EP1703987A1 - Planar electronebulization sources modeled on a calligraphy pen and the production thereof. - Google Patents
Planar electronebulization sources modeled on a calligraphy pen and the production thereof.Info
- Publication number
- EP1703987A1 EP1703987A1 EP04805823A EP04805823A EP1703987A1 EP 1703987 A1 EP1703987 A1 EP 1703987A1 EP 04805823 A EP04805823 A EP 04805823A EP 04805823 A EP04805823 A EP 04805823A EP 1703987 A1 EP1703987 A1 EP 1703987A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- electrospray
- source
- liquid
- support
- plate
- Prior art date
- Legal status (The legal status 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 status listed.)
- Granted
Links
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Classifications
-
- H—ELECTRICITY
- H01—ELECTRIC ELEMENTS
- H01J—ELECTRIC DISCHARGE TUBES OR DISCHARGE LAMPS
- H01J49/00—Particle spectrometers or separator tubes
- H01J49/02—Details
- H01J49/10—Ion sources; Ion guns
- H01J49/16—Ion sources; Ion guns using surface ionisation, e.g. field-, thermionic- or photo-emission
- H01J49/165—Electrospray ionisation
- H01J49/167—Capillaries and nozzles specially adapted therefor
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B05—SPRAYING OR ATOMISING IN GENERAL; APPLYING FLUENT MATERIALS TO SURFACES, IN GENERAL
- B05B—SPRAYING APPARATUS; ATOMISING APPARATUS; NOZZLES
- B05B5/00—Electrostatic spraying apparatus; Spraying apparatus with means for charging the spray electrically; Apparatus for spraying liquids or other fluent materials by other electric means
- B05B5/025—Discharge apparatus, e.g. electrostatic spray guns
- B05B5/0255—Discharge apparatus, e.g. electrostatic spray guns spraying and depositing by electrostatic forces only
-
- H—ELECTRICITY
- H01—ELECTRIC ELEMENTS
- H01J—ELECTRIC DISCHARGE TUBES OR DISCHARGE LAMPS
- H01J49/00—Particle spectrometers or separator tubes
- H01J49/0013—Miniaturised spectrometers, e.g. having smaller than usual scale, integrated conventional components
- H01J49/0018—Microminiaturised spectrometers, e.g. chip-integrated devices, Micro-Electro-Mechanical Systems [MEMS]
Definitions
- the present invention relates to original electrospray sources, their manufacturing process and their applications.
- Electrospray is the phenomenon which transforms a liquid into a nebuliser under the action of a high voltage (M. CLOUPEAU “Electrohydrodynamic spraying functioning modes: a critical revie. Journal of Aérosol Science (1994), 25 (6), 1021-1036 ").
- the liquid is brought into a capillary and is subjected to a direct or alternating high voltage or to a superposition of the two (Z. HUNEITI et al., "The study of AC coupled DC fields on conducting liquid jets", Journal of Electrostatics (1997), 40 & 41 97-102).
- the liquid is nebulized under the action of tension.
- the surface of the meniscus formed by the liquid is elongated to form one or more Taylor cones from which are ejected charged liquid droplets which evolve to give a gas containing charged particles.
- the formation of the nebulisate is observed when the electrical forces due to the application of the voltage compensate for and exceed the surface tension forces of the liquid. on the section of the capillary at the end of said capillary.
- the size of the capillary, and more precisely its outlet orifice, is in direct relation with the flow of liquid leaving the capillary and the voltage to be applied to observe the nebulization phenomenon.
- electrospray regimes There are two distinct electrospray regimes which are distinguished by their establishment characteristics: • the so-called classical regime which corresponds to capillary outlet sizes of 100 ⁇ m, fluid flow rates in the range of 1-20 ⁇ L / min and high voltages of 3-4 kV; • the so-called nanoelectronisation regime where the liquid flow rates are less than 1 ⁇ L / min, the high voltage of approximately 1 kV and the internal diameter of the capillaries of 1-10 ⁇ m (M. WILM et al, "Analytical Properties of the Nanoelectrospray Ion Source ", Analytical Chemistry (1996), 68 (1), 1-8.).
- a voltage comprising an AC component allows the stabilization of the electrospray process by synchronization on its natural frequency (F. CHARBONNIER et al., "Differentiating between Capillary and Counter Electrode Processes during Electrospray lonization by Opening the Short Circuit at the Collector.
- Electrochemically ionizable derivatives Analytical Chemistry (1998), 70 (8), 1544-1554; F. ZHOU and al. "Electrochemistry Combined Online with Electrospray Mass Spectrometry", Analytical Chemistry (1995), 67 (20), 3643-3649).
- the fields of application of electrospray are as follows: • First, the ionization of molecules (M. DOLE et al., "Molecular beams of macroions", Journal of Chemical Physics (1968), 49 (5) , 2240-2249; LL MACK et al., "Molecular beams of macroions. II", Journal of Chemical Physics (1970), 52 (10), 4977-4986; US Patent 4,209,696; M. YAMASHITA et al.
- Such drops can be deposited on a support (CJ McNEAL et al., "Thin film deposition by the electrospray method for californium-252 plasma desorption studies of involatile molecules", Analytical Chemistry (1979), 51 (12), 2036-2039 ; RC MURPHY et al., “Electrospray loading of field desorption emitters and desorption chemical lonization probes", Analytical Chemistry (1982), 54 (2), 336-338) for example a plate for either the production of analysis chips like DNA or peptide chips, dedicated to high-throughput analysis (VN MOROZOV et al., "Electrospray Deposition as a Method for Mass Fabrication of Mono- and Multicomponent Microarrays of Biological and Biologically Active Substances", Analytical Chemistry (1999 ), 71 (15), 3110-3117; R.
- MOERMAN et al. "Miniaturized electrospraying as a technique for the production of microarrays of reproducible micrometer-sized protein spots", Analytical Chemistry (2001 May 15), 73 (10) , 2183-2189; NV AVSEENKO et al., "Imm unoassay with Multicomponent Protein Microarrays Fabricated by Electrospray Déposition ", Analytical Chemistry (2002), 74 (5), 927-933), i.e. the deposit of solutions on a MALDI plate (for" Matrix Assisted Laser Desorption lonization ”) before an analysis by mass spectrometry (J.
- a third application is the deposition of particles of controlled size contained within the liquid (IW LENGGORO et al., "Sizing of Colloidal Nanoparticles by Electrospray and Differential Mobility Analyzer Methods", Langmuir (2002), 18 (12), 4584- 4591). The particles can also be replaced by cells for the preparation of cell chips.
- a fourth application is the injection of the drops formed by electrospray into a liquid leading to well defined size emulsions (RJ PFEIFER et al., "Charge-to-mass relation for electrohydrodynamically sprayed liquid droplets", Physics of Fluids (1958 -1988) (1967), 10 (10), 2149-54; C.
- the sources used for nanoelectronebulization are in the form of capillaries made of glass or fused silica. They are manufactured by hot stretching or by acid attack of the material in order to give an outlet of 1 to 10 ⁇ m (M. WILM et al., "Electrospray and Taylor-Cone theory, Dole 's beam of macromolecules at last?", International Journal of Mass Spectrometry and Ion Processes (1994), 136 (2-3), 167-180).
