WO2012098349A1 - Lab on a chip device - Google Patents
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- WO2012098349A1 WO2012098349A1 PCT/GB2012/000035 GB2012000035W WO2012098349A1 WO 2012098349 A1 WO2012098349 A1 WO 2012098349A1 GB 2012000035 W GB2012000035 W GB 2012000035W WO 2012098349 A1 WO2012098349 A1 WO 2012098349A1
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- microchip
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Classifications
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- 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
- B01L3/502—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
- B01L3/5027—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip
- B01L3/502715—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip characterised by interfacing components, e.g. fluidic, electrical, optical or mechanical interfaces
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- 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
- B01L3/502—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
- B01L3/5027—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip
- B01L3/502761—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip specially adapted for handling suspended solids or molecules independently from the bulk fluid flow, e.g. for trapping or sorting beads, for physically stretching molecules
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- B03—SEPARATION OF SOLID MATERIALS USING LIQUIDS OR USING PNEUMATIC TABLES OR JIGS; MAGNETIC OR ELECTROSTATIC SEPARATION OF SOLID MATERIALS FROM SOLID MATERIALS OR FLUIDS; SEPARATION BY HIGH-VOLTAGE ELECTRIC FIELDS
- B03C—MAGNETIC OR ELECTROSTATIC SEPARATION OF SOLID MATERIALS FROM SOLID MATERIALS OR FLUIDS; SEPARATION BY HIGH-VOLTAGE ELECTRIC FIELDS
- B03C5/00—Separating dispersed particles from liquids by electrostatic effect
- B03C5/005—Dielectrophoresis, i.e. dielectric particles migrating towards the region of highest field strength
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B03—SEPARATION OF SOLID MATERIALS USING LIQUIDS OR USING PNEUMATIC TABLES OR JIGS; MAGNETIC OR ELECTROSTATIC SEPARATION OF SOLID MATERIALS FROM SOLID MATERIALS OR FLUIDS; SEPARATION BY HIGH-VOLTAGE ELECTRIC FIELDS
- B03C—MAGNETIC OR ELECTROSTATIC SEPARATION OF SOLID MATERIALS FROM SOLID MATERIALS OR FLUIDS; SEPARATION BY HIGH-VOLTAGE ELECTRIC FIELDS
- B03C5/00—Separating dispersed particles from liquids by electrostatic effect
- B03C5/02—Separators
- B03C5/022—Non-uniform field separators
- B03C5/024—Non-uniform field separators using high-gradient differential dielectric separation, i.e. using a dielectric matrix polarised by an external field
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B03—SEPARATION OF SOLID MATERIALS USING LIQUIDS OR USING PNEUMATIC TABLES OR JIGS; MAGNETIC OR ELECTROSTATIC SEPARATION OF SOLID MATERIALS FROM SOLID MATERIALS OR FLUIDS; SEPARATION BY HIGH-VOLTAGE ELECTRIC FIELDS
- B03C—MAGNETIC OR ELECTROSTATIC SEPARATION OF SOLID MATERIALS FROM SOLID MATERIALS OR FLUIDS; SEPARATION BY HIGH-VOLTAGE ELECTRIC FIELDS
- B03C5/00—Separating dispersed particles from liquids by electrostatic effect
- B03C5/02—Separators
- B03C5/022—Non-uniform field separators
- B03C5/026—Non-uniform field separators using open-gradient differential dielectric separation, i.e. using electrodes of special shapes for non-uniform field creation, e.g. Fluid Integrated Circuit [FIC]
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- G—PHYSICS
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- G01Q—SCANNING-PROBE TECHNIQUES OR APPARATUS; APPLICATIONS OF SCANNING-PROBE TECHNIQUES, e.g. SCANNING PROBE MICROSCOPY [SPM]
- G01Q30/00—Auxiliary means serving to assist or improve the scanning probe techniques or apparatus, e.g. display or data processing devices
- G01Q30/02—Non-SPM analysing devices, e.g. SEM [Scanning Electron Microscope], spectrometer or optical microscope
- G01Q30/025—Optical microscopes coupled with SPM
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- G—PHYSICS
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- G02B—OPTICAL ELEMENTS, SYSTEMS OR APPARATUS
- G02B1/00—Optical elements characterised by the material of which they are made; Optical coatings for optical elements
- G02B1/02—Optical elements characterised by the material of which they are made; Optical coatings for optical elements made of crystals, e.g. rock-salt, semi-conductors
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
- B01L2200/00—Solutions for specific problems relating to chemical or physical laboratory apparatus
- B01L2200/06—Fluid handling related problems
- B01L2200/0647—Handling flowable solids, e.g. microscopic beads, cells, particles
- B01L2200/0668—Trapping microscopic beads
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- B—PERFORMING OPERATIONS; TRANSPORTING
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- 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
