WO2009027932A1 - Substrat d'analyse et procédé de préparation associé - Google Patents

Substrat d'analyse et procédé de préparation associé Download PDF

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Publication number
WO2009027932A1
WO2009027932A1 PCT/IB2008/053426 IB2008053426W WO2009027932A1 WO 2009027932 A1 WO2009027932 A1 WO 2009027932A1 IB 2008053426 W IB2008053426 W IB 2008053426W WO 2009027932 A1 WO2009027932 A1 WO 2009027932A1
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WO
WIPO (PCT)
Prior art keywords
spots
capture probe
spot
type
area
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Application number
PCT/IB2008/053426
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English (en)
Inventor
Anke Pierik
Willem M. J. M. Coene
Hendrik R. Stapert
Aleksey Kolesnychenko
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Koninklijke Philips Electronics N.V.
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Publication of WO2009027932A1 publication Critical patent/WO2009027932A1/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

Definitions

  • the invention relates to an assay substrate and a method to prepare such a substrate.
  • the assay substrate is especially suitable for use in biological assays.
  • Arrays of biological active materials on a substrate are used in biological test assays, for instance for the analysis of human blood or tissue samples for the presence of certain bacteria, viruses and/or fungi.
  • the arrays consist of capture probe spots with a selective binding capacity for a predetermined indicative factor, such as a protein, DNA or RNA sequence that belongs to a specific bacterium, virus or fungus. By having capture probe spots with different binding specificity for different factors, the array may be used to assay for various different factors at the same time.
  • an indicative factor may be visualized for instance by fluorescent or different labelling of the molecules of the predetermined indicative factor, such as a protein, DNA or RNA sequence that belongs to a specific bacterium, virus or fungus contained in the tested sample, which results in a detectable fluorescence on the spot the specific factor adheres to.
  • the predetermined indicative factor such as a protein, DNA or RNA sequence that belongs to a specific bacterium, virus or fungus contained in the tested sample, which results in a detectable fluorescence on the spot the specific factor adheres to.
  • the invention relates to the substrates to be used in a system to analyse human samples for the presence of bacteria causing an infection.
  • the procedure typically comprises the following subsequent steps: the DNA content of a patient sample is extracted and certain gene sequences are subsequently multiplied and provided with fluorescent markers or other suitable labels.
  • the DNA is forced either to flow over or through a 2-dimensional substrate or to flow through a permeable and porous membrane, with different capture probes on either substrate or membrane, which have been deposited on the substrate or membrane e.g. with an inkjet printing technique.
  • the labelled DNA molecules adhere to the spot locations covered with a complimentary DNA strand that is specific for the DNA molecules.
  • the captured molecules are read by illumination with a light source and a CCD camera records the fluorescent pattern. In case of non- fluorescent labels, different detection techniques may be appropriate.
  • the recorded pattern is a characteristic of the composition of the sample, in this case detecting the presence of a bacterium or a set of bacteria.
  • Typical substrates for arrays of capture probe spots are 2D arrays made out of glass to which the capture probes are attached.
  • the assay substrate comprises microwells to exactly determine the position of the spots.
  • the mixture to be analysed is labelled and brought into contact with the substrates, where the specific labelled analytes adhere to the specific capture probes. After washing off the mixture, the adhered analytes are detected as described above.
  • the capture probe spots are deposited on a porous membrane, for instance by ink jet printing. Subsequently, a fluid comprising labelled analyte can be led through or over the porous membrane, washed and analysed as described above.
  • a higher redundancy of spots containing the same capture probe represents multiple measurements for the same analyte molecule. For instance, if there are at least two spots within the array comprising the same specifically binding material for each distinct analyte molecule that is to be predetermined, the assay becomes less vulnerable towards damage or misprint of a spot when compared to assays where there is only one spot allocated to each analyte.
