EP1703987B1 - Planare elektrosprühquellen auf grundlage einer kalligraphiefeder und herstellung davon - Google Patents

Planare elektrosprühquellen auf grundlage einer kalligraphiefeder und herstellung davon Download PDF

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Publication number
EP1703987B1
EP1703987B1 EP04805823A EP04805823A EP1703987B1 EP 1703987 B1 EP1703987 B1 EP 1703987B1 EP 04805823 A EP04805823 A EP 04805823A EP 04805823 A EP04805823 A EP 04805823A EP 1703987 B1 EP1703987 B1 EP 1703987B1
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EP
European Patent Office
Prior art keywords
electrospray
tip
liquid
support
electrospray source
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French (fr)
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EP1703987A1 (de
Inventor
Steve Arscott
Séverine LE GAC
Christian Druon
Christian Rolando
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Centre National de la Recherche Scientifique CNRS
Universite de Lille 1 Sciences et Technologies
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Centre National de la Recherche Scientifique CNRS
Universite de Lille 1 Sciences et Technologies
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    • 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 method of manufacture and their applications.
  • Electrospray is the phenomenon that transforms a liquid into a nebulisat under the action of a high voltage ( M. CLOUPEAU “Electrohydrodynamic Spraying Operating Modes: A Critical Review.” Journal of Aerosol Science (1994), 25 (6), 1021-1036 To do this, the liquid is fed into a capillary and is subjected to a continuous or alternating high voltage or 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 ). At the outlet of the capillary, the liquid is nebulized under the action of the tension.
  • the surface of the meniscus formed by the liquid is elongated to form a Taylor cone (s) from which charged liquid droplets are ejected, evolving to form a charged particle-containing gas.
  • the formation of the nebulisate is observed when the electrical forces due to the application of the tension compensate for and exceed the surface tension forces of the liquid on the section of the capillary at the end of said capillary.
  • the chemical composition of the drops produced by the electrospray phenomenon can be improved for its applications by the application of multiple and independent voltages that allow the chemical modification species present in the liquid by electrochemistry (see patent application US 2003/0015656 ; GJ VAN BERKEL, "Enhanced Study and Control of Analyzing Oxidation in Electrospray Using a Thin-Channel, Planar Electrode Emitter," Analytical Chemistry (2002), 74 (19), 5047-5056 ; GJ VAN BERKEL et al., “Derivatization for electrospray ionization mass spectrometry.” 3. Electrochemically ionizable derivatives ", Analytical Chemistry (1998), 70 (8), 1544-1554 ; F. Zhou et al. "Electrochemistry Combined Online with Electrospray Mass Spectrometry", Analytical Chemistry (1995), 67 (20), 3643-3649 ).
  • the sources used for nanoelectrospray are in the form of glass or fused silica capillaries. They are manufactured by hot stretching or acid etching of the material 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 a suitable conductive outer coating: a metal 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 ), money ( Y.-R CHEN et al., "A simple method for the manufacture of silver-coated sheathless electrospray emitters", Rapid Communications in Mass Spectrometry (2003), 17 (5), 437-441 ), a carbon-based material ( X.
  • a metal 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 )
  • money Y.-R CHEN et al.,
  • the electrospray voltage can also be applied via the liquid with the introduction of a 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. ).
  • microtechnology techniques are used for the production of integrated microsystems of characteristic size of the order of one micrometer and which bring together a series of reaction and / or analytical, chemical and / or biochemical / biological processes.
  • microfabricated electrospray devices rely, like fluidic microsystems, on the use of different types of materials and different types of processes.
  • nebulizing devices identified above have non-compliant operating conditions for small-scale nebulization (too large dimensions, too high nebulization voltages) and most often result from highly complex manufacturing processes.
  • type of structure chosen for these different devices is virtually indissociable material used for their realization.
  • the nebulization voltage is most often applied at the level of the reservoir of the device, if the system includes a reservoir, or, in the opposite case, at the level of the supply of liquid which is carried out using a capillary connected to the device.
  • the capillary is conductive (stainless steel for example), or the connection is based on a metal connector.
  • it has been proposed to integrate, on the nebulization device, an electrode or conductive zone on which the nebulization voltage is applied ( TC ROHNER et al., "Polymer microspray with an integrated thick-film microelectrode", Analytical Chemistry (2001), 73 (22), 5353-5357 ). This conductive zone is made based on carbon ink in the example cited.
  • the AFM microscopy technique has the advantage of a high resolution and a very high writing accuracy. Three modes of operation are possible, and depending on the mode chosen, the surface condition can be controlled before and after passing the chemical molecular writing solution. Nevertheless, this technique requires the use of heavy equipment, bulky, expensive and complex.
