino-terminated alcohols.
15. A process according to claim 14, wherein said deactivating agent is BSA.
16. A process according to claims 12 or 13, wherein said oxidizing agent is selected from the group consisting of hydrogen peroxide.
17. A process according to any of claims 1 to 16, wherein it includes the step of cleaning said silicon dioxide surface before said step of treating said silicon dioxide surface with a silane.
18. A process according to claim 17, wherein said step of cleaning said silicon dioxide surface comprises the step of cleaning with a cleaning solution for semiconductor substrates.
19. A process according to claim 18, wherein said cleaning solution for semiconductor substrates comprises water, ammonium hydroxide and hydrogen peroxide .
20. A process according to claim 19, wherein the relative quantity of said water, ammonium hydroxide and hydrogen peroxide is 5:1:1.
21. A process according to any of claims 1 to 20, wherein it includes the step of reacting said terminal group of the silane with a cross-linker before said step of grafting nucleic acid probes.
22. A process according to any of the claims 1 to 20, wherein it includes the step of reacting said derivatized nucleic acid probes with a cross-linker before said step of grafting nucleic acid probes.
23. A process according to claims 21 or 22, wherein said 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) .
24. An integrated device for biological analysis, comprising a body (10), a reaction chamber (11) formed in a recess in said body (10) and an array (15) of nucleic acid probes (16) arranged in said reaction chamber (11), wherein said body (10) includes a semiconductor substrate (12); characterized in that a surface (13) of said semiconductor substrate (12) is prepared according any of the claims 1 to 23.
25. An apparatus for biological analysis comprising a reader (8) and an integrated device (5), loadable into said reader (8) and including a body (10), a reaction chamber (11) formed in a recess in said body (10) and an array (15) of nucleic acid probes (16) arranged in said reaction chamber (H), wherein said body (10) further includes a semiconductor substrate (12); characterized in that a surface (13) of said semiconductor substrate (12) is prepared according to any of the claims 1 to 23.
26. An apparatus according to claim 25, wherein said integrated device (5) comprises heaters (18), thermally coupled to said reaction chamber (11), and said reader (2) comprises a processing unit (3) and a power source (4), controlled by said processing unit (3) for delivering electrical power to said heaters (18) .
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/IT2006/000420 WO2007141811A2 (en) | 2006-06-06 | 2006-06-06 | Process for preparing a semiconductor substrate for biological analysis |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
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| PCT/IT2006/000420 WO2007141811A2 (en) | 2006-06-06 | 2006-06-06 | Process for preparing a semiconductor substrate for biological analysis |
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| WO2007141811A2 true WO2007141811A2 (en) | 2007-12-13 |
| WO2007141811A3 WO2007141811A3 (en) | 2008-02-28 |
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| PCT/IT2006/000420 WO2007141811A2 (en) | 2006-06-06 | 2006-06-06 | Process for preparing a semiconductor substrate for biological analysis |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009151407A2 (en) | 2008-06-14 | 2009-12-17 | Veredus Laboratories Pte Ltd | Influenza sequences |
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| WO1990005910A1 (en) * | 1988-11-14 | 1990-05-31 | I Stat Corp | Wholly microfabricated biosensors and process for the manufacture and use thereof |
| 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 (en) * | 1999-08-16 | 2001-02-22 | Pamgene B.V. | Preparation of metal oxide supports loaded with biomolecules |
| WO2003040700A1 (en) * | 2001-11-08 | 2003-05-15 | Ciphergen Biosystems, Inc. | Hydrophobic surface chip |
| WO2004001506A2 (en) * | 2002-06-20 | 2003-12-31 | Affymetrix, Inc. | Antireflective coatings for high-resolution photolithographic synthesis of dna array |
| EP1413352A1 (en) * | 2002-10-21 | 2004-04-28 | Agilent Technologies Inc. (a Delaware Corporation) | Linking to chemical array assemblies with metal layers |
| WO2005005039A1 (en) * | 2003-06-30 | 2005-01-20 | Agilent Technologies, Inc. | Methods for producing ligand arrays |
| WO2005029042A2 (en) * | 2003-09-23 | 2005-03-31 | Massachusetts Institute Of Technology | Fabrication and packaging of suspended microchannel detectors |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009151407A2 (en) | 2008-06-14 | 2009-12-17 | Veredus Laboratories Pte Ltd | Influenza sequences |
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| Publication number | Publication date |
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| WO2007141811A3 (en) | 2008-02-28 |
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