  • the detection of the presence of bonded analyte molecules on the assay becomes less sensitive to any noise that may have originated during deposition of the capture probes, or during flow-over or flow- through of the analyte molecules, or during detection on the imaging device such as a CCD- camera.
  • having an increased number of redundant spots lowers the number of different analyte molecules that can be assayed, as a biological substrate has a limited area and can only contain a limited number of functional spots assigned to specific capture probes.
  • the noise-factor is a simple measure of how the noise-variance is transferred into the variance of the measured concentration of the analyte.
  • the formula (I) used to calculate the noise factor for an assay is given below (with the noise factor being the 2 nd factor on the right-hand- side of the equation):
  • ⁇ ( ⁇ ci) 2 is the variance on the detected concentration
  • ⁇ n> 2 is the noise variance.
  • Current state-of-the-art solutions have spots that represent a single type of capture-probe molecule. For example, if a substrate has an area accommodating 120 spots and a two-fold redundancy, the assay can have only 60 different spots representing 60 different capture probes, enabling the monitoring of 60 different analytes.
  • the noise factor for an assay with 2-fold redundancy is 0.5, which for most purposes is considered to give an insufficient reliability.
  • the invention provides an assay substrate provided with an array of spots, wherein at least part of the spots are mixed spots that comprise at least a first type of specifically binding capture probe and a second type of specifically binding capture probe.
  • This mixture is a well-controlled intended mixture at precise concentrations of its constituents, and should not be confused with accidental mixtures that may occur because of highly unwanted contamination of spots during a badly performing deposition procedure.
  • spots share at least two different capture probe types, making it possible to have more different types of capture probes in the same amount of spots, hereby enabling a redundancy that is in between two integer redundancies of the state-of-the-art solutions, where, opposite to the current invention, only homogeneous spots each of a single capture probe type are being used, for instance, in between 2-fold and 3-fold redundancy as described in the example above.
  • normally 4 spots would be needed to have a 2-fold redundancy for an assay having 2 types of capture probes, each being present in two spots containing a single type of capture probe.
  • spots containing only one type of capture probe it would be possible to have 2 'pure' spots containing only one type of capture probe, and one 'shared' spot containing both types of capture probe. Thus, only 3 spots would be needed instead of 4 spots, saving 25% of the area of the substrate.
  • This example addresses a redundancy between 2-fold redundancy and no redundancy or 1-fold redundancy; for the sake of simplicity, it could be called 1.5-fold redundancy. It is preferred if spots containing the same type of capture probe are not adjacent within the matrix, in other words they are preferably positioned at a mutual distance.
  • At least part of the spots comprise at least three different types of capture probes. Sharing spots by three types of capture probes would even further increase the flexibility in choice of the redundancies, leading in this case to (n+1/3)- fold or (n+2/3)-fold redundancies..
  • At least part of the spots comprises a first area zone comprising the first capture probe and a second area zone comprising the second capture probe, wherein the first area zone and the second area zone at least partially overlap, that is, forming an overlap zone that covers at least part of the spot area.
  • the spot area for a given type of capture probe at a given spot location on the substrate or membrane is the area in which capture probes of that type have been deposited. It is further assumed that said area zones do not overlap with respective area zones of neighbouring spots in the lay-out of the assay.. Having a larger overlap zone leads to a more efficient use of the area.
  • the overlap zone covers the complete spot area for each of the constituent capture probe types completely.
  • the first and second area zones are completely overlapping, leading to a complete mixture of the first and second type of capture probes and an optimal use of the substrate area.
  • the overlap zone covers at least 20% of the spot area.
  • the overlap zone covers between 20%-80% of the spot area.
  • the improvement in the efficient use of the substrate area is significant, but there remains a non-overlapping zone for at least one of the first and second area zones, making it easier to distinguish between binding to the first and/or second type of capture probe.