- the electrospray voltage can be applied via an appropriate conductive external coating: a metallic coating such as gold or an Au / Pd alloy (GA VALASKOVIC et al., “Long-lived metalized tips for nanoliter electrospray mass spectrometry", Journal of the American Society for Mass Spectrometry (1996), 7 (12), 1270-1272), argent (Y.-R CHEN et al., "A simple method for fabrication of silver-coated sheathless electrospray emitters", Rapid Coiximunications in Mass Spectrometry (2003), 17 (5), 437-441), a carbon-based material (X.
- a metallic coating such as gold or an Au / Pd alloy
- GA VALASKOVIC et al. “Long-lived metalized tips for nanoliter electrospray mass spectrometry", Journal of the American Society for Mass Spectrometry (1996), 7 (12), 1270-1272
- argent Y.-R CHEN et al., "
- the electrospray voltage can also be applied via the liquid with the introduction of a metallic wire into the source (KWY FONG et al., "A novel nonmetallized tip for electrospray mass spectrometry at nanoliter flow rate", Journal of the American Society for Mass Spectrometry (1999), 10 (1), 72-75).
- KWY FONG et al. "A novel nonmetallized tip for electrospray mass spectrometry at nanoliter flow rate", Journal of the American Society for Mass Spectrometry (1999), 10 (1), 72-75.
- the devices of the prior art dedicated to nanoelectronebulization suffer from several weaknesses (B. FENG et al., "A Simple Nanoelectrospray Arrangement With Controllable Flowrate for Mass Analysis of Submicroliter Protein Samples", Journal of the American Society for Mass Spectrometry (2000), 11, 94-99): • First of all, these capillaries are not very robust.
- Standard commercial sources are therefore unsuitable, firstly for controlled, reproducible and quality nebulization, secondly for the use of robots due to the entirely manual nature of their mode of use, and thirdly, for integration on a fluid microsystem, as discussed below.
- These faults hamper certain fields of application of electrospray which currently require robotization and process automation. This is the case of the fields of application listed above: analysis by mass spectrometry, the deposition of drops of calibrated size and writing on a scale less than a micrometer using a tip.
- microtechnology techniques are used for the manufacture of integrated microsystems of characteristic size of the order of a micrometer and which bring together a series of reaction and / or analytical, chemical and / or biochemical / biological processes.
- the rise of microfluidics in the fields of chemistry and biology, where speed and process automation are required today, can be explained by: • the gain in speed of the processes, due to the fact that the speed mainly depends on the size of the devices; this gain in speed is particularly important for fields of application such as medical diagnosis or environmental analysis, where an instant response is often expected, • the possibility of parallelization of processes; microtechnology allows the simultaneous manufacture of a large number of identical devices, • the compatibility of microfabricated objects with a robotic interface for the automation of processes, • the adequacy of the volumes handled with those available to the experimenter in the case, inter alia, biological or environmental analyzes, • the limitation going until the suppression of the human intervention, which is often source of error and contamination, • a gain in sensitivity, for certain analysis techniques, including mass spectrometry with
- Microfluidic devices are manufactured using microtechnology techniques.
- Today a wide range of materials is available for these microfabrications, ranging from silicon and quartz (common materials in microtechnology) to glasses, ceramics and polymer-type materials, such as elastomers or plastics.
- microfluidics benefits from both: • the heritage of materials and manufacturing techniques developed and used for microelectronic applications and, • new manufacturing processes, developed in parallel and adapted to others emerging materials of great interest for microfluidic applications, such as plastic-type materials, the main attraction of which is their low cost. More specifically, the possible materials for technological manufacturing applicable to chemistry and biology are (T.
- McCREEDY "Fabrication techniques and materials co monly used for the production of microreactors and micro total analytical Systems", TrAC, Trends in Analytical Chemistry (2000), 19 (6), 396-401): • materials of the semiconductor type such as silicon, traditional materials in microtechnology which benefit from robust and proven manufacturing techniques; among these manufacturing techniques are lithography, physical and chemical engravings among others (PJ FRENCH et al., “Surface versus bulk micromachining: the contest for suitable applications", Journal of Micromechanics and Microengineering (1998), 8 (2 ), 45-53). Therefore, silicon in particular is the most interesting material in terms of manufacturing small structures at scales of ten nanometers.
- glass a less expensive material than quartz and silicon, which is widely used because of its surface properties suitable for establishing an electroosmotic flux (K. SATO et al., "Integration of chemical and biochemical analysis Systems into a glass microchip", Analytical Sciences (2003), 19 (1), 15-22).
- silanol groups line the surface of the glass. They suggest a subsequent chemical modification of the glass surfaces.
- its transparency properties make it a material of choice in the case of optical detection.
- microfabrication techniques have been applied to the production of electrospray or advanced needle-type sources with a view to: • improving the overall quality of the capillaries in terms of control of the manufacturing processes, reproducibility of the sources and their dimensions, • to produce a large number of identical or differing devices by one or several dimensions, on the same material plate, like microcomponents in microelectronics, in order to promote the automation and robotization of electrospray.
- the manufacture using microtechnology techniques of electrospray tips obeys two trends: • the manufacture of an electrospray tip which reproduces classic geometry, that is to say a microfabricated capillary and, most often of circular section. Also included in this class are microfabricated needles intended for another application, such as injecting chemical substances or measuring biological potential.
- electrospray source such as a microchannel or capillary outlet manufactured using microtechnology techniques and having a tapered profile.
- microfabricated electrospray devices are based, like fluidic microsystems, on the use of different types of materials and different types of processes. According to the first trend, which aims to produce a capillary type geometry, the following descriptions are listed: • According to this approach, electrospray sources made of silicon nitride have been manufactured using conventional photolithography techniques and engraving (A. DESAI et al., "MEMS Electrospray Nozzle for Mass Spectrometry", Int. Conf. on Solid-State Sensors and Actuators, Transducers '97, (1997)).
- the dimensions of said devices are a length of 40 ⁇ m and an internal diameter of the outlet orifice of 1 to 3 ⁇ m. Said sources were tested in mass spectrometry at nebulization voltages close to 4 kV and a liquid flow rate of
- TANG et al. "Generation of multiple electrosprays using microfabricated emitter arrays for improved mass spectrometrie sensitivity", Analytical Chemistry (2001), 73 (8), 1658-1663).
- Their dimensions are as follows: 30 ⁇ m in internal diameter at their outlet orifice and 250 ⁇ m in height.
- the dimensions of said devices are too large for a nanoelectronebulization regime since the voltage required for the observation of a nebulisate is 7 kV and the fluid flow rate is estimated at 30 ⁇ L / min.
- the manufacturing process is also complex. These sources are in the form of a series of nine sources arranged in a 3 x 3 square. They operate simultaneously and nebulize the same solution.
- the second tendency is to machine a point at the exit of a microchannel or to create a point structure which acts as a source of electrospray.
- the angle of the pointed structure does not seem to have any influence on the nebulization phenomenon.
- the voltage to be applied is very high and, under these conditions, the liquid tends to spread over the exit surface, on the edge of the microsystem (R. RAMSEY et al., "Generating Electrospray from Microchip Devices Using Electroosmotic Pumping” , Analytical Chemistry (1997), 69 (6), 1174-1178; Q.
