WO2016046408A1 - Régulation optique d'une réaction chimique - Google Patents

Régulation optique d'une réaction chimique Download PDF

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Publication number
WO2016046408A1
WO2016046408A1 PCT/EP2015/072184 EP2015072184W WO2016046408A1 WO 2016046408 A1 WO2016046408 A1 WO 2016046408A1 EP 2015072184 W EP2015072184 W EP 2015072184W WO 2016046408 A1 WO2016046408 A1 WO 2016046408A1
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WO
WIPO (PCT)
Prior art keywords
substrate
light
cleavage
conductive element
heat conductive
Prior art date
Application number
PCT/EP2015/072184
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English (en)
Inventor
Pieter Jan Van Der Zaag
Anke Pierik
Original Assignee
Koninklijke Philips N.V.
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
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Publication of WO2016046408A1 publication Critical patent/WO2016046408A1/fr

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Classifications

    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
    • B01L3/508—Containers for the purpose of retaining a material to be analysed, e.g. test tubes rigid containers not provided for above
    • B01L3/5085—Containers for the purpose of retaining a material to be analysed, e.g. test tubes rigid containers not provided for above for multiple samples, e.g. microtitration plates
    • B01L3/50851—Containers for the purpose of retaining a material to be analysed, e.g. test tubes rigid containers not provided for above for multiple samples, e.g. microtitration plates specially adapted for heating or cooling samples
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
    • G01N21/63—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
    • G01N21/64—Fluorescence; Phosphorescence
    • G01N21/6428—Measuring fluorescence of fluorescent products of reactions or of fluorochrome labelled reactive substances, e.g. measuring quenching effects, using measuring "optrodes"
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
    • G01N21/63—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
    • G01N21/64—Fluorescence; Phosphorescence
    • G01N21/645—Specially adapted constructive features of fluorimeters
    • G01N21/648—Specially adapted constructive features of fluorimeters using evanescent coupling or surface plasmon coupling for the excitation of fluorescence
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/75—Systems in which material is subjected to a chemical reaction, the progress or the result of the reaction being investigated
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/06—Auxiliary integrated devices, integrated components
    • B01L2300/0627—Sensor or part of a sensor is integrated
    • B01L2300/0636—Integrated biosensor, microarrays
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/18—Means for temperature control
    • B01L2300/1805—Conductive heating, heat from thermostatted solids is conducted to receptacles, e.g. heating plates, blocks
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
    • G01N21/63—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
    • G01N21/64—Fluorescence; Phosphorescence
    • G01N2021/6417—Spectrofluorimetric devices
    • G01N2021/6419—Excitation at two or more wavelengths
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/483—Physical analysis of biological material