  • the first area zone and the second area zone have an elongated shape, and the elongated shapes partially overlap.
  • the elongated shapes make it easier to distinguish the first and second area zones representing the first and second type of capture probe.
  • the longitudinal axes of the first area zone and the second area zone may coincide or may at an angle.
  • distal ends of the first and second zone make the partial overlap.
  • the longitudinal axes of the first elongated area zone and the second elongated area zone define an angle smaller than 180°.
  • the mixed spots in the case of mixed spots with two types of capture probes as constituents, contain the first capture probe and the second capture probe in a ratio ranging from 10:90 to 90:10.
  • both species are detectable if labelled material binds to any of the first and second capture probes.
  • the dynamic range for detection remains within reasonable limits, allowing for a better overall sensitivity.
  • the ratios are determined by the maximum amount of labelled material that binds to each type of capture probe.
  • the mixed spots contain the first capture probe and the second capture probe in ratio of from 40:60 to 60:40.
  • the dynamic range for detection remains within acceptable limits.
  • the ratio is approximately 50:50.
  • At least one type of capture probe is present in at least two spots of the array.
  • Such an embodiment leads to a yield factor of at least close to standard two-fold redundancy for that type of capture probe, which is found to be acceptable for a rapid, qualitative analysis. A higher redundancy of at least 2.5-fold redundancy, is preferred for a more precise quantitative analysis.
  • each type of capture probe in the array is present in at least two spots of the array.
  • At least one type of capture probe is present in at least three spots of the array. This enables test results with a noise factor close to standard (non-mixed) three-fold redundancy, which is a vast improvement of the noise factor when compared to two-fold redundancy, and yields very reliable quantitative analysis results.
  • the noise factor may be further improved if the capture probe is present in more than three spots in the array. It is advantageous if at least one type of capture probe in the array is present in at least one pure spot comprising only one type of capture probe and at least one mixed spot comprising at least two different types of capture probes. This combination yields a good noise factor and an efficient use of the substrate area.
  • At least one type of capture probe in the array is present in at least two pure spots comprising only one type capture probe and at least one mixed spot comprising at least two different types of capture probes.
  • the amount of capture probe in the mixed spot is at least 10% compared to the amount of capture probe in the pure spot (a pure spot is a spot containing only a single type of capture probe).
  • the capture probe in the mixed probe yields a significant contribution to lowering the noise factor compared to the pure spots. More preferably, the amount of capture probe in the mixed spot is at least 20% compared to the amount of capture probe in the pure spot.
  • the preferred amount is approximately 50% and the ratio between the two capture probes in the mixed spot is 50:50. In case the mixed spot contains three types of capture probes, the preferred amount is approximately 33% and the ratio between the three capture probes in the mixed spot is 33:33:33.
  • the total amount of capture probes in the mixed spot is from 50% to 200% compared to the amount of corresponding capture probes in pure spots.
  • the dynamic detection range is limited.
  • the total amount of capture probes in the mixed spot is from 90% to 110% compared to the amount of corresponding capture probes in pure spots.
  • the dynamic detection range of pure spots is essentially the same as for mixed spots.
  • the invention further provides a method for the preparation of a biological assay, comprising the steps of providing a substrate, application of a plurality of different binding capture probes to the substrate, forming spots, wherein at least part of the spots are formed as mixed spots by applying at least a first type of capture probe and a second type of capture probe to the same area location on the substrate.
  • the substrate may be any suitable substrate type for the application of microarrays, for instance manufactured by inkjet techniques adapted for use with bio fluids.
  • the same area location implies that the capture probes are applied at essentially the same area location on the substrate, in other words, on essentially the same coordinates in the array.