- the peak effect can be achieved by inserting a triangular planar structure between the two plates of materials defining a microchannel (the support in which the microchannel is machined and the cover). consists of a parylene sheet 5 ⁇ m thick (J. KAMEOKA et al., "An electrospray lonization source for integration with microfluidics", Analytical Chemistry (2002), 74 (22), 5897-590 1).
- the system incorporates four identical electrospray devices placed in parallel.
- the nebulization voltage required is 2.5-3 kV for a fluid flow of 300 nL / min. No inter-source interference was observed.
- An eight-pointed star-shaped device was made of polymethylmethacrylate (PMMA) (C.-H. YUAN et al., "Sequential Electrospray
- Each of the branches of the star constitutes an independent microfluidic system and the tip of each branch is a source of nebulization.
- Each branch thus integrates a microchannel with a section of 300 x 376 ⁇ m, the pointed structure forms an angle of 90 ° and the eight liquid reservoirs are grouped in the center of the star.
- the voltage applied for the establishment of a Taylor cone is high and equal to 3.8 kV, which is explained by the very large dimensions of the section of the microchannel at its end.
- the manufacturing process described is based on the machining of channels using a knife, a technique which does not allow channels and nebulization devices of small dimensions to be produced.
- PDMS polydimethylsiloxane
- the nebulization orifice is rectangular and of variable dimensions ranging from 30 x 100 ⁇ m to 30 x 50 ⁇ m according to the microtechnology process used for their manufacture.
- nebulization voltage ranged from 2.5 kV to 3.7 kV for solutions at 1 to 10 ⁇ M and high flow rates from a few 100 nL / min to several ⁇ L / min.
- polyimide another material of relatively hydrophobic polymer type, was used for the manufacture of nebulization sources (GB-A-2 379 554; V.
- GOBRY et al. "Microfabricated polymer injector for direct mass spectrometry coupling", Proteomics (2002), 2 (4), 405-412; JS ROSSIER et al., "Thin-chip microspray System for high-performance Fourier-transform ion-cyclotron resonance mass spectrometry of biopolymers", Angewandte Chemie, International Edition (2003 ), 42 (1), 54-58) integrated on a microsystem, or at least, connected to a microchannel of section 120 x 45 ⁇ m.
- the system, the microchannel and the point structure are produced by plasma etching of the polyimide.
- the system cover is made of polyethylene / polyethylene terephthalate.
- the type of structure chosen for these different devices is practically inseparable from the material used for their production.
- the nebulization voltage is most often applied at the reservoir of the device, if the system includes a reservoir, or, if not, at the level of the liquid supply which is carried out using a capillary connected to the device.
- the capillary is conductive (in stainless steel for example), or the connection rests on a metal fitting.
- These beam-type structures which have a width of 210 ⁇ m at their point, are manufactured in parallel on the same system. They allow the ejection of drops having a volume in the range from femtoliter to picolitre, the volume deposited depends linearly on the contact time between the tip and the surface, with a flow rate of up to 100 deposits per minute.
- the AFM microscopy technique has the advantage of high resolution and very high writing precision. Three operating modes are possible, and depending on the mode chosen, the surface condition can be checked before and after passing the chemical molecular writing solution. However, this technique requires the use of heavy, bulky, expensive and complex equipment. Two molecular writing devices described in the literature can also be cited. They derive from the technique using an AFM microscopy tip but are based on the use of a microfabricated tip. The first device (A. LEWIS et al., "Fountain pen nanochemistry: Atomic force control of chrome etching", Applied Physics Letters (1999), 75 (17), 2689-2691; H.
- TAHA et al. "Protein printing with an atomic force sensing nanofountainpen”, Applied Physics Letters (2003), 83 (5), 1041-1043), is in the form of a micropipette manufactured using microtechnology techniques and the tip of which can have dimensions as small as 3 and 10 nm for its internal and external diameters respectively.
- This micropipette is nevertheless integrated into an AFM apparatus for its use.
- the ejection of the solution is here caused not by contacting but by exerting pressure on the liquid column.
- This device has been tested for its ability to deliver solutions for etching a layer of chromium deposited on a glass plate.
- the second device (IW RANGELOW et al., "" NANOJET “: Tool for the nanofabrication", Journal of Vacuum Science & Technology, B: Microelectronics and Nanometer Structures (2001), 19 (6), 2723-2726; J. VOIGT et al., "Nanofabrication with scanning nanonozzle 'Nanojet'", Microelectronic Engineering (2001), 57-58 1035-1042) consists of spikes made of silicon covered with Cr / Au, having a pyramidal shape and an outlet for size less than .100 nm.
- This device does not deliver a chemical solution as in the previous example, but free radicals in the gas phase produced by a plasma discharge which attack the material placed opposite the tip.
- the device does not only consist of a microfabricated tip but it also includes machinery for producing highly reactive species, such as a radiofrequency or microwave plasma discharge, which can attack the substrate.
- highly reactive species such as a radiofrequency or microwave plasma discharge
- these two examples certainly present a microfabricated tip which replaces the conventional AFM microscopy tip, but they do not make it possible to dispense with the heavy and expensive peripheral machinery necessary for their operation.
- this technique is based on bringing into contact or almost bringing into contact the tip and the substrate. As a result, the parameters of operation must be very carefully checked to avoid any deterioration of the surface finish due to excessive force exerted on the tip.
- the present invention relates to a two-dimensional electrospray device having a geometry of the calligraphy feather type, the tip of which acts as a seat for nebulization.
- the subject of the invention is therefore a source of electrospray comprising a structure comprising at least one flat and thin point in cantilever with respect to the rest of the structure, said point being provided with a capillary slot practiced throughout the thickness of the tip and which terminates at the end of the tip to form the ejection orifice of the electrospray source, the source comprising means for supplying the capillary slit with liquid to be nebulized and means for application of an electrospray voltage on said liquid.
- the supply means comprise at least one reservoir in fluid communication with the capillary slot.
- the structure comprises a support and a plate integral with the support and a part of which constitutes said point.
- the supply means may comprise a reservoir constituted by a recess formed in said plate and in fluid communication with the capillary slot.
- the means for applying an electrospray voltage may comprise at least one electrode arranged so as to be in contact with said liquid to be nebulized.
- the means for applying an electrospray voltage may comprise the support, at least partially electrically conductive, and / or the plate at least partially electrically conductive.
- the plate has a surface hydrophobic to the liquid to be nebulized.
- the means for applying an electrospray voltage may comprise an electrically conductive wire arranged to be able to be in contact with said liquid to be nebulized.
- the supply means may include a capillary tube. They can comprise a channel produced in a microsystem supporting said structure and in fluid communication with the capillary slit.
- the means for applying the voltage also allow the application of the voltages necessary for any device placed upstream in fluid continuity with the object of the present invention.
- the subject of the invention is also a method of manufacturing a structure being a source of electrospray, comprising: - The production of a support from a substrate, the production of a plate comprising a part constituting a flat and thin tip, said tip being provided with a capillary slot, for conveying a liquid to be nebulized, practiced throughout the thickness of the tip and which ends at the end of the tip, - the solidarisatiori of said plate on the support, the tip being in cantilever with respect to the support.
- This process can include the following stages: - the supply of a substrate to make the support, - the delimitation of the support by means of trenches engraved in the substrate, the deposition, on an area of the substrate corresponding to the future point of the structure , of sacrificial material according to a determined thickness, - the deposition of the plate on the support delimited in the substrate, the point of the plate being located on the sacrificial material, - the elimination of the sacrificial material, - the detachment of the support relative to to the substrate by cleavage at said trenches.