  • This micropipette is nevertheless integrated in an AFM apparatus for its use.
  • the ejection of solution here is caused not by contacting but by exerting pressure on the liquid column.
  • This device has been tested for its ability to deliver etching solutions of a chromium layer deposited on a glass plate.
  • the second device IW RANGELOW et al., "" NANOJET “: Tool for 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 Cr / Au-covered silicon, having a pyramidal shape and an outlet orifice smaller than 100 nm.
  • This device delivers not a chemical solution as in the previous example, but free radicals in the gas phase produced by a plasma discharge that attack the material placed opposite the tip.
  • the device does not consist not only in a microfabricated tip but also includes machinery for producing highly reactive species, such as a radiofrequency or microwave plasma discharge, which can attack the substrate.
  • the present invention relates to a two-dimensional electrospray device having a calligraphy feather type geometry, the tip of which acts as a seat for nebulization.
  • the subject of the invention is therefore an electrospray source comprising a structure comprising at least one flat and thin tip cantilevered with respect to the remainder of the structure, said tip being provided with a capillary slot practiced throughout the body. thickness of the tip and which ends at the end of the tip to form the ejection orifice of the source of electrospray, the source comprising means for supplying the capillary slit with liquid to be sprayed and means for applying an electrospray voltage to 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 tip.
  • the supply means may comprise a reservoir consisting of 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 to be in contact with said liquid to be sprayed.
  • the means for applying an electrospray voltage may comprise the support, at least partially electrically conductive, and / or the at least partially electrically conductive plate.
  • the plate has a hydrophobic surface to the liquid to be sprayed.
  • the means for applying an electrospray voltage may comprise an electrically conductive wire arranged to be in contact with said liquid to be sprayed.
  • the supply means may comprise a capillary tube. They may comprise a channel made in a microsystem supporting said structure and in fluid communication with the capillary slot.
  • 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 step of depositing the plate may be a deposit of a plate comprising a recess in fluid communication with the capillary slot to form a reservoir.
  • the method may further comprise a step of depositing at least one electrode intended to provide electrical contact with the liquid to be sprayed.
  • the source of electrospray according to the invention can be used to obtain ionization of a liquid by electrospray before its analysis by mass spectrometry. It can also be used to obtain a production of liquid drops of calibrated size or the ejection of particles of fixed size. It can still be applied to the realization of a molecular writing with the help of chemical compounds. It can still be applied to the definition of the electric potential of junction of a device in fluidic continuity.
  • the present invention is inspired by the structure and 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 tip.
  • the present invention may comprise, if necessary, an electrical contact zone on which is applied the voltage necessary to the establishment of a nebulisat.
  • 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 to promote or study the electrospray process. These electrodes also allow the control of the electrospray process by synchronization on its own frequency.
  • the liquid is brought by capillarity into the slot towards the end of the tip of the feather-type structure where it is ejected.
  • the ejection takes place not by mechanical action, but in the form of nebulization by applying a high voltage on the liquid.
  • FIGS. Figures 1A and 1B An electrospray source according to the present invention is shown in FIGS. Figures 1A and 1B , the Figure 1A being a view from above and the Figure 1B a side view.
  • This source of electrospray comprises a support 1 and a plate 2 integral with the support 1.
  • a portion of the plate 2 forms a tip 3 cantilevered with respect to the support 1.
  • the plate 2 comprises at its center a recess 4 revealing the surface of the support 1 and constituting a reservoir.
  • a capillary slot 5, also revealing the support 1, connects the reservoir 4 to the end 6 of the tip 3 which forms a ejection port for the electrospray source.
  • the operation of the device is based on the following stated 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.
  • the liquid of interest is deposited or conveyed into the liquid reservoir 4 by a suitable method. It is guided towards the end 6 of the structure by capillarity.
  • the source is brought to its site of use (for example in front of a mass spectrometer). A potential is applied to the liquid so as to observe the nebulisat at the tip 6 of the tip.
  • the physics of the source having a feather-type geometry rests on the properties of the materials that constitute it and on the dimensions of its different elements.
  • the figure 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 gradually feed the capillary slot 5.
  • the topology of the structure is two-dimensional.
  • the plate 2 is a hydrophobic material, and even more hydrophobic than that constituting the support 1 supporting the plate 2, material lining the bottom of the tank. this allows to limit the losses of liquid out of the tank.
  • the liquids envisaged for nebulization are a priori rather hydrophilic character, such as purely aqueous or half-aqueous solutions half-alcoholic, for example 50/50 methanol / water mixtures.
  • 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.
  • the source of electrospray is presented next to the area where the nebulization is desired, the effect of gravity on this liquid is negligible.