  • the mixed spots are formed by applying the first type of capture probe to the spot, followed by applying the second type of capture probe to the spot. For instance for inkjet techniques, this may be employed by applying a drop of a medium containing the first capture probe to the substrate, and subsequently applying a drop of another medium containing the second type of capture probe to the same spot. An offset may be used for the first and second type of capture probes, resulting in partially overlapping zones containing different capture probes.
  • a first capture probe is mixed with a second capture probe to form a capture probe mixture at a well-defined ratio of their concentrations, followed by the application of the capture probe mixture to the spot.
  • a mixed spot may be achieved in only one application step, and the different types of capture probes can be mixed homogeneously.
  • the assay substrate is a biological assay substrate.
  • Figs. Ia, Ib and Ic describe biological assay substrates according to the invention.
  • Figs. 2a and 2b describe another biological substrate assay according to the invention.
  • Figs. 3a-3c show various types of overlapping, mixed spots.
  • Fig. Ia shows a detail of a biological assay substrate 1 comprising a non- permeable 2D substrate or a permeable membrane 2 provided with multiple printed area zones 3, 4, 5, 6 comprising different specifically binding capture probes A and B, wherein each type of capture probe has a double redundancy.
  • the substrate is provided with pure spots 3, 6 comprising either A or B, and mixed spots 4,5 wherein the spot is formed by a first area zone 4 comprising a first capture probe A that partially overlaps a second area zone 5 comprising a second capture probe B.
  • the overlapping area 7 covers approximately 20% of the total area covered by the combined areas 4,5. Also situations where the overlapping area 7 covers 100% of the area zones are possible.
  • the area zones 3, 4, 5, 6 have a circular shape, but other shapes may be used as well. Only three spot locations in the matrix are needed instead of 4 spot locations that would be needed if a 2-fold redundancy was achieved using only non-mixed spots, yielding an improvement in the area use of 25% compared to separated spots and offering the possibility to include more different spots for more different species in the assay. For simplicity, only two species A and B are shown here; in reality the number of species would typically be from approximately 50 different species to hundreds of different species, usually arranged in a pattern to ensure that redundant spots of the same species lie at remote locations in the array, and preferably with different "neighbourhoods", that is, different spot types at the neighbouring locations of each of the redundant spots. Fig.
  • Ib is similar to Fig. 1, but instead both species A and B are present in triplicate redundancy, having one in three spots overlapping with a spot of another species.
  • the printed areas 10, 11, 12, 13, 14, 15 have an elongated shape, allowing for a better detection of the overlapping area 16 by automated digital means.
  • the elongated shapes are ellipsoids and overlap in the direction of their coinciding longitudinal axes 17, 18. It is preferred, however, to have the ellipsoid dots overlap with their longitudinal axis under an angle as shown in Fig. Ic for the same set of printed areas 10, 11, 12, 13, 14, 15, which makes it even easier to distinguish the areas containing A and B within the mixed spot.
  • the spots have been shown here at adjacent positions: it is preferable to have spots containing the same type of capture probe at remote positions within the array.
  • Fig. 2a shows an array 20 of spots of specifically binding capture probes, wherein rows 22 of single, non-overlapping spots 21 alternate with rows 23 of mixed spots 24.
  • a 3 -fold redundancy is used which means that for each type of capture probe in the hybridisation experiment, three independent spots are allocated on the 2D array.
  • a higher redundancy results in a higher quality of detection and thus diagnosis.
  • the higher the redundancy the lower the amount of different (capture probe) spots that can be located on the array 20.
  • optimised trade-off in quality of detection and number of parallel testing It is shown that the detection method of this "shared" redundancy is almost as good as the standard 3-fold redundancy.
  • the total number of fluids that can be printed on the substrate and thus screened for in parallel increases with 20%.
  • array patterns are used wherein each probe spot is applied on a predefined, separated region, not sharing any locations or having overlap with other probes of a different type, that is, those spots are completely homogeneous with respect to the capture probe type.
  • a shared spot 24 gives a positive signal than a non- shared spot 21.