- the plate deposition step can be a deposition of a plate comprising in recess in fluid communication with the capillary slot in order to constitute a reservoir.
- the method may further comprise a step of depositing at least one electrode intended to ensure electrical contact with the liquid to be nebulized.
- the source of electrospray according to the invention can be used to obtain ionization of a liquid by electronebulization before its analysis in mass spectrometry. It can also be used to obtain a production of drops of liquid of calibrated size or the ejection of particles of fixed size. It can also be applied to the production of molecular writing using chemical compounds. It can also be applied to the definition of the electrical junction potential of a device in fluid continuity.
- FIGS. 1A and 1B are top and side views respectively of a source of electrospray according to the present invention
- - Figure 2 is a perspective view of the tip end of a source of electrospray according to the present invention
- FIGS. 3A to 3H are top views illustrating a method of manufacturing the electrospray source shown in FIGS. 1A and 1B
- FIGS. 4A and 4B illustrate a cleavage technique that can be used for the implementation of the manufacturing process illustrated by FIGS. 3A to 3H
- FIG. 1A and 1B are top and side views respectively of a source of electrospray according to the present invention
- FIGS. 3A to 3H are top views illustrating a method of manufacturing the electrospray source shown in FIGS. 1A and 1B
- FIGS. 4A and 4B illustrate a cleavage technique that can be used for the implementation of the manufacturing process illustrated by FIGS. 3A to 3H
- FIG. 5 represents an assembly used during a test during which a source of electrospray according to the invention is associated with a mass spectrometer
- - Figure 6 is a graph representing the total ion current obtained during the test using a source of electrospray according to the invention
- Figure 7 is a mass spectrum obtained during the test using a source of electrospray according to the invention in the assembly of FIG. 5
- - FIG. 8 represents another assembly used during a test during which a source of electrospray according to the invention is associated with a mass spectrometer
- - Figure 9 is a graph representing the total ion current obtained during the test using a source of electrospray according to the invention ion, in the assembly of FIG. 8, - FIG.
- FIG. 10 is a mass spectrum obtained during the test using a source of electrospray according to the invention in the assembly of FIG. 8, - FIG. 11 represents a mass spectrum fragmentation of the glu-fibrinopeptide obtained with a source of electrospray according to the present invention, - Figure 12 represents a mass spectrum obtained for a digest of Cytochrome C via a source of electrospray according to the present invention, - Figure 13 is a graph representing the total ion current obtained during a test using a source of electrospray according to the invention, - Figure 14 represents a mass spectrum obtained during a test using a source of electrospray according to the present invention, - Figure 15 is a graph representing the total ion current recorded on a mass spectrometer of the ion trap type during a coupling test using an electrospray source according to the present invention, - Figure 16 represents the corresponding mass spectrum to the graph in Figure 15.
- the present invention is inspired by the structure and the mode of operation of a calligraphy pen.
- the planar sources which are the subject of the present invention consist of the same elements as a calligraphy pen: a liquid reservoir and a two-dimensional capillary slot formed in a point.
- the present invention may include, if necessary, an electrical contact zone to which the voltage necessary to apply is applied. the establishment of a nebulisate.
- This contact zone can be structured with multiple and independent contacts and in particular three contacts corresponding to a working electrode, also making it possible to apply the electrospray voltage, a reference electrode and a measurement electrode to allow chemical modification. by electrochemistry in order to favor the process of electrospray or to study it.
- FIG. 1A and 1B A source of electrospray according to the present invention is shown in Figures 1A and 1B, Figure 1A being a top view and Figure 1B a side view.
- This source of electrospray comprises a support 1 and a plate 2 integral with the support 1. A part of the plate 2 forms a point 3 in cantilever with respect to the support 1.
- the plate 2 has in its center a recess 4 revealing the surface of the support 1 and constituting a reservoir.
- the operation of the device is based on the following principles.
- the liquid reservoir 4 contains the liquid or serves as a transit for the supply of liquid.
- the liquid is then guided by the capillary slot 5 upstream of which is located the reservoir 4 of liquid.
- the tip of the structure allows the establishment of an electrospray. This results in the following operating mode.
- the liquid of interest is deposited or conveyed in the liquid reservoir 4 by an appropriate method. It is guided towards the end 6 of the structure by capillarity.
- FIG. 2 represents a three-dimensional view of the capillary slot at the end 6 of the tip 3.
- the role of the reservoir 4 is to contain the liquid to be nebulized and to gradually supply the capillary slot 5.
- the topology of the structure is two-dimensional.
- the plate 2 is made of a material of hydrophobic nature, and even more hydrophobic than that constituting the support 1 supporting the plate 2, material which lines the bottom of the tank.
- the liquids envisaged for the nebulization will a priori be of rather hydrophilic character, such as purely aqueous solutions or semi-aqueous semi-alcoholic, for example mixtures methanol / water 50/50.
- the capillary slot 5 and the end 6 of the tip 3 are made of the material forming the plate 2 and their dimensions are determined during the manufacturing process. In FIG. 2 are indicated dimensions to be considered for the operation of the electrospray source: the width w of the slit, its height h and its length 1. It is assumed that liquid is present in the capillary slit 5.
- Equation 1 governing the capillarity effect of a liquid in a capillary tube, the cosine of the contact angle ⁇ must be positive to observe the capillary effect, and this, independently of the effect of gravity.
- Equation 1 where (r) is the internal radius of the capillary, (h r ) the height by which the liquid rises in the capillary tube, (p) the density of the liquid, ( ⁇ ) is the contact angle of the liquid on the internal walls of the capillary tube and (g) is the acceleration of gravity.
- r C S a r sv - ⁇ SL (Eq u ati on 2) where ⁇ sv is the surface tension at the solid-vapor interface and ⁇ SL is the surface tension at the solid-liquid interface.
- Young's equation (equation 2) implies that Ysv> YS L and therefore that the solid-liquid interaction is favored compared to that solid- steam.
- the term r appears in equation 1. Whether or not the capillary effect is observed depends on its value.
- the term r corresponds to the radius of the capillary tube and, in the case of the device which is the subject of the present invention, to the dimension of the capillary slot 5.
- the nebulization device may or may not include conductive zones (see Figure 3H). These conductive zones if they are located at the level of the liquid reservoir 4 serve as electrodes for bringing the nebulization voltage.
- these electrodes will be used to modify the species present in the liquid.
- electrochemical processes take place during the ionization of the molecules.
- the conductive areas located on either side of the capillary slot 5 at the end 6 of the tip 3 would allow them to be studied. Furthermore, these phenomena lead to an increase in the ionization yield and, as a result, to an improvement in the analysis conditions.
- the presence of a greater quantity of radical species increases the speed of etching of the substrate.
- these conductive zones in particular if their role is to bring the nebulization voltage, may not be necessary. Indeed, if a conductive material (metal, Si ..) is used to make the support 1 or the plate 2, the voltage will be directly applied to this conductive material. Finally, a device which does not include conductive zones and for which the materials are not conductive can * be used in electronebulization provided that the electrical contact is made via the liquid. A metal wire immersed in the solution to be nebulized, at the level of the reservoir 4 or any other conductive contact will thus ensure the role of application of the nebulization voltage.