Definitions

  • the present invention relates to a device and a method for enabling an optically controlled chemical reaction in a reaction chamber comprising a reagent fluid.
  • the present invention relates to a device for enabling an optically controlled iterative stepwise reaction to determine a sequence of a nucleic acid, and a method for enabling an optically controlled iterative stepwise reaction to determine a sequence of nucleic acid.
  • the device comprises a removable cartridge comprising a substrate for binding at least one molecule on a first surface of the substrate, and an optical arrangement configured to direct cleavage light to the substrate to optically induce a photochemical cleavage reaction.
  • WO 2013/105025 Al which is incorporated into the present text by reference, describes a device and a method for optically controlling the iterative incorporation of fluorescent ly labeled nucleic acids into a molecule attached to the surface of a wiregrid substrate. Based on a strong optical confinement of excitation light and of cleavage light by evanescent waves, the sequencing reaction can be read-out without washing the surface. Stepwise sequencing is achieved by using nucleotides with optically cleavable blocking moieties. After read-out the built-in nucleotide is deblocked by cleavage light through the same substrate. This ensures that only bound nucleotides will be unblocked.
  • the cleavage light required for this method must be a high intensity UV light.
  • the object is achieved by a device for enabling an optically controlled chemical reaction in a reaction chamber comprising a reagent fluid, said device comprising: a removable cartridge comprising a substrate for binding at least one molecule on a first surface of the substrate; an optical arrangement configured to direct cleavage light to the substrate to optically induce a photochemical cleavage reaction; wherein the substrate further comprises a wiregrid, and wherein the wiregrid is further thermally coupled to a heat conductive element.
  • the reagent fluid may be cooled. Cooling may for example be achieved by connecting the wiregrid to a conductive element having a higher thermal mass than the substrate, through which excess heat can be transferred to a cooling medium (e.g. the surrounding atmosphere). Additionally or alternatively, means for actively cooling the reagent fluid may be provided, too, for example a Peltier element.
  • thermal mass it is intended the ability of a body to store thermal energy.
  • the object is achieved by a method for optically controlling a chemical reaction in a reaction chamber comprising a reagent fluid, said method comprising the following steps: providing a substrate with a molecule bound on a first surface of the substrate , wherein said first surface is a wall of the reaction chamber;
  • the device and the method allow for (photo-) chemical reactions taking place with a high throughput at the surface of the substrate. This is because the heat conductive element coupled to the substrate allows the excessive heat which is produced by the irradiation of cleavage light to be carried away. Hence high intensities of cleavage light can be applied without damaging material at the surface, which enables higher reaction rates.
  • the heat conductive element allows the substrate to be heated by an external heat source.
  • the heat conductive element is capable of actively cooling and/or heating the substrate.
  • the reaction temperature is the temperature of the fluid while the reaction takes place; the reaction temperature is raised by the cleavage light, which heats up both the substrate and the reaction fluid.
  • the heat conductive element is further connected to a device for controlling the temperature.
  • a device for controlling the temperature An advantage of this embodiment is that the reaction temperature can be more finely controlled by such device.
  • the reaction temperature may for example be controlled in a feedback loop based on a sensed temperature (e.g. of the reagent fluid or of the substrate) such that the temperature at the reaction surface is always kept at an optimal level.
  • intensity of the cleavage light is larger than about 0.1 mW/cm 2 , larger than about 0.5 mW/cm 2 , larger than about 1 mW/cm 2 , or larger than about 5 mW/cm 2 .
  • Stepwise sequencing is achieved by using nucleotides with optically cleavable blocking groups. After read-out, the built-in nucleotide is unblocked by cleavage light like for example UV radiation through the same nano-photonic substrate. This ensures that only bound nucleotides will be unblocked.
  • the wiregrid may comprise a pattern of metal wires on, for example, a glass substrate.
  • the spacing between the wires acts as a metal-clad slab waveguide, in which the major contribution comes to two fundamental modes.
  • a wiregrid may comprise aluminium wires which reflect excitation light with polarization parallel to the wires (TE polarization) and which transmit polarization orthogonal to the wires (TM polarization).
  • TE polarization polarization parallel to the wires
  • TM polarization transmit polarization orthogonal to the wires
  • the evanescent mode For example, with a wire height of 60 nanometres the TM polarized mode is transmitted with a loss of light in the order of 10% or less, while the TE polarized mode is evanescently decaying.
  • the use of the wiregrid has the additional advantage of being largely independent on the angle in incidence. Therefore, it can be used in combination with focussed beams to achieve a high intensity locally while keeping the rest in the dark.
  • the wiregrid allows to excite and be sensitive to only those molecules, for example DNA fragments, that are very close to the surface in the evanescent field and thus no detection or effect on any label nucleotide outside the evanescent field is caused.
  • the evanescent field may elongate about 20 nanometres from the first surface of the substrate. This may be the case for both the excitation light and the cleavage light.
  • excitation light in the context of the present invention applies to the wavelength ⁇ ⁇ ⁇ , ⁇ ⁇ 2 , ⁇ ⁇ 3 and ⁇ ⁇ 4 , respectively. Consequently, for all four excitation wavelengths the substrate ensures that confinement and a creation of an evanescent wave of the respective light are generated. If desired, more or less light sources and/or fluorescent labels can be used without departing from the present invention.
  • the cleavage light is in an evanescent mode with respect to the substrate provides for the advantage that a repeated exposure does not lead to fluorescent labels in the solution which are bleached and which lose their function.
  • the presented embodiment avoids such a bleaching and function- losing of fluorescent labels in solution.