  • the factors that will intervene for the filling of the capillary gap by the liquid are: the contact angle ( ⁇ ) of the liquid on the material constituting the plate 2, the surface tension ( ⁇ ) of the liquid and the dimensions (1 and h) of the capillary slot 5.
  • Equation 2 the Young equation (equation 2) implies that ⁇ SV > ⁇ SL and thus that the solid-liquid interaction is favored compared to that solid-vapor.
  • the term r appears in Equation 1. Its value depends on the observation or not of the capillarity effect.
  • the term r corresponds to the radius of the capillary tube and, in the case of the device forming the subject of the present invention, to the size of the capillary slot 5. If the liquid penetrates into the capillary slot, a liquid bridge is formed. between the two walls of the capillary cleft. It is thus possible to define a ratio of shape R for the capillary slot 5, corresponding to the ratio h / w. It follows from the above that R must be greater than a critical value to observe a capillary effect in the capillary slot 5 and that the formation of the liquid bridge in the capillary slot 5 is favored from the energy point of view.
  • the nebulizing device may or may not include conductive areas (see figure 3H ). These conductive areas if they are located at the level of the liquid reservoir 4 serve as electrodes to bring the nebulization voltage. On the other hand, if they are located at the level of the capillary slot 5, these electrodes will be used to modify the species present in the liquid.
  • electrospray-type application before analysis by mass spectrometry electrochemical processes occur during the ionization of the molecules.
  • the conductive zones implanted on either side of the capillary slot 5 at the end 6 of the tip 3 would make it possible to study them. Moreover, these phenomena lead to an increase in the ionization efficiency and, as a result, to an improvement in the analysis conditions.
  • the presence of a larger amount of radical species increases the etching rate 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 that does not include conductive zones and for which the materials are not conductive can be used in Electro-fogging provided that the electrical contact is made via the liquid. A metal wire immersed in the solution to be sprayed, at the reservoir 4 or any other conductive contact and ensure the role of application of the nebulization voltage.
  • a conductive material metal, Si ..
  • the device may also be connected to a liquid supply source upstream of the tank 4, such as a capillary delivering a solution from another apparatus of another structure.
  • a capillary may correspond to a separation column output.
  • this capillary brings the liquid to the nebulization device from its initial location.
  • Said capillary may be a conventional commercial fused silica capillary. It can also be a microfabricated capillary, that is to say a microchannel integrated on the system supporting the source.
  • the capillary may be a hydrophilic track materialized on the support 1.
  • the plate 2 is integrated on a fluidic microsystem and acts as an interface between said microsystem and the outside world where the solution leaving the microsystem is used .
  • the conductive properties of the device or one of its elements can be used to electrically power any system in fluidic relation with the device.
  • said feather plates can be used in isolation or be integrated in large numbers on the same support, and for the parallelization of the nebulization.
  • said feather-type plates are independent or not of 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 pens function 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 circularly on a round support. The passage from one source to another is then performed respectively by translation or by rotation of the support.
  • a wide range of materials is nowadays conceivable for microtechnological manufacturing and in particular for fluidic microsystems: glass, silicon-based materials (Si, SiO 2 , silicon nitride, etc.), quartz, ceramics and a large number of materials. number of macromolecular materials, plastics or elastomers.
  • the geometry selected for the present invention is compatible with fabrications using any type of materials, and this, for the different parts of the source of electrospray: the support 1, the feather plate 2 and the conductive areas.
  • the technological manufacturing process also involves one or more other material (s) whose choice is adapted depending on the materials selected for elements 1, 2 and 3.
  • FIG. 3A to 3H A generic method for manufacturing electrospray sources according to the invention is shown in Figures 3A to 3H . This manufacturing process can be cut into seven major steps which are detailed below, so as to be applicable to any type of material.
  • the first step of this manufacturing process is the choice of the substrate intended to constitute the support of the source of electrospray.
  • This substrate 10 can be of macromolecular material, glass or silicon or metal. In the case of this embodiment, it is a silicon substrate of 250 .mu.m thick.
  • the beginning of the process conditions the end of the manufacture of electrospray devices. It is the materialization on the support of the device of lines which will help the cleavage of the substrate in order to release the point of the source and to allow nebulization.
  • a layer 11 of protective material is deposited on a portion 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 of the layer 11 does not affect the substrate 10.
  • the layer of protective material is a 20 nm thick layer of silicon oxide.
  • the layer 11 is of variable thickness depending on the nature of the materials of the substrate 10 and the layer 11.
  • the layer 11 is subjected to a lithography step intended to reveal the areas of the substrate to be attacked to define cleavage lines delimiting the support of the structure.