- a conductive material metal, Si ..
- the device can also be connected to a source of liquid supply upstream of the reservoir 4, like a capillary supplying a solution coming from another device, from another structure.
- the capillary can correspond to an outlet of the separation column.
- this capillary brings the liquid to the nebulization device from its initial location.
- Said capillary can be a conventional commercial capillary made of fused silica. It can also be a microfabricated capillary, that is to say a microchannel integrated on the system supporting the source.
- the capillary can be a hydrophilic track materialized on the support 1.
- the plate 2 is integrated on a fluid microsystem and plays the role of interface between said microsystem and the outside world where the solution leaving the microsystem is used .
- the conductive properties of the device or of one of its elements can be used to electrically supply any system in fluid relationship with the device.
- said feather type plates can be used in isolation or be integrated in large numbers on the same support, and this, for the parallelization of the nebulization.
- said feather-type plates are independent or not from each other and the nebulized solutions are either the same in order to increase the nebulization of said solution, or different and, in this case, the feathers operate sequentially in nebulization.
- the integration of said feather-type plates can be carried out linearly with an alignment of said plates on one side of the support or in a circular fashion on a round support.
- the passage from one source to the other then takes place respectively by translation or by rotation of the support.
- a wide range of materials can now be envisaged for microtechnological manufacturing and in particular of fluidic microsystems: glass, silicon-based materials (Si, Si0 2 silicon nitride ...), quartz, ceramics as well as a large number macromolecular, plastic or elastomeric materials.
- the geometry chosen for the present invention is compatible with manufacturing using any type of material, and this, for the different parts making up the electrospray source: the support 1, the feather-type plate 2 and the conductive areas.
- the technological manufacturing process also involves one or more other material (s), the choice of which is suitable. depending on the materials selected for elements 1, 2 and 3.
- a generic process for manufacturing electrospray sources according to the invention is shown in FIGS. 3A to 3H. This manufacturing process can be divided into seven major steps which are detailed below, so as to be applicable to any type of material.
- the first step in this manufacturing process is the choice of the substrate intended to constitute the support for the electrospray source.
- This substrate 10 (see FIG. 3A) can be made of macromolecular material, glass or else silicon or even metal. In the case of this exemplary embodiment, it is a silicon substrate 250 ⁇ m thick.
- the start of the process conditions the end of the manufacturing of the electrospray devices.
- a layer 11 of so-called protective material is deposited on part of the substrate 10.
- the material of the layer 11 is chosen according to the nature of the material of the substrate 10 so that an attack on the layer 11 does not affect the substrate 10.
- the layer of protective material is a layer of silicon oxide 20 nm thick.
- the layer 11 is of variable thickness according to the nature of the materials of the substrate 10 and layer 11.
- Layer 11 is subjected to a lithography step intended to reveal the areas of the substrate to be attacked in order to define. cleavage lines delimiting the support of the structure.
- FIG. 3C shows the result obtained: the lines 13, consisting of V-shaped trenches, delimiting the support of the structure to be obtained.
- a layer of sacrificial material is deposited on the substrate 10. This layer of sacrificial material 14 will allow, at the end of manufacture at the tip of the structure, to overhang its support before the cleavage operation.
- the substrate 10 is covered with a thin layer of sacrificial material of sufficient thickness so that, after its removal, the tip is sufficiently separated from the substrate 10, but nevertheless sufficiently fine to be able to overcome any problem of stress and curvature of the point overhanging the support.
- the layer of sacrificial material is a layer of nickel 150 nm thick.
- the layer of sacrificial material is then subjected to an appropriate lithography and etching step in order to keep only a zone of this material. 14 corresponding to the tip of the structure (see Figure 3D).
- the fourth step can be implemented.
- the substrate 10 is then covered with a layer of a material intended to constitute the plate of the structure.
- the material of this layer may be silicon or based on silicon, a metal or even a material of the polymer or ceramic type.
- the layer of material intended to constitute the plate is a layer 35 ⁇ m thick in polymer SU-8 2035 purchased in pre-poly erect form from Microchem and polymerized by a photolithographic process.
- the thickness of this layer is chosen appropriately. On this thickness indeed depend the performance in ionization of the nebulization device, as it was explained previously.
- the thickness of this layer directly influences the height h of the capillary slit and, according to the above, the greater h, the greater w must be so as not to modify the ratio R.
- the challenge is to reduce w as much as possible in order to increase performance.
- the overhanging point can bend once detached from the support due to the stresses exerted on the material.
- Those skilled in the art are able to adapt the present specifications according to the nature of the material of this layer and thus to define the optimal thickness of material to be deposited.
- This layer then undergoes a lithography step and an attack in order to form the feather-type plate 2, that is to say in addition to its bulk, the reservoir 4, the capillary slot 5 and the tip 3 (see the figure 3E). This attack is adapted according to the material of the plate.
- the fifth step can then be undertaken.
- the zone 14 of sacrificial material under the tip 3 can be removed.
- the sacrificial material is removed by an appropriate chemical attack.
- the solution for this chemical attack must be chosen judiciously so that all the sacrificial material is removed without neither the support nor the plate being affected. The materials of these elements must therefore not be sensitive to this chemical solution.
- the structure shown in Figure 3F is obtained.
- the sixth step concerns the implantation of conductive zones on the structure.
- this step is only included in the manufacturing process if such conductive zones are provided. Whether these zones are located at the level of the reservoir 4 (application of the nebulization voltage) or at the level of the tip (physicochemical study electrodes), the manufacturing process is the same.
- the realization of the conductive zones 3 at the level of the tank alone will be detailed here. These conductive zones can be made of metal or carbon.
- the structure is first subjected to a masking step so that only the zones corresponding to the formation of the conductive zones are exposed.
- the conductive material chosen is then deposited by a PECVD technique (vapor deposition by chemical plasma techniques) on the structure.
- the conductive zones are made of palladium and have a thickness of 400 nm.
- Figure 3G shows the structure obtained.
- Two conductive zones 7 and 8 surround the reservoir 4 and allow an electrical potential to be applied to it.
- the seventh step of this method of manufacturing the nebulization source is the detachment of the support 1 relative to the substrate 10 and in particular, the overhanging of the tip 3 relative to the support 1 using the cleavage lines 13 materialized at the second step in this manufacturing process.
- the structure obtained is shown in Figure 3H.
- An advantageous cleavage technique is illustrated by FIGS. 4A and 4B in the case of the overhang of the point.
- a fixed metal wire 20 is placed under the support 1 at the level of the cleavage trenches 13 formed on either side of the point. Jointly, two forces are exerted on the substrate at the locations indicated in Figure 4A by arrows.
- FIG. 4B shows the cleavage in progress.
- This generic manufacturing process is then adapted according to the materials chosen for each element of the electrospray source.
- the first field of applications targeted by the present invention is the electrospraying of biological or chemical solutions to be analyzed by mass spectrometry. Mass spectrometry is currently the technique of choice for the analysis, characterization and identification of proteins. However, since the end of the genome decryption, biologists in particular are increasingly interested in proteomics, a science which aims to study and characterize all the proteins of an individual. These proteins, in every human being, are present in more than 10 6 different molecules including post-translational modifications.
- the second type of targeted applications by the present invention is the deposit of calibrated drops on a smooth or rough surface. This is of prime interest for the preparation of DNA chips, peptides, PNA or any other type of molecules.