  • Fig. 1 depicts an embodiment of a device 100 for optically controlling a chemical reaction according to the invention, in this case particularly an iterative stepwise reaction to determine a sequence of a nucleic acid by synthesis.
  • the device comprises a substrate 101 for binding at least one molecule 102 on the first surface 103 of the substrate.
  • the molecule 102 which is bound on the first or front surface 103 of the substrate 101 can for example be a fragment of a DNA.
  • the first surface 103 constitutes a wall or border of a reaction chamber 149 in which a fluid to be processed (here a reagent fluid 114 that is described in more detail below) can be accommodated.
  • the reaction chamber is typically a part of a larger (micro) fluidic device or cartridge that is not shown in more detail.
  • Fig. 1 the optical arrangement 104 is shown in Fig. 1.
  • the optical arrangement is configured to direct excitation light 110 of for example the first excitation wavelength ⁇ to the substrate.
  • four different nucleotides are schematically shown and are depicted with reference signs 109, 116, 117 and 118.
  • a first nucleotide 109 is shown as Thymine, T.
  • the nucleotide 109 comprises a blocking moiety 119.
  • the blocking moiety 119 comprises the first fluorescent label 105.
  • second nucleotide 116 is schematically depicted in Fig. 1, from which can be gathered that also a blocking moiety 119 and the second fluorescent label 106 is comprised.
  • the third nucleotide 117 comprises also a blocking moiety and a third fluorescent label 107.
  • nucleotide 118 is schematically depicted which comprises also a blocking moiety and a fourth fluorescent label 108.
  • solution 114 may comprise a much larger plurality of such nucleotides, and nucleotides 109, 116, 117 and 118 are shown here merely as a symbolic depiction.
  • Fig. 1 shows a solution 114 which fills the reaction chamber 149 and in which the nucleotides and the enzyme 115 are comprised.
  • the presented device 100 provides for the following advantages.
  • the optical arrangement is configured to receive and detect fluorescence light emitted by the fluorescent label of the first nucleotide incorporated into the bound molecule 102.
  • the optical arrangement is configured to direct cleavage light 112 of cleavage wavelength ⁇ to the substrate. This allows for optically inducing a photochemical cleavage reaction at the first incorporated nucleotide to cleave the respective fluorescence label from the first incorporated nucleotide.
  • the substrate 101 is configured to confine excitation light such that an evanescent wave of the excitation light at the first surface of the substrate is created.
  • the substrate is configured to confine also the cleavage light such that an evanescent wave of the cleavage light at the first surface of the substrate is created.
  • the substrate 101 is configured as a wiregrid 130 for the excitation light 110 and for the cleavage light 112. Therefore, the wiregrid 130 comprises a regular pattern, like for example a regular structure made of a plurality of metal wires 131. As can be gathered from Fig. 1, slit-like openings are provided between the wires 131, in which openings the bound molecules 102 are immobilized at the first surface 103 of the substrate 101.
  • Fig. 1 depicts a processing unit 120 which comprises a computer-readable medium 121 on which a computer program element 122 is stored. Said program element 122 is adapted to instruct the processing unit 120 to further instruct the device 100 to perform the above and below described method for optically controlling an iterative stepwise reaction to determine a sequence of a nucleic acid by synthesis.
  • the device 100 of Fig. 1 is configured to stepwise and optically induce the incorporation of nucleotides
  • nucleotides comprised by the solution 114 are incorporated into molecule 102 in a sequence that corresponds to the nucleotide sequence of molecule 102.
  • the device is further configured to base the determination of the sequence of the incorporated nucleotides on the received and detected response fluorescence light emitted by the fluorescent label of the respective incorporated nucleotide. Therefore, the presented device 100 of Fig. 1 firstly ensures that only nucleotides are read-out by the excitation light
  • the device 100 of Fig. 1 ensures that only bound nucleotides will be unblocked by the cleavage light which avoids a bleaching and loss of function of nucleotides that are not yet contained i.e. incorporated by the molecule 102. Consequently, the detected fluorescence signal 100 may be seen as the light 111, is highly reliable for the determination of the sequence of the nucleic acids.
  • the device of Fig. 1 shows a simplification and cost reduction of sequencing.
  • the presented device 100 of Fig. 1 allows for a new process combination by allowing an assemble-based easy read-out without any washing step, meaning a single reagent filling for all reads.
  • the blocking moieties used within the exemplary nucleotides 109, 116, 117, 118 may for example be a photo-cleavable 3'-unblocked reversible terminator. However, also other blocking moieties, using for example steric hindering, may be used to reach the desired and above described effects.
  • the intensity of the cleavage light of the device of Fig.1 is adapted such that for the used combination of nucleotides and blocking moieties the cleaving reaction time t c i ea vage is smaller than ti ncorpora ti on .
  • the following set-up of device 100 may be provided to the user. If the reagent fluid is stationary and movement of molecules driven by diffusion, then the residence may be seen as an average residence time in the spot of cleavage light of a non- incorporated nucleotide.
  • An optical arrangement may further be configured to provide the irradiated cleavage light with an intensity such that t c i ea vage is smaller than t res idence. Consequently, no degradation of free and unbound nucleotides due to an undesired cleavage reaction happens.
  • the probability of damage can be derived. Assume an illumination time of 0.1 s this would be 1 :4000, with an illumination time of 10 ms it would be 1 :400, etc.
  • heat conductive element 132 The aforementioned proposal is realized in the device 100 of Fig. 1 by a heat conductive element 132.
  • wiregrid 130 is coupled to at least one heat conductive element 132, wherein said heat conductive element 132 is in physical contact with at least one of the metal wires 131, more preferably with a plurality or even all wires 131.
  • heat conductive element 132 is depicted in Fig. 1 as being in contact with the lower portion of two wires 131 , it is understood that heat conductive element 132 can also contact wiregrid 130 in any other position, for example on the top of it, and it can be in contact with any number of wires.