- B01L2300/0654—Lenses; Optical fibres
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- 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
- B01L2300/08—Geometry, shape and general structure
- B01L2300/0809—Geometry, shape and general structure rectangular shaped
- B01L2300/0816—Cards, e.g. flat sample carriers usually with flow in two horizontal directions
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
- B01L2400/00—Moving or stopping fluids
- B01L2400/04—Moving fluids with specific forces or mechanical means
- B01L2400/0403—Moving fluids with specific forces or mechanical means specific forces
- B01L2400/0415—Moving fluids with specific forces or mechanical means specific forces electrical forces, e.g. electrokinetic
- B01L2400/0424—Dielectrophoretic forces
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- 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
- G01N21/6452—Individual samples arranged in a regular 2D-array, e.g. multiwell plates
-
- 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
- G01N21/6456—Spatial resolved fluorescence measurements; Imaging
- G01N21/6458—Fluorescence microscopy
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- G—PHYSICS
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- G02B—OPTICAL ELEMENTS, SYSTEMS OR APPARATUS
- G02B21/00—Microscopes
- G02B21/34—Microscope slides, e.g. mounting specimens on microscope slides
Definitions
- the present invention relates to a Lab on a Chip (LOAC) device and in particular but not exclusively to a LOAC device used as a bioanalytical device with optical transparent characteristics.
- LOAC Lab on a Chip
- pTASs Micro Total Analysis Systems
- MEMS MicroElectroMechanical Systems
- LOAC devices can allow biological investigation at the single cell or sub-cellular level. Such a chip would require the ability to sort cells by type, separate them and deliver them in a controlled manner to an experimental micro-site for experimentation and analytical investigation. Whilst well known cell sorting techniques that are suitable for chip integration such as fluorescence and magnetic activated cell sorting (FACS and MACS) are effective, they suffer from the general requirement to modify the cells by staining with dyes or antibodies and hence increase the complexity of the experimentation and analysis tools.
- FACS and MACS fluorescence and magnetic activated cell sorting
- the present invention seeks to overcome the problems associated with the prior art by providing a portable, standardized, cost effective and rapid system for analyzing biological samples.
- a lab on a chip device including a microchip having a first and a second surface, the first surface having at least one opening in proximity to one or more electrodes on the first surface, with the at least one opening having a dielectric contained therein which forms a base of the opening, characterized in that the second surface has at least one channel that extends into the microchip such that a terminal wall of the at least one channel abuts against the base of the at least one opening, the channel forming an optical passage extending into the microchip such that a sample placed on the first surface and extending over the at least one opening can be viewed through said optical passage. It is envisaged that the area where the terminal wall of a channel in the second surface abuts an opening in the first service provides an optical window through the microchip.
- the sides of the opening in the upper surface are substantially parallel to one another.
- the sides of the channel in the lower surface are angled to one another with the channel being wider at the lower surface of the microchip than at the base of the opening in the upper surface.
- the microchip if formed of a substrate that is predominantly silicon based.
- the microchip has a chamber attached to the surface of the chip to receive a sample.
- the chamber is in the form of a microchamber.
- the electrodes and openings containing the dielectric in the first surface are formed in an array.
- am electrode extends around the periphery of an opening containing the dielectric.
- a method of making a lab on a chip microchip having a first and a second surface wherein an opening is formed in the first surface of the chip and filled with a dielectric material, at least two electrodes are formed adjacent the opening characterized in that a channel is formed in the second surface and aligned with the opening thereby providing an optical passage extending into the microchip.
- the present invention provides a robust technology platform that combines the advantages of a transparent substrate for 'top down' AFM (and other) probing with 'bottom up' epi-fluorescence and other microscopy techniques whilst maintaining a silicon substrate for on-chip' functionality would allow untold possibilities for highly advanced biological experimentation using multiple analytical tools.