- This type of application requires a device capable of delivering fluid in discrete form, drops of liquid of calibrated size, the size depending most often on the resolution expected in the preparation of the analysis plates. The smaller the drops, the closer their deposition can be on the plate and the greater the density of deposits and therefore of substances to be analyzed.
- the device forming the subject of the present invention can be re used for this purpose.
- the width of the capillary slot 5, as well as the value of the voltage applied for the ejection of the drops conditions the size of the drops ejected by said nebulization device.
- the resolution of the analysis plates can be adjusted according to the width of the slot of the device.
- the nebulization voltage can be alternating and thus give a deposition rate in drops / minute directly dependent on the frequency of the alternating voltage.
- the deposit of calibrated drops as presented above can be used for the preparation of analysis plates such as DNA chips.
- the present nebulization device having a feather type geometry can it for example be connected at the outlet of the separation column and allow coupling between a separation technique and an online analysis by mass spectrometry of the MALDI type.
- the drops of liquid can be replaced by cells. In this case, the cells are likewise discreetly ejected and deposited, for example, on a plate for the preparation of cell chips.
- the third application targeted by the present invention is molecular writing at scales of the order of a hundred nanometers.
- this type of operation is carried out at using AFM microscopy tips, operating using heavy and bulky equipment.
- the ejection of the liquid is based on bringing the tip and the deposition substrate into contact or quasi-contact in the case of AFM or on the application of pressure on the liquid.
- An adaptation of this technique is to eject the liquid under the action of a tension and not using pressure or contacting. Indeed, in both cases, the ejection is caused when the tensioning forces of the liquid at the tip of the pipette are "exceeded" by another force applied to the column of liquid.
- the formation of reactive species is intrinsic to the process of electrospraying.
- This fluid ejection technique eliminates any complex apparatus for producing reactive species such as free radicals, such as a plasma or microwave discharge, upstream of the structure which delivers the liquid.
- the present invention can therefore be used for such molecular writing purposes on a smooth or rough substrate, the release of the writing solution (pseudo-ink) here being controlled by applying a voltage.
- a major stake is to minimize the size of the tip of the tip, this dimension conditioning the size of the ejections by nebulization and consequently the resolution expected in writing on the final substrate.
- the width of the tip is less than or equal to a micrometer.
- Another factor influencing the size of the ejections and the fluid flow rate is the nebulization voltage applied to the liquid.
- Example 1 Design of microfabricated nanoelectronebulization sources according to the present invention.
- a first example concerns the dimensions and the shapes chosen to produce a nebulization device as described in the present invention.
- This first device has small dimensions at its tip due to the field of applications targeted, that is to say a nanoelectronebulization for the ionization of solutions before their analysis by mass spectrometry.
- the device is produced in accordance with FIGS. 1A and 1B.
- the reservoir 4 of the device has the dimensions 2.5 mm x 2.5 mm xe ( ⁇ m) where e is the thickness of the layer of material used to make the plate 2.
- the value of e is close to that of h, considered below, the thickness of sacrificial material being the order of a hundred nanometers.
- Example 2 Manufacture of the design sources described in Example 1 using silicon and SU-8 materials.
- the second example relates to the fabrication by microtechnology of the nebulization sources, as described in example 1.
- the materials used are silicon for the support 1 and the negative photolithographic resin SU-8 for the feather-type plate 2.
- the method of manufacturing follows from the process described above. It is suitable for the materials chosen.
- a 3 inch oriented n-doped silicon substrate (100) is covered with a 200 nm layer of silicon oxide (Si0 2 ), then masked by lithography.
- the Si0 2 layer is attacked by a acid solution of HF: H 2 0 on the unmasked areas.
- the exposed silicon is then attacked by a sodium hydroxide solution (KOH) so as to materialize the cleavage lines.
- KOH sodium hydroxide solution
- a 150 nm layer of nickel is then deposited on the silicon surface by spraying technique under argon (Plassys MP 450S).
- the nickel layer is attacked locally by UV photolithography (positive photosensitive resin AZ1518 [l, 2 ⁇ m], etching solution HN0 3 / H 2 0 (1: 3)) so that only nickel remains under the tip of the pen.
- UV photolithography positive photosensitive resin AZ1518 [l, 2 ⁇ m], etching solution HN0 3 / H 2 0 (1: 3)
- the silicon wafer is dehydrated at 170 ° C. for 30 min, so as to optimize the adhesion of the SU-8 resin to the silicon surface.
- a 35 ⁇ m layer of SU-8 resin is spread on the silicon substrate using a spinner to homogenize the thickness thereof before the next photolithography step.
- the feather-type plate 2 is produced in this layer of resin SU-8 using conventional UV photolithography techniques.
- the nickel layer is attacked with the acid solution (HN0 3 / H 2 0) described above. This nickel etching step does not affect the SU-8 resin even if this process can take several hours.
- the silicon substrate 1 is sawn according to the technique illustrated in FIGS. 4A and 4B.
- the technique used here preserves the structure of the pen, as it was previously detached from its support.
- a photograph of scanning electron microscopy (Hitachi S4700) of the feather-type nebulization source manufactured according to this process confirms the correct detachment of the point relative to its support.
- the manufacturing process described above does not include the production of electrodes.
- Example 3 Design of a particle ejection device of a hundred micrometers.
- a third example relates to the dimensions and the shapes chosen to make a particle ejection device having a size of a hundred micrometers, as described in the present invention.
- This device has larger dimensions than that described in Example 1.
- the dimensions of the capillary slot 5 and of the reservoir 4 must be compatible with the handling of objects of a hundred micrometers. Because of this range of dimensions, the device described in Example 3 also applies to the handling of cells of size approaching 100 ⁇ m in diameter, for the preparation of cell chips for example.
- the reservoir 4 of said device has the dimensions 1 cm x 1 cm xe ( ⁇ m) where e is the thickness of the plate 2.
- the value of e is defined as a function of the width of the capillary slot 5 so as to have a form factor R at the end 6 of the plate which is greater than 1.
- the particles handled by this device have a size of a hundred micrometers, therefore the capillary slot 5 must have a width greater than 100 ⁇ m. However, since the particles may tend to aggregate, this width should not be chosen too large. It is preferably close to twice the size of the particles handled. Therefore, the width of the slot is fixed at 150 ⁇ m, and the thickness of the plate at 200 ⁇ m.
- the material retained for the manufacture of the feather-type plate 2 is here again the negative photolithographic resin SU-8 and the material chosen for the support 1 is glass.
- the SU-8 resin is interesting here for handling particles such as cells, because these cells do not adhere to this material. Therefore, the glass support 1 is also covered with a thin layer of SU-8 resin in order to prevent any unwanted adhesion of the cells to the device.
- Example 4 Test of the nebulization sources manufactured according to Example 2 in mass spectrometry. I: Application of the voltage using a platinum wire.
- Example 4 is the test of the nebulization sources manufactured as described in Example 2 for an analysis in mass spectrometry.
- the nebulization voltage is applied to the liquid to be nebulized using a platinum wire immersed in the liquid at the level of the reservoir as illustrated in FIG. 5.
- the nebulization device is placed on a part.
- mobile 30 can be moved in xyz. This moving part 30 comprises a metal part 31 on which the ionization voltage is applied in the mass spectrometer 25.