  • a signal of up to 200% intensity compared to pure spots may be detected. Therefore, care must be taken to prevent that these intense spots require a broader dynamic range of detection and may overpower weak spots, which may not be detected. It is most efficient to locate these spots at places where they have less neighbouring spots, which means at the corners and edges of the pattern. It also gives input on possible non- linear behaviour of intensity measurements as a function of illumination strength. This information can again be used to correct for non-linear behaviour.
  • Fig. 2b describes a hexagonal grid array 25, wherein each pair of overlapping dots 26 is surrounded by 6 single, non-overlapping dots 27.
  • the capture probe spots as shown in the figures described above are printed onto a substrate such as a membrane.
  • a substrate such as a membrane.
  • a suitable biological active material may for instance be a solution of a specific DNA sequence and/or antibody.
  • Molecular diagnostics demands for a very high reliability of the overall process of making the substrate provided with the different capture probe spots, and more specifically the printing process of the capture probe spots.
  • the read-out of the assay substrate for instance relates diseases directly to the positions of the specific capture probes. The resolution must be sufficient to distinguish not only separated spots but also overlapping spots as shown in the figures. It is therefore important to be able to position the capture probes on the membrane reliably and correctly, using a suitable printing device.
  • Fig. 3a shows a mixed spot 30 comprising multiple types of capture probes, as well as pure spots 31, 32 each containing only one type of capture probe.
  • the filling patterns overlap.
  • Such spot may be obtained by superimposing depositions of pure spots of the same size, of by depositing a premixed composition containing a plurality of capture probes.
  • Fig. 3b shows another type of mixed spot 35 and corresponding pure spots 36, 37.
  • a first zone 38 only contains the first capture probe that is also present in the circular pure spot 37.
  • An overlap zone 39 comprises both the first capture probe type from the circular pure spot 37 as well as the second capture probe type present in the rectangular pure spot 36.
  • Such overlapping spots may for instance be obtained by depositing pure spots of different capture probes at the same location on the substrate.
  • Fig. 3c shows yet another type of mixed spot 40, and the corresponding pure spots 41, 42 from which the mixed spot may be constructed in a way similar to fig. 3b.
  • the mixed spot contains two 'pure' zones 43 containing the first capture probe from the first pure spot 41, a 'pure' zone 44 containing the second type of capture probe corresponding to the second pure spot 42, and an overlapping mixed zone 45 comprising both types of capture probe.
  • this noise factor increases to a high extent.
  • a substantially lower noise factor is obtained in case of a 2, 5-fold redundancy according to the current invention, wherein 2 dots of two species containing only half the specifically binding material completely overlap (a 50%-50% mixture of two different capture probes).
  • a better, lower noise factor is obtained in the case of the "shared" three-fold redundancy , according to a further embodiment of the current invention, wherein the overlapping spots contain the same amount of specifically-binding material as the non-overlapping spots.
  • the result of shared three-fold redundancy is almost as good as the standard 3-fold redundancy without overlapping spots, while saving space and enabling a larger number of different spots per substrate area.
  • the spots are applied to the predetermined spot locations on the substrate using inkjet printing devices suitable for printing fluids comprising specifically binding biomaterials such as DNA, RNA, antibodies and derivatives thereof, depending on the type of test that is to be performed.
  • the diameter of the spot increases with increasing amount of fluid printed.
  • the diameter increases with the number of identically printed droplets with: D ⁇ f(Ndr)(l/3). In the case of porous membranes, this power is around 0.2.
  • the "shared" 3-fold redundancy is based on the fact that first the total amount of fluid 1 is printed on the spot. After printing, this spot dries within seconds.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
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  • Wood Science & Technology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Health & Medical Sciences (AREA)
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  • Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
  • Apparatus Associated With Microorganisms And Enzymes (AREA)