  • the corresponding areas of the layer 11 are etched to provide windows 12 revealing the substrate 10 (see FIG. figure 3B ).
  • FIG. 3C shows the result obtained: the lines 13, consisting of trenches V section, defining the support of the structure to obtain.
  • a layer of sacrificial material is deposited on the substrate 10.
  • This layer of sacrificial material 14 will ultimately enable 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 thin enough to be able to overcome any problem of stress and curvature from the point above 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 one area of the material 14 corresponding to the tip of the structure (see 3D figure ).
  • 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 silicon-based, a metal or even a material of polymer or ceramic type.
  • the layer of material intended to constitute the plate is a 35 ⁇ m thick layer of polymer SU-8 2035 purchased in pre-polymerized form from Microchem and polymerized by a photolithographic process. The thickness of this layer is chosen appropriately. This thickness indeed depend on the ionization performance of the nebulization device, as explained above.
  • this layer directly influences the height h of the capillary slit and, according to the foregoing, plus h is large, plus w must be large in order not to modify the ratio R. Or, depending on the final application of the source of nebulization, the stake is to decrease to the maximum w in order to increase the performances. On the other hand, if the thickness of the layer intended to constitute the plate is too thin, the overhanging tip may 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 specification depending on the nature of the material of this layer and thus to define the optimum thickness of material to be deposited.
  • This layer then undergoes a lithography step and an attack 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 FIG. figure 3E ).
  • This attack is adapted according to the material of the plate. It can be a chemical etching technique, a physical attack in the case of a silicon-based material or a metal, a physical attack or a photolithography followed by a revelation in the case of a photolithographable polymer.
  • 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 appropriate chemical attack.
  • the solution for this chemical attack must be carefully chosen so that all the sacrificial material is removed without the support or plate being affected.
  • the materials of these elements must not be sensitive to this chemical solution.
  • the sixth step concerns the implantation of conductive zones on the structure. As mentioned above, this step is included in the manufacturing process only if such conductive areas are provided.
  • These conductive zones may be 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 disengaged.
  • the conductive material chosen is then deposited by a PECVD (chemical vapor deposition technique) technique on the structure.
  • the conductive zones are made of palladium and have a thickness of 400 nm.
  • the figure 3G shows the structure obtained.
  • Two conductive areas 7 and 8 surround the tank 4 and allow to apply an electric potential.
  • the seventh step of this method of manufacturing the source of nebulization is the detachment of the support 1 with respect to the substrate 10 and in particular, the overhang of the tip 3 relative to the support 1 by using the cleavage lines 13 materialized in FIG. second step of this manufacturing process.
  • the structure obtained is represented in figure 3H .
  • FIG. 4A and 4B An advantageous cleavage technique is illustrated by the Figures 4A and 4B in the case of overhanging the tip.
  • a fixed wire 20 is placed under the support 1 at the cleavage trenches 13 made on either side of the tip. Together, two forces are exerted on the substrate at the locations indicated on the Figure 4A by arrows. The separation previously made of the tip 3 relative to the support 1 thus ensures that not damage the tip during the cleavage step.
  • the Figure 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 application targeted by the present invention is the electrospray 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.
  • biologists in particular are increasingly interested in proteomics, a science that aims to study and characterize all the proteins of an individual.
  • These proteins, in any human being, are present in more than 10 6 different molecules including post-translational modifications. This point justifies the need at the present time for analytical techniques and tools that are compatible with automation for high-throughput analysis, especially for mass spectrometry because of its relevance in the field of mass spectrometry. framework of the study of proteins.
  • the second type of application targeted by the present invention is the deposition 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 most often depending on the resolution expected in the preparation of the analysis plates. The smaller the drops, the closer their deposit can be on the plate and the higher the density in deposits and therefore in analytes.
  • the device which is the subject of the present invention can be used for this purpose.
  • the width of the capillary slot 5, as well as the value the voltage applied for the ejection of the drops conditions the size of the drops ejected by said nebulizing device.
  • the resolution of the analysis plates can be adjusted according to the width of the slot of the device.
  • the nebulization voltage may be alternating and thus give a deposition rate in drops / minute directly dependent on the frequency of the AC voltage.
  • the deposition of calibrated drops as presented above can be used for the preparation of assay plates such as DNA chips. It can also be applied to the preparation of MALDI targets (for "Matrix-Assisted Laser Desorption / Ionization") on which the samples to be analyzed by mass spectrometry with a MALDI ionization here, are deposited in a discrete manner before their crystallization and their introduction. in the mass spectrometer.
  • the present nebulizing device having a feather-type geometry can it be for example connected to the output of the separation column and allow coupling between a separation technique and an online analysis by mass spectrometry MALDI type.