- the silicon support 1 is carefully insulated from this metal part 31 when the device is fixed to said moving part 30 because semiconductor properties of this material.
- the electrical contact between the metal part 31 and the reservoir of the device is ensured using a platinum wire 32 introduced into the reservoir and which plunges into the solution to be analyzed 33.
- the solution used for the nebulization tests a standard peptide solution (Gramicidine S), is deposited in the device reservoir and the moving part 30 is introduced into the inlet of the mass spectrometer 25.
- the tests are carried out on a mass spectrometer of the ion trap type from Thermo Finnigan (LCQ DE ⁇ A XP +). Voltage is then applied to the liquid.
- FIG. 6 is a graph representing the total ion current recorded by the mass spectrometer for an experiment carried out for 2 minutes with a solution of Gramicidine S at 5 ⁇ M and an ionization voltage at 0.8 kV.
- the ordinate axis represents the relative intensity I R.
- the abscissa axis represents time.
- FIG. 7 corresponds to the mass spectrum obtained with a solution of Gramicidine S at 5 ⁇ M and a voltage of 1.2 kV. The mass spectrum was average over 2 minutes of signal acquisition, ie 80 scans.
- Example 5 Test of the nebulization sources manufactured according to Example 2 in mass spectrometry. II: Application of the voltage on the silicon support Example 5 is close to Example 4, but here the voltage is not applied using a platinum wire but by exploiting the semiconductor properties silicon. Example 5 is therefore the mass spectrometry test of nebulization sources manufactured according to Example 2 with an application of the ionization voltage on the material constituting the support 1 of the nebulization device.
- the nebulization device is fixed on a movable part 40 which can be moved in xyz and comprising a metallic part 41.
- the silicon support 1 is brought into electrical contact with the metallic part 41 of the movable part 40 on which is applied the ionization voltage in the mass spectrometer 25.
- the device is fixed to the movable part 40 using a teflon tape which surrounds the device upstream of the tank.
- the test is carried out as previously after introduction of the moving part 40 into the ion trap 25 and application of the voltage.
- the capillary slot has a width of 8 ⁇ m.
- the tests were carried out with another standard peptide, Glu-Fibrinopeptide B.
- the ionization voltages, here, are in the same range as before, from 1 to 1.4 kV for concentrations in peptide less than 1 ⁇ M.
- FIG. 9 represents the total ion current measured during 3 minutes of signal acquisition with a 0.1 ⁇ M solution and a voltage of 1.1 kV.
- I R is the relative intensity and t the time.
- Figure 10 is the mass spectrum obtained for this acquisition and average over the period of 3 minutes, ie 120 scans. I R is the relative intensity.
- Example 6 Test of the nebulization sources produced according to Example 2 in mass spectrometry. III: Fragmentation experience (MS / MS).
- Example 6 is identical to Example 5 on how to conduct the test.
- the test setup is identical to that of the previous example, the nebulization device corresponds to that described in Example 1 and produced according to the manufacturing process described in Example 2.
- the voltage is applied directly to the material of the support 1, silicon, via the metallic zone 41 included on the moving part 40 introduced into the mass spectrometer 25 (see FIG. 8).
- the capillary slot has a width of 8 ⁇ m.
- the solution is the same as above, a standard peptide solution, Glu-Fibrinopeptide B at concentrations less than or equal to 1 ⁇ M.
- FIG. 11 represents the fragmentation spectrum obtained during this experiment with a 0.1 ⁇ M solution and a voltage of 1.1 kV.
- I R is the relative intensity. The spectrum was average over 2-3 minutes of acquisition of the nebulization signal. The different MS / MS fragments are annotated with their sequence.
- Example 7 Test of the nebulization sources produced according to Example 2 in mass spectrometry. IV: Application to the analysis of a biological mixture.
- Example 7 is identical to Example 5 (same device manufactured according to the same process and tested under the same conditions with application of the voltage on the silicon support 1) except that the sample analyzed here is no longer a peptide standard but a complex mixture of peptides obtained by digestion of a protein, Cytochrome C. This digestate is made up of 13 peptides of different lengths and physicochemical properties. This digestate is tested at a concentration of 1 ⁇ M and with an ionization voltage of 1.1-1.2 kV. The width of the capillary slot is 8 ⁇ m.
- Example 12 represents the mass spectrum obtained for the digest of Cytochrome C at 1 ⁇ M with a voltage of 1.2 kV.
- I R is the relative intensity. The peaks are annotated with the sequence of the fragment and its state of charge. Of the 15 peptides, 11 are clearly identified during this experiment.
- Example 8 Test of the nebulization sources produced according to Example 2 in mass spectrometry.
- V Continuous supply of said device using a syringe pump or a nanoLC chain placed upstream.
- Example 8 is identical to Example 5 (same device manufactured according to the same process and tested under the same conditions with application of the voltage on the silicon support 1) except that the sample analyzed here is brought to said device in continuous by a capillary connected to a syringe pump or a chain of nanoLC upstream.
- the liquid flow rate was set at 500 nL / min.
- the solution for this test is identical to that of Example 5, except that the concentration of the Glu-Fibrinopeptide B peptide is here 1 ⁇ M and the nebulization voltage has been set at 1.2 kV.
- the width of the capillary slot is 8 ⁇ m.
- FIG. 13 shows the total ion current recorded during a nebulization test carried out over a period of 6 minutes under said conditions.
- I R is the relative intensity and t the time.
- FIG. 14 represents the corresponding and average mass spectrum over this 6-minute acquisition period, ie 240 scans.
- I R is the relative intensity.
- the coupling to a nanoLC chain liquid chromatography at a flow rate of 1 to 1000 nL / min
- the fluid flow rate is 100 nL / min, the ionization voltage of 1.5 kV.
- the separation experiment is carried out on a Cytochrome C digestate at 800 fmol / ⁇ L and 800 fmol of this digestate are injected onto the separation column.
- the width of the capillary slot is 10 ⁇ m.
- Figure 15 shows the total ion current detected on the mass spectrometer during the separation experiment. I R is the relative intensity and t the time.
- FIG. 16 is the mass spectrum obtained for the peak indicated in FIG. 15 at the retention time of 23.8 min. It corresponds to the elution and analysis of the 92-99 fragment of Cytochrome C.
- I R is the relative intensity.