  • Heat conductive element 132 can be a single metallic bar, but it can also comprise two or more metallic and/or non-metallic elements attached to different sides of wiregrid 130, and it can have any shape.
  • Heat conductive element 132 acts as a heat sink, attracting the heat away from the wires 131 , thanks to the high thermal capacity, in turn lowering the temperature of the wiregrid 130 and hence of the solution 1 14 and of the reaction chamber 149. Molecules 102 are always surrounded by the chemicals they need while excess heat, particularly heat generated by cleavage light, is carried away from the surface to avoid overheating.
  • sequencing system in which sequencing is done using a wiregrid connected to a heat sink to avoid overheating the system while de-blocking using UV light.
  • Fig. 2 shows a device 200 which is configured to optically control an iterative stepwise reaction to determine a sequence of a nucleic acid by synthesis.
  • a substrate 201 is shown on which a plurality of molecules 202 are immobilized, i.e. are bound.
  • the metallic wires 231 of a wiregrid 230 similar to that of Fig. 1 provides for slit-like openings 215 in which the molecules 202 are bound on the first surface 203.
  • the substrate comprises several adjacent binding positions 209, 210, 21 1 and 212 for binding molecules to the first surface along a first direction 213.
  • Said binding positions may be seen as spots which can be covered with clones of identical molecules, such that the optical signal, which is generated, can be increased.
  • the substrate 201 then provides for an array of such spots, i.e. of such binding positions, with respectively different clones. This may enhance the throughput.
  • Both devices 100 and 200 of Figs. 1 and 2 allow a nucleic acid sequencing with only one liquid, thereby avoiding the need to provide for washing steps in which the solution liquid is changed.
  • the optical arrangement 204 comprises five different light sources 201 to 205.
  • the light sources 201 to 204 may be seen as excitation light sources in order to provide for four different excitation wavelength ⁇ ⁇ ⁇ to ⁇ ⁇ 4 as described previously.
  • the light source 205 provides for cleavage light with a wavelength ⁇
  • the light source 205 may emit UV light.
  • Reference numeral 206 symbolically depicts a switching device which allows the optical arrangement 204 to switch between the five wavelengths ⁇ ⁇ to ⁇ £ ⁇ 4 and CL- Furthermore, the light emitted by at least one of said light sources 201 to 205 is directed towards the polarization filter 200.
  • the device allows to perform the optical scan such that each binding position is firstly irradiated with the excitation light and subsequently and secondly is irradiated the cleavage light of the cleavage wavelength in a movement along the first direction 213.
  • the unblocking step, using the cleavage light, can thus be carried out after reading the fluorescence of the excited incorporated nucleotides.
  • Fig. 2 further shows a heat conductive element 232 as described above with respect to Fig. 1 which allows for a dispersion of excess heat generated by the UV light.
  • Fig. 3 schematically shows a top view close-up of substrate 301, wherein wiregrid 330 is coupled to a heat conductive element 332.
  • Element 332 comprises in turn a first bar 332a and a second bar 332b, attached parallel to each other to opposite sides of wires 331.
  • each of the metal wires 331 is in contact with both bar 332a and bar 332b, so that the heat sink function of heat conductive element 332 is doubled.
  • heat conductive element 332 can have any shape or size, and it can be coupled to wiregrid 330 in any position and with any configuration which are possible to imagine.
  • the heat conductive element is capable of actively controlling the temperature of the wiregrid.
  • Fig. 4 schematically shows a top view of a close-up of substrate 401 according to the latter embodiment.
  • substrate 401 is shown as comprised within reaction chamber 449, containing reagent fluid 414, similarly to the previous embodiments.
  • a temperature detector 437 measures the temperature of the reaction chamber 449.
  • temperature detector 437 can also measure the temperature of reagent fluid 414, and/or of substrate 401. Temperature detector 437 is coupled to processing unit 438, which in turn is connected to temperature control unit 436.
  • Processing unit 438 can correspond to processing unit 120 of Fig. 1, but it can also be an independent processing unit, or it can be integrated in temperature control unit (436).
  • Bars 432a and 432b are each connected to temperature control unit 436, such as a Peltier element. According to this embodiment, it is possible not only to disperse the excess heat generated by the UV light, but to maintain a constant temperature in the wiregrid 430, and hence in the reaction chamber 449.
  • processing unit 438 It is possible to set processing unit 438 so that it maintain a predetermined temperature; based on the temperature detected and communicated to the processing unit 438 by temperature detector 437, processing unit 438 can control temperature control unit 436 so that it will either heat or cool substrate 401 through bars 432a and 432b until the temperature in the reaction chamber 449 corresponds to the desired temperature. It is thus possible to set temperature control unit 436 so that the sequencing reaction can be optimized and made more efficient; for example, the temperature of the reaction chamber 449 can be set at different amount depending on the specific protocol used.
  • heat conductive element 132 can be part of the removable cartridge that also comprises substrate 101 and wiregrid 130.
  • device 100 is designed in a way that when said cartridge is inserted into device 100, heat conductive element 132 is in physical contact with the other features it interact with, for example temperature control unit (436).
  • heat conductive element 132 is integrated into device 100.
  • device 100 is designed so that heat conductive element 132 will be in physical contact with wiregrid 130, once the removable cartridge is inserted into device 100.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Physics & Mathematics (AREA)
  • Analytical Chemistry (AREA)
  • Immunology (AREA)
  • General Health & Medical Sciences (AREA)
  • Pathology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Biochemistry (AREA)
  • General Physics & Mathematics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Plasma & Fusion (AREA)
  • Engineering & Computer Science (AREA)
  • Optics & Photonics (AREA)
  • Hematology (AREA)
  • Clinical Laboratory Science (AREA)
  • Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
  • Apparatus Associated With Microorganisms And Enzymes (AREA)