  • the drops of liquid finally can be replaced by cells.
  • the cells are likewise ejected discretely and deposited for example on a plate for the development of cell chips.
  • the third application targeted by the present invention is the molecular writing at scales of the order of one hundred nanometers.
  • this type of operation is carried out at using AFM microscopy tips, operating with heavy and bulky equipment.
  • the ejection of the liquid is based on a contact or quasi-contact of the tip and the deposition substrate in the case of the AFM or the application of a pressure on the liquid.
  • An adaptation of this technique is to eject the liquid under the action of a voltage and not with the help of pressure or contact. Indeed, in both cases, the ejection is caused when the liquid tension forces at the tip of the pipette are "exceeded" by another force applied to the liquid column.
  • the present invention can therefore be used for such purposes of molecular writing on a smooth or rough substrate, the release of the writing solution (pseudo-ink) being governed here by applying a voltage.
  • a major stake is to minimize the size of the end of the tip, this dimension conditioning the size of the ejections by nebulization and consequently the expected resolution write on the final substrate.
  • the width of the tip is less than or equal to one micrometer. Another factor influencing the size of the ejections and the fluid flow is the nebulization voltage applied to the liquid.
  • the production of reactive species if the device is used to dispense an etching solution from the substrate, can be increased with the implantation of electrodes within the feather-like structure that delivers the fluid. These electrodes are then the seat of electrochemical reactions leading to the formation of reactive species.
  • Example 1 Design of microfabricated nanoelectrospray sources according to the present invention.
  • a first example concerns the dimensions and shapes chosen for producing a nebulization device as described in the present invention.
  • This first device has small dimensions in its tip because of the intended field of application, that is to say a nanoelectro-debulization for the ionization of solutions before their analysis by mass spectrometry.
  • the device is made in accordance with Figures 1A and 1B .
  • the reservoir 4 of the device has 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.
  • the width of the capillary slot 5 is 8 ⁇ m at the end 6 of the tip 3.
  • Example 2 Manufacture of design sources described in Example 1 using silicon and SU-8 materials.
  • the second example relates to the fabrication by microtechnology of nebulization sources, as described in Example 1.
  • the materials used are silicon for support 1 and photolithographable negative resin SU-8 for the feather plate 2.
  • the method of The manufacture derives from the process described above. It is adapted to the chosen materials.
  • An oriented silicon substrate (100) and n-doped, 3 inches, is coated with a 200 nm layer of silicon oxide (SiO 2 ), and masked by lithography.
  • the SiO 2 layer is attacked by a acid solution of HF: H 2 O on unmasked areas.
  • the exposed silicon is then attacked with a sodium hydroxide solution (KOH) so as to materialize the cleavage lines.
  • a layer of 150 nm of nickel is then deposited on the silicon surface by argon sputtering technique (Plassys MP 450S).
  • the nickel layer is etched locally by UV photolithography (positive photoresist AZ1518 [1.2 ⁇ m], etching solution HNO 3 / H 2 O (1: 3)) so that only nickel remains under the tip of the pen.
  • UV photolithography positive photoresist AZ1518 [1.2 ⁇ m], etching solution HNO 3 / H 2 O (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 spinning wheel to homogenize the thickness before the next photolithography step.
  • the feather plate 2 is made in this SU-8 resin layer using conventional UV photolithography techniques.
  • the nickel layer is etched with the acid solution (HNO 3 / H 2 O) described above. This nickel etching step does not affect the SU-8 resin even though this process may take several hours.
  • the silicon substrate 1 is sawn according to the technique illustrated in FIGS. Figures 4A and 4B .
  • the technique used here preserves the structure of the feather, as the latter was previously peeled off its support.
  • a photograph of Scanning electron microscopy (Hitachi S4700) of the feather-type fogging source manufactured according to this method confirms the correct detachment of the tip from its support.
  • the manufacturing method described above does not include the production of electrodes.
  • Example 3 Design of particle ejection device of a hundred micrometers.
  • a third example concerns the dimensions and shapes chosen for producing a device for ejecting particles 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 the tank 4 must be compatible with the handling of objects of a hundred microns. Because of this range of dimensions, the device described in Example 3 also applies to the manipulation of cells of size close to 100 ⁇ m in diameter, for the preparation of cell chips, for example.
  • the reservoir 4 of said device has the dimensions 1 cm ⁇ 1 cm ⁇ ( ⁇ m) where e is the thickness of the plate 2.
  • 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 that is greater than 1.
  • the particles handled by this device have a size of one hundred micrometers, so the capillary slot 5 must have a width greater than 100 ⁇ m. However, the particles may tend to aggregate, this width should not be chosen too large. It is preferably close to double the size of the particles handled. As a result, the width of the slot is set 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 photolithographable 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.