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Abstract
Description
Claims
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
FR0350820A FR2862006B1 (en) | 2003-11-12 | 2003-11-12 | PLANAR ELECTRONEBULATING SOURCES ON THE MODEL OF A CALLIGRAPHIC FEATHER AND THEIR MANUFACTURE. |
PCT/FR2004/050580 WO2005046881A1 (en) | 2003-11-12 | 2004-11-10 | Planar electronebulization sources modeled on a calligraphy pen and the production thereof. |
Publications (2)
Publication Number | Publication Date |
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EP1703987A1 true EP1703987A1 (en) | 2006-09-27 |
EP1703987B1 EP1703987B1 (en) | 2008-04-16 |
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EP04805823A Not-in-force EP1703987B1 (en) | 2003-11-12 | 2004-11-10 | Planar electronebulization sources modeled on a calligraphy pen and the production thereof. |
Country Status (8)
Country | Link |
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US (1) | US8294119B2 (en) |
EP (1) | EP1703987B1 (en) |
JP (1) | JP4800218B2 (en) |
AT (1) | ATE392261T1 (en) |
CA (1) | CA2545213C (en) |
DE (1) | DE602004013195T2 (en) |
FR (1) | FR2862006B1 (en) |
WO (1) | WO2005046881A1 (en) |
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US7446311B1 (en) * | 2005-02-07 | 2008-11-04 | The Board Of Trustees Of The Leland Stanford Junior University | Method of coating an electrospray emitter |
DE102006051877A1 (en) * | 2006-10-31 | 2008-05-29 | Studiengesellschaft Kohle Mbh | Microfluidic glass chips with monolithic electrospray emitter for chip-MS coupling |
FR2934179B1 (en) * | 2008-07-24 | 2010-09-17 | Commissariat Energie Atomique | LABORATORY ON CHIP COMPRISING A MICRO-FLUIDIC NETWORK AND A COPLANAR ELECTRONEBULATING NOSE. |
JP4818399B2 (en) * | 2009-06-15 | 2011-11-16 | 三菱電機株式会社 | Electrostatic atomizer and air conditioner |
GB0914762D0 (en) | 2009-08-24 | 2009-09-30 | Univ Glasgow | Fluidics apparatus and fluidics substrate |
KR101233100B1 (en) * | 2010-08-27 | 2013-02-14 | 전자부품연구원 | Liquid droplet ejection apparatus |
US8519330B2 (en) * | 2010-10-01 | 2013-08-27 | Ut-Battelle, Llc | Systems and methods for laser assisted sample transfer to solution for chemical analysis |
GB201103211D0 (en) | 2011-02-24 | 2011-04-13 | Univ Glasgow | Fluidics apparatus, use of fluidics apparatus and process for the manufacture of fluidics apparatus |
GB201108462D0 (en) * | 2011-05-19 | 2011-07-06 | Univ Glasgow | Sample nebulization |
WO2014179417A1 (en) * | 2013-05-01 | 2014-11-06 | Ut-Battelle, Llc | Afm fluid delivery/liquid extraction surface sampling/electrostatic spray cantilever probe |
WO2016010748A1 (en) | 2014-07-14 | 2016-01-21 | Li-Cor, Inc. | Analyte separator with electrohydrodynamic taylor cone jet blotter |
GB201420061D0 (en) | 2014-11-11 | 2014-12-24 | Univ Glasgow | Nebulisation of liquids |
US9406492B1 (en) * | 2015-05-12 | 2016-08-02 | The University Of North Carolina At Chapel Hill | Electrospray ionization interface to high pressure mass spectrometry and related methods |
EP3411896A4 (en) | 2016-02-01 | 2019-09-04 | Li-Cor, Inc. | Capillary electrophoresis inkjet dispensing |
CN109564188A (en) | 2016-08-08 | 2019-04-02 | 利康公司 | The distribution of minor effect genes ink jet type |
EP3497433A1 (en) | 2016-08-08 | 2019-06-19 | Li-Cor, Inc. | Multi-sheath flow and on-chip terminating electrode for microfluidic direct-blotting |
WO2019102894A1 (en) * | 2017-11-24 | 2019-05-31 | パナソニックIpマネジメント株式会社 | Electrostatic atomizer |
US20210257204A1 (en) * | 2018-08-25 | 2021-08-19 | Jp Scientific Limited | Method and device for sample introduction for mass spectrometry |
US20220181136A1 (en) * | 2020-12-07 | 2022-06-09 | Thermo Finnigan Llc | Sample supports for solid-substrate electrospray mass spectrometry |
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US1565603A (en) | 1918-10-04 | 1925-12-15 | Western Electric Co | Electron-discharge device |
US4209696A (en) * | 1977-09-21 | 1980-06-24 | Fite Wade L | Methods and apparatus for mass spectrometric analysis of constituents in liquids |
JPS59131259U (en) * | 1983-02-22 | 1984-09-03 | トリニテイ工業株式会社 | Electrostatic oil applicator |
US5165601A (en) * | 1990-04-11 | 1992-11-24 | Terronics Development Corporation | Nozzle for low resistivity flowable material |
JPH06346139A (en) | 1993-06-15 | 1994-12-20 | Nippon Steel Corp | Electric heating apparatus |
EP0958593A4 (en) * | 1997-01-27 | 2006-08-30 | California Inst Of Techn | Mems electrospray nozzle for mass spectroscopy |
CN1312473C (en) * | 1998-09-17 | 2007-04-25 | 阿德文生物科学公司 | Liquid phase chromatographic system, chemical separating device and mass spectrometer and method |
US6633031B1 (en) * | 1999-03-02 | 2003-10-14 | Advion Biosciences, Inc. | Integrated monolithic microfabricated dispensing nozzle and liquid chromatography-electrospray system and method |
DE19947495C2 (en) * | 1999-10-01 | 2003-05-28 | Agilent Technologies Inc | Microfluidic microchip |
JP4112780B2 (en) | 2000-05-31 | 2008-07-02 | 株式会社島津製作所 | Liquid chromatograph mass spectrometer |
WO2002055990A2 (en) * | 2001-01-11 | 2002-07-18 | Musc Foundation For Research Development | Microfabrication process for electrospray ionization mass spectrometry emitters |
SE0102736D0 (en) * | 2001-08-14 | 2001-08-14 | Patrick Griss | Side opened out-of-plane microneedles for microfluidic transdermal interfacing and fabrication process of side opened out-of-plane microneedles |
AU2002360446A1 (en) * | 2001-11-30 | 2003-06-17 | Northwestern University | Direct write nanolithographic deposition of nucleic acids from nanoscopic tips |
US7273636B2 (en) * | 2001-12-17 | 2007-09-25 | Northwestern University | Patterning of solid state features by direct write nanolithographic printing |
-
2003
- 2003-11-12 FR FR0350820A patent/FR2862006B1/en not_active Expired - Fee Related
-
2004
- 2004-11-10 JP JP2006538911A patent/JP4800218B2/en not_active Expired - Fee Related
- 2004-11-10 DE DE602004013195T patent/DE602004013195T2/en active Active
- 2004-11-10 AT AT04805823T patent/ATE392261T1/en not_active IP Right Cessation
- 2004-11-10 WO PCT/FR2004/050580 patent/WO2005046881A1/en active IP Right Grant
- 2004-11-10 US US10/578,879 patent/US8294119B2/en not_active Expired - Fee Related
- 2004-11-10 CA CA2545213A patent/CA2545213C/en not_active Expired - Fee Related
- 2004-11-10 EP EP04805823A patent/EP1703987B1/en not_active Not-in-force
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See references of WO2005046881A1 * |
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CA2545213A1 (en) | 2005-05-26 |
US20070252083A1 (en) | 2007-11-01 |
ATE392261T1 (en) | 2008-05-15 |
EP1703987B1 (en) | 2008-04-16 |
WO2005046881A1 (en) | 2005-05-26 |
DE602004013195T2 (en) | 2009-06-25 |
CA2545213C (en) | 2012-02-21 |
FR2862006A1 (en) | 2005-05-13 |
FR2862006B1 (en) | 2006-01-27 |
DE602004013195D1 (en) | 2008-05-29 |
JP4800218B2 (en) | 2011-10-26 |
US8294119B2 (en) | 2012-10-23 |
JP2007516071A (en) | 2007-06-21 |
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