Abstract

L'invention concerne un substrat d'analyse biologique et son procédé de préparation. En préparant un substrat d'analyse biologique pourvu d'un réseau de points, dans lequel au moins une partie de ces points sont des points mélangés, qui comprennent au moins un premier type de sonde de capture de liaison spécifique, on obtient une utilisation plus efficace de la zone du substrat, ce qui permet davantage de types différents de sondes de capture telles que ADN, ARN ou anticorps au moyen de la même quantité d'emplacements de points, sans compromettre la fiabilité de l'analyse.
PCT/IB2008/053426 2007-08-27 2008-08-26 Substrat d'analyse et procédé de préparation associé WO2009027932A1 (fr)

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EP07115040.3 2007-08-27

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Cited By (5)

* Cited by examiner, † Cited by third party
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CN102883459A (zh) * 2011-07-12 2013-01-16 华为技术有限公司 随机接入响应的接收和发送方法、用户设备、基站及系统
WO2014108322A1 (fr) * 2013-01-08 2014-07-17 Rainer Hintsche Détection de molécules à l'aide de matrices dotées de différentes molécules de capture à chaque position de matrice
EP3342851A4 (fr) * 2015-08-26 2019-04-03 Kaneka Corporation Dispositif de détection d'acide nucléique et procédé de détection d'acide nucléique
WO2022128610A1 (fr) * 2020-12-16 2022-06-23 Robert Bosch Gmbh Procédé et appareil pour attribuer un réactif spécifique à un espace de réaction
US11371988B2 (en) 2009-08-02 2022-06-28 Qvella Corporation Cell concentration, capture and lysis devices and methods of use thereof

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GB2355716A (en) * 1999-04-30 2001-05-02 Agilent Technologies Inc Polynucleotide array fabrication
US20040018635A1 (en) * 2002-07-26 2004-01-29 Peck Bill J. Fabricating arrays with drop velocity control
EP1442789A1 (fr) * 2003-01-31 2004-08-04 Agilent Technologies, Inc. Matrices multiples
US20070259347A1 (en) * 2006-05-03 2007-11-08 Agilent Technologies, Inc. Methods of increasing the effective probe densities of arrays
US20070259344A1 (en) * 2006-05-03 2007-11-08 Agilent Technologies, Inc. Compound probes and methods of increasing the effective probe densities of arrays
US20070259346A1 (en) * 2006-05-03 2007-11-08 Agilent Technologies, Inc. Analysis of arrays

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Publication number Priority date Publication date Assignee Title
GB2355716A (en) * 1999-04-30 2001-05-02 Agilent Technologies Inc Polynucleotide array fabrication
US20040018635A1 (en) * 2002-07-26 2004-01-29 Peck Bill J. Fabricating arrays with drop velocity control
EP1442789A1 (fr) * 2003-01-31 2004-08-04 Agilent Technologies, Inc. Matrices multiples
US20070259347A1 (en) * 2006-05-03 2007-11-08 Agilent Technologies, Inc. Methods of increasing the effective probe densities of arrays
US20070259344A1 (en) * 2006-05-03 2007-11-08 Agilent Technologies, Inc. Compound probes and methods of increasing the effective probe densities of arrays
US20070259346A1 (en) * 2006-05-03 2007-11-08 Agilent Technologies, Inc. Analysis of arrays

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11371988B2 (en) 2009-08-02 2022-06-28 Qvella Corporation Cell concentration, capture and lysis devices and methods of use thereof
CN102883459A (zh) * 2011-07-12 2013-01-16 华为技术有限公司 随机接入响应的接收和发送方法、用户设备、基站及系统
US9565701B2 (en) 2011-07-12 2017-02-07 Huawei Technologies Co., Ltd. Random access response receiving and sending method, user equipment, base station and system
WO2014108322A1 (fr) * 2013-01-08 2014-07-17 Rainer Hintsche Détection de molécules à l'aide de matrices dotées de différentes molécules de capture à chaque position de matrice
EP3342851A4 (fr) * 2015-08-26 2019-04-03 Kaneka Corporation Dispositif de détection d'acide nucléique et procédé de détection d'acide nucléique
WO2022128610A1 (fr) * 2020-12-16 2022-06-23 Robert Bosch Gmbh Procédé et appareil pour attribuer un réactif spécifique à un espace de réaction

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