- Figure 1 shows a cross section of a device according to an embodiment of the invention
- Figure 2 shows a sequence of steps in the manufacture of a device according to an embodiment of the invention
- Figure 3 shows a plan view of possible optical layouts for a device according to an embodiment of the invention.
- Figure 4 shows a schematic drawing of a LOAC according to an embodiment of the invention having metal electrode connections, Si0 2 top trench fill and micro-fluidic chamber.
- FIG. 1 shows the cross-sectional view of the microchip, which in this case is provided in the form of a silicon wafer.
- the microchip has an upper surface 2 and a lower surface 3.
- the upper surface 2 has at least one opening 4 which extends into the microchip and the opening has side walls 41 and a base 42 extending between the side walls and which forms the bottom of the opening or trench.
- the side walls 41 are substantially perpendicular to the base 42.
- the opening can be filled with a dielectric such as silicon dioxide.
- the channel extends a small finite distance through the thickness of the microchip. A typical distance would be l Omicrons. .
- the walls of the opening have a coating 43 which is an antireflective coating that can reflect light passing through the LOAC and optimize light transmission so samples on the chip can be seen as clearly as possible.
- the lower surface has a channel 5 in the lower surface 3 of the microchip.
- the channel has side walls 51 which are angled so that the mouth of the channel which is at the surface 3 of the microchip is larger than the end wall 52 of the channel which meets the base 42 of the opening 4.
- the base 42 and end wall 52 meet and form a dividing wall between the opening and channel.
- the opening 4 is aligned with the channel 5.
- the channel and/or the opening are formed by aligned etching from the top to the bottom of the wafer.
- the opening is filed with a dielectric.
- the channel allows for an optically transparent path from the bottom of the wafer to the top.
- the channel will allow the aspirations of cell separation and manipulation on the top surface of the microchip using techniques such as dielectrophoresis.
- the microchip can include or be connected to integrated control circuitry.
- the use of an integrated LOAC which has an optical path that can pass through the chip allows for the combined AFM and optical technique investigation from the top and bottom of the wafer simultaneously.
- DEP dielectrophoresis
- the cell may move towards an increasing field strength, positive DEP (pDEP) or alternatively towards a decreasing negative field negative DEP (nDEP) depending upon the physical properties of the cell and medium, and epi- fluorescence microscopy from underneath.
- pDEP positive DEP
- nDEP decreasing negative field negative DEP
- the microchip may be a CMOS technology silicon microchip having an array of channels (for example a 300x300 array) and software is used to control actuation electrodes allowing DEP control of up to 9000 living cells.
- the chip has actuator control electronics integrated into it, together with: memory and photodiodes to detect micro-site cell occupancy. This technology allows for the ability to control the co- localisation of two different cells for studies relating to cell interactions.
- microbeads can be used which are coated with known antibodies or other cell stimuli and these microbeads can be manipulated using DEP forces to develop analyze cell function in health and disease.
- Figure 2 shows a cross-sectional view of the proposed core processing steps that will be used to fabricate the initial concept structure and the steps are numbered 2.1 to 2.6
- the techniques used in the manufacture of the microchips include e-beam and Mine photolithography, plasma resist strip, chemical cleans, Plasma Enhanced Chemical Vapour Deposition (PECVD) , silicon plasma etch and Deep Re-active Ion Etch (DRIE).
- PECVD Plasma Enhanced Chemical Vapour Deposition
- DRIE Deep Re-active Ion Etch
- openings 4 are etched into the upper surface 2 of the microchip 1.
- the positioning of the openings can be controlled using software that controls etching devices such as an e-beam tool.
- the mask that is used to locate the openings is based on the requirements for position of the cells and for the investigative techniques used to analyze them.
- the openings are filled with a dielectric 6 such as SiO 2 by techniques including as Chemical Vapour Deposition or Spin-On-Glass.
- the thickness of the S1O2 windows will only be in the order of several microns and therefore transmission should be extremely high across the visible and UV spectrum of interest regardless of deposition morphology.
- metal is deposited on the surface of the microchip and areas are again etched to leave discrete areas of metal 7 that will provide the location of the circuitry on the chip and this is shown in diagram 2.2.