  • the glass support 1 is also covered with a thin layer of SU-8 resin to prevent unwanted adhesion of the cells to the device.
  • Example 4 Test Nebulization Sources Manufactured According to Example 2 in Mass Spectrometry. I: Application of the tension using a platinum wire.
  • Example 4 is the test of nebulization sources manufactured as described in Example 2 for mass spectrometry analysis.
  • the nebulizing voltage is applied to the liquid to be sprayed using a platinum wire immersed in the liquid at the reservoir as shown in FIG. figure 5 .
  • the nebulizing device is placed on a moving part 30 that can be moved in xyz.
  • This mobile 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 isolated from this metal part 31 when the device is fixed on 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 by means of a platinum wire 32 introduced into the reservoir and which is immersed in the solution to be analyzed 33.
  • the solution used for the nebulization tests a standard peptide solution (Gramicidin S) is deposited in the reservoir of the device and the moving part 30 is introduced into the input of the mass spectrometer 25.
  • the tests are carried out on an ion trap type mass spectrometer from Thermo Finnigan (LCQ DECA XP +).
  • the voltage is then applied to the liquid.
  • a camera installed on the ion trap allows to visualize the formation of the Taylor cone, once the applied voltage.
  • the capillary slit at a width of 8 ⁇ m.
  • the figure 6 is a graph representing the total ion current recorded by the mass spectrometer for an experiment conducted for 2 minutes with a solution of Gramicidin S at 5 ⁇ M and a ionization voltage at 0.8 kV.
  • the y-axis represents the relative intensity I R.
  • the x-axis represents time.
  • the figure 7 corresponds to the mass spectrum obtained with a solution of Gramicidin S at 5 ⁇ M and a voltage of 1.2 kV. The mass spectrum was averaged over 2 minutes of signal acquisition, ie 80 scans.
  • Example 5 Test 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 exploiting the semiconductor properties of 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 nebulizing device is fixed on a moving part 40 that can be moved in xyz and having a metal part 41.
  • the support 1 of silicon is placed in electrical contact with the metal part 41 of the moving part 40 on which the ionization voltage is applied in the mass spectrometer 25.
  • the device is fixed on the mobile part 40 by means of a Teflon tape which surrounds the device upstream of the tank. The test is conducted as previously after introduction of the moving part 40 into the ion trap and application of the voltage.
  • the capillary gap has a width of 8 ⁇ m.
  • the tests were conducted with another standard peptide Glu-Fibrinopeptide B.
  • the ionization voltages here are in the same range as above, from 1 to 1.4 kV for peptide less than 1 ⁇ M.
  • the figure 9 represents the total ionic current measured during 3 minutes of signal acquisition with a solution of 0.1 ⁇ M and a voltage of 1.1 kV.
  • I R is the relative intensity and t is the time.
  • the figure 10 is the mass spectrum obtained for this acquisition and averaged over the period of 3 minutes, ie 120 scans.
  • I R is the relative intensity.
  • Example 6 Test Nebulization Sources Manufactured 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 assembly is identical to that of the previous example, the nebulization device corresponds to that described in Example 1 and carried out according to the manufacturing method described in Example 2.
  • the voltage is applied directly to the material of the invention. support 1, the silicon, via the metal zone 41 included on the moving part 40 introduced into the mass spectrometer 25 (see FIG. figure 8 ).
  • the capillary gap has a width of 8 ⁇ m.
  • the solution is the same as above, a standard peptide solution, Glu-Fibrinopeptide B at concentrations of less than or equal to 1 ⁇ M.
  • the peptide is subjected to a fragmentation experiment.
  • Peptide in dicharged form (M + 2H) 2+ is specifically isolated in the ion trap and is fragmented (standardized collision energy parameter of 30%, radiofrequency activation factor set at 0.25).
  • the figure 11 represents the fragmentation spectrum obtained during this experiment with a solution of 0.1 ⁇ M and a voltage of 1.1 kV.
  • I R is the relative intensity.
  • the spectrum was averaged over 2-3 minutes of acquisition of the nebulization signal.
  • the different fragments of MS / MS are annotated with their sequence.
  • Example 7 Test Nebulization Sources Manufactured 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 composed 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 slit is 8 ⁇ m.
  • the figure 12 represents the mass spectrum obtained for the digestate 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 as well as its state of charge. Of the 15 peptides, 11 are clearly identified in this experiment.
  • Example 8 Test Nebulization Sources Manufactured According to Example 2 in Mass Spectrometry V: Feeding said device continuously using a syringe pump or a chain of nanoLC placed upstream.
