US20090261244A1 - Microengineered nanospray electrode system - Google Patents
Microengineered nanospray electrode system Download PDFInfo
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- US20090261244A1 US20090261244A1 US11/487,735 US48773506A US2009261244A1 US 20090261244 A1 US20090261244 A1 US 20090261244A1 US 48773506 A US48773506 A US 48773506A US 2009261244 A1 US2009261244 A1 US 2009261244A1
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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
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- 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, MicroElectro-Mechanical Systems [MEMS]
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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
- H01J49/04—Arrangements for introducing or extracting samples to be analysed, e.g. vacuum locks; Arrangements for external adjustment of electron- or ion-optical components
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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
- H01J49/06—Electron- or ion-optical arrangements
- H01J49/067—Ion lenses, apertures, skimmers
Definitions
- This invention relates to mass spectrometry, and in particular to the use of mass spectrometry in conjunction with liquid chromatography or capillary electrophoresis.
- the invention particularly relates to a system and method that is implemented in a microengineered configuration.
- Electrospray is a common method of soft ionisation in biochemical mass spectrometry (MS), since it allows the analysis of fluid samples pre-separated by liquid chromatography (LC), the ionization of complex molecules without fragmentation, and a reduction in the mass-to-charge ratio of heavy molecules by multiple charging [Gaskell 1997; Abian 1999]. It may be used in a similar way with fluid samples pre-separated by other methods such as capillary electrophoresis (CE).
- CE capillary electrophoresis
- a voltage is applied between an electrode typically consisting of a diaphram containing an orifice and a capillary needle containing the analyte. Liquid is extracted from the tip and drawn into a Taylor cone, from which large charged droplets are emitted. The droplets are accelerated to supersonic speed, evaporating as they travel. Coulomb repulsion of the charges in the shrinking droplet results in fragmentation to ions when the Rayleigh stability limit is reached. The resulting ions can be multiply charged.
- An electrospray mass spectrometer system contains a number of key elements:
- the spray is passed from atmospheric pressure via a chamber held at an intermediate pressure.
- Several vacuum interfaces that use differential pumping to match flow rates to achievable pressures have been developed [Duffin 1992].
- the ion optics normally consist of input and output orifices such as capillaries, capillary arrays and skimmer electrodes, and occasionally also a quadrupole lens operating as an ion guide in all-pass mode. These components are used to maximise the ratio of coupled ions to neutrals, which would otherwise swamp the chamber.
- Solvent can be preferentially driven off, by direct heating [Lee 1992]. Advantages may be obtained by the use of a sheath gas flow [Huggins 1993], and nebulisation may be enhanced by ultrasound [Hirabayashi 1998].
- Alignment in electrospray is not critical, and the spray may simply be directed towards the MS input. Alternatively, an off-axis spray direction may be used to promote the separation of neutrals.
- Co-axial lenses mounted directly on the capillary have been developed to focus the spray [U.S. Pat. No. 6,462,337]; however, there are limits to the electrode complexity that can be achieved using such simple mechanical systems.
- the invention addresses these and other problems by providing a solution to the problems of alignment and electrode mounting in a low-cost nanospray source by using microelectromechanical systems technology to form appropriate mechanical alignment and conducting electrode features on insulating plastic substrates in an integrated manner.
- the approach also allows integration of features for fluid drainage, spray heating and sheath gas flow.
- This invention provides a method of aligning a nanospray capillary needle, a set of electrodes, and the capillary input to an API mass spectrometer.
- the electrode system is formed using microelectromechanical systems technology, as an assembly of two separate chips. Each chip is formed on an insulating plastic substrate. The first chip carries mechanical alignment features for the capillary electrospray needle and the API mass spectrometer input, together with a set of partial electrodes. The second chip carries a set of partial electrodes.
- the complete electrode system is formed when the chips are assembled in a stacked configuration, and consists of an einzel lens capable of initiating a Taylor cone and separating ions from neutrals by focusing.
- the invention provides a system according to claim 1 with advantageous embodiments provided in the dependent claims thereto.
- the invention also provides a method of fabricating such a system as detailed in the main independent method claim.
- FIG. 1 shows in schematic form a microengineered nanospray system aligning a nanospray needle with the capillary input to an atmospheric pressure ionisation mass spectrometer according to an embodiment of the present invention.
- FIG. 2 shows construction of a microengineered nanospray system as a stacked assembly of two chips according to an embodiment of the present invention.
- FIG. 3 is a process flow for construction of a microengineered nanospray chip according to an embodiment of the present invention.
- FIG. 4 a shows the layout of a lower and FIG. 4 b the layout of an upper substrate of a microengineered nanospray chip according to an embodiment of the present invention.
- FIG. 5 shows an assembly of a microengineered nanospray chip according to an embodiment of the present invention.
- FIG. 6 shows electrostatic operation of a microengineered nanospray chip according to an embodiment of the present invention.
- FIG. 7 shows operation of the sheath gas inlet of a microengineered electrospray chip according to an embodiment of the present invention.