Abstract

La présente invention concerne un dispositif pour permettre une réaction chimique régulée de manière optique dans une chambre de réaction ; il comprend un substrat sur une cartouche amovible pour la liaison d'au moins une molécule sur une première surface du substrat, un agencement optique conçu pour diriger la lumière de clivage sur le substrat en vue d'induire optiquement une réaction de clivage photochimique et une grille en fer métallique en outre couplée thermiquement à un élément thermoconducteur. Un tel dispositif peut être utilisé, par exemple, pour effectuer une réaction chimique régulée de manière optique, en particulier une réaction de séquençage nucléique. Il peut être utilisé pour effectuer des réactions à un débit augmenté sans surchauffe du dispositif lui-même ou des réactifs utilisés.
PCT/EP2015/072184 2014-09-26 2015-09-25 Régulation optique d'une réaction chimique WO2016046408A1 (fr)

Applications Claiming Priority (2)

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EP14186554.3 2014-09-26
EP14186554 2014-09-26

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WO2016046408A1 true WO2016046408A1 (fr) 2016-03-31

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006105360A1 (fr) * 2005-03-29 2006-10-05 Applera Corporation Systeme a base de nanofils conçu pour l'analyse d'acides nucleiques
US20090312188A1 (en) * 2008-06-16 2009-12-17 Reuven Duer System and method for nucleic acids sequencing by phased synthesis
WO2013105025A1 (fr) * 2012-01-13 2013-07-18 Koninklijke Philips N.V. Séquençage d'adn avec recyclage du réactif sur la grille métallique

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006105360A1 (fr) * 2005-03-29 2006-10-05 Applera Corporation Systeme a base de nanofils conçu pour l'analyse d'acides nucleiques
US20090312188A1 (en) * 2008-06-16 2009-12-17 Reuven Duer System and method for nucleic acids sequencing by phased synthesis
WO2013105025A1 (fr) * 2012-01-13 2013-07-18 Koninklijke Philips N.V. Séquençage d'adn avec recyclage du réactif sur la grille métallique

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
CARL W FULLER ET AL: "The challenges of sequencing by synthesis", NATURE BIOTECHNOLOGY, vol. 27, no. 11, 1 November 2009 (2009-11-01), pages 1013 - 1023, XP055013694, ISSN: 1087-0156, DOI: 10.1038/nbt.1585 *

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