- a further dielectric layer 8 of S1O2 is put down and there is further etching to form recesses 9 which sit over the areas of metal 7 and this is shown in diagram 2.3
- electrodes 10 are connected to the discrete areas of metal. The electrodes form a contact area on the chip. This etching again uses a mask to form areas where metal that will form electrodes is deposited.
- channels 11 are etched in the lower surface of the microchip, which align with the openings 4 in the upper surface.
- a further dielectric layer 12 is formed on the upper surface of the microchip as shown in diagram 2.6.
- a microfluidic chamber 13 is then formed over the dielectric, preferably using a commonly used photo-resist process such as SU8 to produce structures such as microfluidic chambers requiring high aspects ratios and micro-fluidic device containment.
- etching with the facility to have integrated circuitry means that the LOAC structure of the present invention will be easy to manufacture.
- the silicon substrate will have etched holes or windows in a continuous honeycomb like structure and as such will have good mechanical stability.
- Figures 3a and 3b show the arrays that can be used.
- Figure 3a shows a hexagonal electrode array with electrodes 10 and optical window 11 whilst Figure 3b places the etched windows inside the metal electrode. It is envisaged that other arrangements could be used for optimal control of the cells.
- an array of optical windows and electrodes will be used as such arrays are useful for the manipulation of T cells.
- the metal interconnects are connected to bond pads outside the area of the array.
- the devices are attached to a surface such as a transparent glass substrate by bonding agents that are selected so as not to obstruct optical pathways.
- bonding agents that are selected so as not to obstruct optical pathways.
- epoxy resins are used.
- Conductive wires such as gold wire bonds will electrically connect the chip to the substrate or package.
- Separate or integrated electronic controller circuitry will be used to connect to the package and subsequently control the voltage and frequency to each electrode allowing experimentation on cell separation and positioning
- Figure 4 shows use of a device according to an embodiment of the invention.
- An atomic force microscope 14 is positioned above the microfluidic chamber 13 that is positioned on the microchip 1.
- the microfluidic chamber 13 holds a sample in solution, which may be an aqueous solution, and in this case the sample is a T-cell suspension 16 in liquid medium. Fluorescence signals 17 are transmitted through the medium and the S1O2 layer 12 on the microchip.
- Metal electrodes 10 are used for DEP positioning. It is possible to position cells above the metal electrodes used for dielectrophoretic control but a transparent window is required beneath the cell for investigation by microscopy and spectroscopy.
- the electrode shape, size and position relative to the T cell in addition to the voltage, frequency and the liquid medium used for suspension of the cell in the microfluidic chamber have an effect on the positioning of the cells on the LOAC.
- a Perkin Elmer spectrophotometer will be used to measure the transmission spectrum between 200nm - 2500nm and the microscope objective is shown as 15. Of particular interest is the wavelength range between 400nm and 1000nm that contains the various laser excitation and emission wavelengths of the fluorophores typically used for biological investigation.
- S1O2 can exist in several forms such as Silica or Quartz with varying optical transmission characteristics.
- CMOS Complementary Metal Oxide Semiconductor
- chip or "microchip” or “microfluidic chip” as used herein means a microfluidic device generally containing a multitude of microchannels and chambers that may or may not be interconnected with one another.
- biochips include a multitude of active or passive components such as microchannels, microvalves, micropumps, biosensors, ports, flow conduits, filters, fluidic interconnections, electrical interconnections, microelectrodes and related control systems.