  • Example 8 is identical to Example 5 (same device manufactured according to the same method and tested under the same conditions with application of the voltage on the silicon support 1) except that the sample analyzed here is fed 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 of 1 ⁇ M and the nebulization voltage was set at 1.2 kV.
  • the width of the capillary slit is 8 ⁇ m.
  • the figure 13 shows the total ion current recorded during a nebulization test conducted over a period of 6 minutes under said conditions.
  • I R is the relative intensity and t is the time.
  • the figure 14 represents the corresponding mass spectrum averaged over this acquisition period of 6 minutes, ie 240 scans.
  • I R is the relative intensity.
  • the coupling to a nanoLC chain was carried out with conventional coupling conditions between a nanoLC separation and an on-line mass spectrometry analysis on a hatch. ionic.
  • the fluid flow rate is 100 nL / min, the ionization voltage is 1.5 kV.
  • the separation experiment is performed on a Cytochrome C digestate at 800 fmol / ⁇ L and 800 ⁇ mol of this digestate are injected onto the separation column.
  • the width of the capillary slit is 10 ⁇ m.
  • the figure 15 represents the total ionic current detected on the mass spectrometer during the separation experiment.
  • I R is the relative intensity and t is the time.
  • the figure 16 is the mass spectrum obtained for the peak indicated on the figure 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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Claims (18)

  1. Elektrosprühquelle, umfassend eine Struktur, die wenigstens eine flache und dünne Spitze (3) enthält, welche bezogen auf den Rest der Struktur vorsteht, dadurch gekennzeichnet, dass die Spitze (3) mit einem kapillaren Schlitz (5) versehen ist, der in der gesamten Dicke der Spitze vorgesehen ist und am Ende (6) der Spitze (3) mündet, um die Ausstoßöffnung der Elektrosprühquelle zu bilden, wobei die Quelle Mittel (4) zur Versorgung des kapillaren Schlitzes (5) mit zu versprühender Flüssigkeit sowie Mittel zum Anlegen einer Elektrosprühspannung an die Flüssigkeit umfasst.
  2. Elektrosprühquelle nach Anspruch 1, dadurch gekennzeichnet, dass die Mittel zur Versorgung wenigstens einen Behälter (4) in Fluidverbindung mit dem kapillaren Schlitz (5) umfassen.
  3. Elektrosprühquelle nach Anspruch 1, dadurch gekennzeichnet, dass die Struktur einen Träger (1) sowie eine Platte (2) umfasst, die mit dem Träger verbunden ist und von der ein Teil die Spitze (3) bildet.
  4. Elektrosprühquelle nach Anspruch 3, dadurch gekennzeichnet, dass die Mittel zur Versorgung einen Behälter (4) umfassen, der durch eine Aussparung gebildet ist, welche in der Platte (2) gebildet und in Fluidverbindung mit dem kapillaren Schlitz (5) ist.
  5. Elektrosprühquelle nach einem der Ansprüche 1 - 4, dadurch gekennzeichnet, dass die Mittel zum Anlegen einer Elektrosprühspannung wenigstens eine Elektrode (7, 8) umfassen, die derart angeordnet ist, dass sie in Kontakt mit der zu versprühenden Flüssigkeit ist.
  6. Elektrosprühquelle nach einem der Ansprüche 3 oder 4, dadurch gekennzeichnet, dass die Mittel zum Anlegen einer Elektrosprühspannung den Träger umfassen, der wenigstens teilweise elektrisch leitend ist, und/oder die Platte, die wenigstens teilweise elektrisch leitend ist.
  7. Elektrosprühquelle nach einem der Ansprüche 1 - 4, dadurch gekennzeichnet, dass die Mittel zum Anlegen einer Elektrosprühspannung einen elektrisch leitenden Draht (32) umfassen, der so angeordnet ist, dass er in Kontakt mit der zu versprühenden Flüssigkeit gelangen kann.
  8. Elektrosprühquelle nach einem der Ansprüche 1 - 7, dadurch gekennzeichnet, dass die Mittel zur Versorgung ein kapillares Rohr umfassen.
  9. Elektrosprühquelle nach einem der Ansprüche 1 - 7, dadurch gekennzeichnet, dass die Mittel zur Versorgung einen Kanal umfassen, der in einem Mikrosystem realisiert ist, das die Struktur trägt und in Fluidverbindung mit dem kapillaren Schlitz ist.
  10. Elektrosprühquelle nach einem der Ansprüche 3 oder 4, dadurch gekennzeichnet, dass die Platte (2) eine für die zu versprühende Flüssigkeit hydrophobe Oberfläche aufweist.