- FIG. 8 shows thermal operation of a microengineered electrospray chip according to an embodiment of the present invention.
- FIG. 9 shows electrode configurations realisable using a stacked electrode assembly with FIG. 9 a ) being a closed pupil arrangement, FIG. 9 b ) a horizontally split pupil, FIG. 9 c ) a vertically split pupil and FIG. 9 d ) a quadrant pupil arrangement.
- MEMS microspray ionisation
- widely used methods of lithographic patterning, oxidation and metallisation are combined with specialised techniques such as anisotropic wet chemical etching [Bean 1978] and deep reactive ion etching [Hynes 1999] to form three-dimensional features in crystalline semiconductors such as silicon.
- UV exposure of specialised photosensitive polymers such as SU-8 may be used to form three-dimensional features in plastics [Lorenz 1997].
- These methods may be used to combine insulating substrates, alignment features and conducting electrodes.
- the present inventor has realised that at least potentially, they may therefore form an integrated nanospray ionisation source at low cost.
- MEMS technology could be used to provide nanospray devices.
- the device must typically operate with high voltages, in a wet environment, so that electrical isolation and drainage are both required.
- the substrate material most commonly used in MEMS, silicon is therefore not appropriate; however, other insulating materials such as glasses are difficult to micromachine.
- an electrode containing an axially aligned orifice is typically required.
- electrostatic deflection or focusing is required.
- further electrodes containing aligned orifices are needed. If the ion path is itself in the plane of a substrate, such orifices are extremely difficult to form by in plane patterning alone.
- FIG. 1 illustrates the concept of a microengineered nanospray electrode system.
- a mass spectrometer 101 is provided in a high-vacuum enclosure 102 pumped (for example) by a turbomolecular pump 103 . Ions are channelled into this chamber via a further chamber 104 held at an intermediate pressure and pumped (again, for example) by a rotary pump 105 .
- the inlet to the vacuum system is assumed to be a capillary 106 .
- the filter element of the mass spectrometer could be an ion trap, a quadrupole, a magnetic sector, a crossed-field or a time of flight device.
- the intermediate vacuum chamber could contain a range of components including further capillaries and skimmer electrodes.
- the overall input to the system is provided by a nanospray capillary 107 .
- Alignment between the nanospray capillary 107 and the capillary input to the mass spectrometer 106 is provided by a microengineered chip 108 .
- the chip contains a first set of mechanical alignment features 109 for the nanospray capillary and a second set of alignment features 110 for the capillary input to the mass spectrometer.
- the chip also contains a set of electrodes 111 set up perpendicular to the ion path, which may (for example, but not exclusively) consist of diaphragm electrodes. Other features may be integrated on the chip, including holes for drainage and gas inlet.
- FIG. 2 illustrates the main features of the chip 108 .
- the chip is constructed from two separate substrates, each carrying microengineered features, which are arranged in a stacked assembly.
- the first substrate consists of a base 201 formed in insulating material and carrying a mechanical alignment feature for the nanospray capillary corresponding to the feature 109 in FIG. 1 , which may (for example, but not exclusively) consist of a groove 202 etched into a conducting or semiconducting block 203 .
- This substrate also carries an alignment feature for the capillary input to the mass spectrometer corresponding to the feature 110 in FIG. 1 , which may again for example consist of a further groove 204 etched into a block of similar material 205 .
- This substrate also carries a set of electrodes corresponding to part of the features 111 in FIG. 1 and consisting of grooves 206 etched into upright plates of similar material 207 .
- the second substrate again consists of a base 208 formed in insulating material, and carrying a further set of electrodes corresponding to a further part of the features 111 in FIG. 1 and consisting of grooves 209 etched into upright plates of conducting or semiconducting material 210 .
- the partial electrode sets combine to form complete diaphragm electrodes with closed pupils 211 .
- a so-called ‘einzel’ or unipotential electrostatic lens is formed.
- This type of lens allows focusing of ions passing axially through the stack of electrodes in a simple and controlled manner, and hence allows the ion spray to be focused onto the capillary input to the mass spectrometer to present a concentrated stream of analyte ions.
- the alignment grooves 202 and 204 may all be defined by similar photolithographic processes, and may therefore be registered together.
- This aspect provides a solution to the first problem identified above in the Background to the Invention section, of constructing an accurately aligned set of mechanical features and electrodes.
- the use of an insulating substrate that may be patterned with drain holes provides a solution to the problem of maintaining high voltages in a wet environment.
- a stacked combination of partial electrodes provides a solution to the problem of forming diaphragm electrodes arranged normal to a substrate.
- FIG. 3 shows a process, which is intended to be exemplary rather than exclusive.
- the materials used are low cost, and only three lithographic steps are required.
- the process is based on crystalline silicon substrates on which plastic virtual substrates are subsequently formed.
- the individual process steps are indicated by a set of evolving wafer cross-sections containing typical features.
- a (100)-oriented silicon substrate 301 is first oxidised to form a SiO 2 layer 302 on both sides.