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- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Physics & Mathematics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Dispersion Chemistry (AREA)
- Clinical Laboratory Science (AREA)
- Analytical Chemistry (AREA)
- Hematology (AREA)
- General Physics & Mathematics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Radiology & Medical Imaging (AREA)
- Fluid Mechanics (AREA)
- Crystallography & Structural Chemistry (AREA)
- Optics & Photonics (AREA)
- Life Sciences & Earth Sciences (AREA)
- Electrochemistry (AREA)
- Molecular Biology (AREA)
- Engineering & Computer Science (AREA)
- Microelectronics & Electronic Packaging (AREA)
- Investigating Or Analysing Materials By Optical Means (AREA)
- Optical Measuring Cells (AREA)
- Investigating, Analyzing Materials By Fluorescence Or Luminescence (AREA)
Abstract
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GB1310086.2A GB2500515A (en) | 2011-01-20 | 2012-01-16 | Lab on a chip device |
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GB1100967.7 | 2011-01-20 | ||
GBGB1100967.7A GB201100967D0 (en) | 2011-01-20 | 2011-01-20 | Lab on a chip device |
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Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2017178209A1 (en) * | 2016-04-13 | 2017-10-19 | Commissariat A L'energie Atomique Et Aux Energies Alternatives | Method and apparatus for positioning a micro- or nano-object under visual observation |
CN108445260A (en) * | 2018-04-10 | 2018-08-24 | 北京航空航天大学 | A kind of multiband sample irradiation device based on atomic force microscope |
US10702866B2 (en) | 2017-02-15 | 2020-07-07 | International Business Machines Corporation | Layered silicon and stacking of microfluidic chips |
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DE10118568A1 (en) * | 2001-04-14 | 2002-10-17 | Bosch Gmbh Robert | Production of optically transparent regions in a silicon substrate used for optical investigations of small amounts of liquid in medicine and analysis comprises etching and oxidizing the defined transparent regions in the substrate |
US20070035724A1 (en) * | 2003-07-10 | 2007-02-15 | Yissum Research Development Company Of The Hebrew University Of Jerusalem | Nanoparticles functionalized probes and methods for preparing such probes |
US20080281471A1 (en) * | 2007-05-09 | 2008-11-13 | Smith Gregory F | Droplet Actuator Analyzer with Cartridge |
US20090107907A1 (en) * | 2007-10-24 | 2009-04-30 | University Of Alaska Fairbanks | Droplet-based digital microdialysis |
WO2009157096A1 (en) * | 2008-06-27 | 2009-12-30 | Nippon Telegraph And Telephone Corporation | Stage for scanning probe microscopy and sample observation method |
-
2011
- 2011-01-20 GB GBGB1100967.7A patent/GB201100967D0/en not_active Ceased
-
2012
- 2012-01-16 WO PCT/GB2012/000035 patent/WO2012098349A1/en active Application Filing
- 2012-01-16 GB GB1310086.2A patent/GB2500515A/en not_active Withdrawn
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DE10118568A1 (en) * | 2001-04-14 | 2002-10-17 | Bosch Gmbh Robert | Production of optically transparent regions in a silicon substrate used for optical investigations of small amounts of liquid in medicine and analysis comprises etching and oxidizing the defined transparent regions in the substrate |
US20070035724A1 (en) * | 2003-07-10 | 2007-02-15 | Yissum Research Development Company Of The Hebrew University Of Jerusalem | Nanoparticles functionalized probes and methods for preparing such probes |
US20080281471A1 (en) * | 2007-05-09 | 2008-11-13 | Smith Gregory F | Droplet Actuator Analyzer with Cartridge |
US20090107907A1 (en) * | 2007-10-24 | 2009-04-30 | University Of Alaska Fairbanks | Droplet-based digital microdialysis |
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Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2017178209A1 (en) * | 2016-04-13 | 2017-10-19 | Commissariat A L'energie Atomique Et Aux Energies Alternatives | Method and apparatus for positioning a micro- or nano-object under visual observation |
FR3050275A1 (en) * | 2016-04-13 | 2017-10-20 | Commissariat Energie Atomique | METHOD AND APPARATUS FOR POSITIONING A MICRO OR NANO-OBJECT UNDER VISUAL CONTROL |
US10705115B2 (en) | 2016-04-13 | 2020-07-07 | Commissariat A L'energie Atomique Et Aux Energies Alternatives | Method and apparatus for positioning a micro- or nano-object under visual observation |
US10702866B2 (en) | 2017-02-15 | 2020-07-07 | International Business Machines Corporation | Layered silicon and stacking of microfluidic chips |
US11529627B2 (en) | 2017-02-15 | 2022-12-20 | International Business Machines Corporation | Layered silicon and stacking of microfluidic chips |
CN108445260A (en) * | 2018-04-10 | 2018-08-24 | 北京航空航天大学 | A kind of multiband sample irradiation device based on atomic force microscope |
Also Published As
Publication number | Publication date |
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GB2500515A (en) | 2013-09-25 |
GB201310086D0 (en) | 2013-07-17 |
GB201100967D0 (en) | 2011-03-02 |
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