  11. Verfahren zur Herstellung einer Struktur, die eine Elektrosprühquelle bildet, umfassend:
    - die Realisierung eines Trägers (1) ausgehend von einem Substrat (10),
    - die Realisierung einer Platte (2), umfassend einen Teil, der eine flache und dünne Spitze (3) bildet, wobei die Spitze mit einem kapillaren Schlitz (5) versehen ist, um eine zu versprühende Flüssigkeit zu führen, und der über die gesamte Breite der Spitze vorgesehen ist und am Ende der Spitze mündet,
    - die Verbindung der Platte (2) auf dem Träger (1), wobei die Spitze (3) in Bezug auf den Träger vorsteht.
  12. Verfahren nach Anspruch 11, dadurch gekennzeichnet, dass es die folgenden Schritte umfasst:
    - die Bereitstellung eines Substrats (10) zur Realisierung des Trägers (1),
    - die Begrenzung des Trägers (1) mit Hilfe von Gräben (13), die in das Substrat (10) graviert werden,
    - die Aufbringung von Opfermaterial (14) gemäß einer vorbestimmten Dicke auf einer Zone des Substrats, die der zukünftigen Spitze der Struktur entspricht,
    - die Aufbringung der Platte (2) auf dem begrenzten Träger (1) im Substrat (10), wobei die Spitze (3) der Platte (2) auf dem Opfermaterial (14) angeordnet ist,
    - die Entfernung des Opfermaterials (14),
    - die Ablösung des Trägers (1) in Bezug auf das Substrat (10) durch Spaltung im Bereich der Gräben (13).
  13. Verfahren nach Anspruch 12, dadurch gekennzeichnet, dass der Schritt des Aufbringens der Platte (2) ein Aufbringen einer Platte mit einer Aussparung in Fluidverbindung mit dem kapillaren Schlitz (5) ist, um einen Behälter (4) zu bilden.
  14. Verfahren nach einem der Ansprüche 12 oder 13, dadurch gekennzeichnet, dass es ferner einen Schritt des Aufbringens wenigstens einer Elektrode (7, 8) umfasst, die dazu bestimmt ist, einen elektrischen Kontakt mit der zu versprühenden Flüssigkeit sicherzustellen.
  15. Verwendung der Elektrosprühquelle gemäß einem der Ansprüche 1 - 10 zur Erzielung einer lonisation einer Flüssigkeit durch Elektrosprühen vor ihrer Massenspektrometrie-Analyse.
  16. Verwendung der Elektrosprühquelle nach einem der Ansprüche 1 - 10 zur Erzielung einer Produktion von Flüssigkeitstropfen mit kalibrierter Größe oder des Ausstoßes von Partikeln mit fester Größer.
  17. Verwendung der Elektrosprühquelle nach einem der Ansprüche 1 - 10 bei der Durchführung einer molekularen Beschriftung mit Hilfe von chemischen Verbindungen.
  18. Verwendung der Elektrosprühquelle nach einem der Ansprüche 1 - 10 bei der Bestimmung des elektrischen Diffusionspotentials einer Fluidkontinuitätsvorrichtung.
EP04805823A 2003-11-12 2004-11-10 Planare elektrosprühquellen auf grundlage einer kalligraphiefeder und herstellung davon Not-in-force EP1703987B1 (de)

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FR0350820A FR2862006B1 (fr) 2003-11-12 2003-11-12 Sources d'electronebulisation planaires sur le modele d'une plume de calligraphie et leur fabrication.
PCT/FR2004/050580 WO2005046881A1 (fr) 2003-11-12 2004-11-10 Sources d'electronebulisation planaires sur le modele d'une plume de calligraphie et leur fabrication.

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FR2934179B1 (fr) * 2008-07-24 2010-09-17 Commissariat Energie Atomique Laboratoire sur puce comprenant un reseau micro-fluidique et un nez d'electronebulisation coplanaires.
JP4818399B2 (ja) * 2009-06-15 2011-11-16 三菱電機株式会社 静電霧化装置及び空気調和機
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FR2862006B1 (fr) 2006-01-27
EP1703987A1 (de) 2006-09-27
DE602004013195D1 (de) 2008-05-29
JP4800218B2 (ja) 2011-10-26
US8294119B2 (en) 2012-10-23
JP2007516071A (ja) 2007-06-21
FR2862006A1 (fr) 2005-05-13
DE602004013195T2 (de) 2009-06-25
ATE392261T1 (de) 2008-05-15
CA2545213C (fr) 2012-02-21
WO2005046881A1 (fr) 2005-05-26
US20070252083A1 (en) 2007-11-01
CA2545213A1 (fr) 2005-05-26

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