- the SiO 2 is patterned and etched to form a channel-shaped opening 303 , by (for example) photolithography and reactive ion etching.
- the underlying silicon substrate is anisotropically etched down (111) crystal planes to form a V-shaped groove 304 .
- an etchant consisting of potassium hydroxide (KOH), water and isopropanol (IPA) may be used for this purpose.
- KOH potassium hydroxide
- IPA isopropanol
- step 3 the wafer is spin coated with a thick layer of the epoxy-based photoresist SU-8 305 .
- This resist may be coated and exposed in layers of at least 0.5 mm thickness, has excellent adhesion, and is extremely rugged after curing, allowing it to be used as a virtual substrate material after processing.
- the resist is lithographically patterned to form a dicing groove 306 around each die, together with any drain holes 307 and gas inlets.
- step 4 the front side of the wafer is metallised to increase conductivity, typically with an adhesion layer of Cr metal and a further thicker layer of Au 308 .
- step 5 the front side of the wafer is coated in a photoresist 309 . Since the wafer is non-planar, an electrodeposited resist is used in preference to spin-coated resist for this step.
- the resist is patterned to define the outlines of all electrode and alignment blocks 310 , and the pattern is transferred through the metal.
- step 6 the pattern is transferred through the silicon wafer by deep reactive ion etching, to form deep separation features 311 between elements.
- the photoresist is then removed, and individual dies are separated in step 7.
- step 8 two dies are stacked together to form a complete nanospray chip, by soldering or bonding the metal layers 312 together.
- a conducting epoxy may be used for this step.
- the chip is mounted on a carrier circuit board, and wirebond connections 313 are made to appropriate features on the lower substrate.
- a first alternative process is offered by forming the conducting alignment and electrode elements by electroplating a metal inside a mould, which may itself be formed by a sequence of patterning and etching steps.
- this alternative requires the separate formation of a mould, which is a laborious process.
- a second alternative process is offered by forming the alignment and electrode elements by sawing or otherwise eroding a conducting layer attached to an insulating substrate.
- the substrate bases may be also defined by sawing or by erosion, and the grooves may be formed, by partial sawing.
- this alternative offers less flexibility in the range of structures that may be created.
- FIG. 4 shows the layout of individual substrates that can be realised using the process of FIG. 3 .
- the larger plastic substrate-base 401 carries a mounting block 402 for the nanospray capillary, formed in etched, metallised silicon and having an etched alignment groove 403 .
- the substrate carries a similar mounting block 404 for the mass spectrometer input capillary, with a similar etched alignment groove 405 , and a set of partial electrodes 406 with etched grooves 407 .
- the electrodes are widened at their extremities to assist in the stacked assembly and to allow bonding.
- a large hole 408 through the plastic substrate-base provides a drain, and a smaller hole 409 provides a channel for sheath gas to flow into an etched plenum chamber 410 .
- the smaller plastic substrate-base 411 carries a further set of partial electrodes 412 and further features 413 defining the sheath gas plenum.
- FIG. 5 shows assembly.
- the smaller substrate 501 is inverted, aligned on top of the larger substrate 502 , and the electrodes are bonded together.
- the device is mounted on an external printed circuit board, and wirebond connections 503 are attached to the alignment features and electrodes.
- the chip is aligned and connected electrically to the input capillary 504 of the mass spectrometer, and the nanospray capillary 505 is inserted into its input alignment feature and connected electrically.
- a stop may be provided on each capillary to ensure that it may only be inserted into its alignment groove for a fixed distance.
- FIG. 6 shows electrostatic operation of the device.
- the capillary input to the mass spectrometer and its alignment feature 601 both are assumed to be at ground potential.
- a large DC voltage V 1 is applied to the nanospray capillary via its associated mount 602 .
- the voltage may be applied via a wire passing into the capillary.
- An intermediate voltage V 2 is applied to the outer electrodes 603 , 604 of the lens element and a further voltage V 3 to the centre element 605 .
- the spray 606 is emitted from a Taylor cone created at the exit of the nanospray capillary due to the potential difference V 1 ⁇ V 2 .
- the ion stream is focused onto the capillary input to the mass spectrometer 607 due to the action of the focus voltage V 3 .
- FIG. 7 shows operation of the sheath gas inlet.
- Sheath gas is passed through the lower substrate-base 701 of the assembly via an inlet hole 702 .
- the gas flows into a plenum 703 formed in the nanospray capillary mount 704 .
- the gas leaks from the plenum around the capillary, because it does not fully seal the orifice formed by the grooves in the upper and lower nanospray capillary mount.
- the natural taper of the capillary 705 ensures that the majority of the leakage takes place in a forward axial direction 706 , forming a sheath around the spray.
- FIG. 8 shows a mode of thermal operation.
- a current I is passed through one or more of the electrodes 801 to provide local heating, which may preferentially evaporate more volatile components in the spray such as a carrier solvent, thus enriching the analyte ion stream.
- FIGS. 9 a - 9 d shows different possible electrode cross sections.
- the assembly of two plates 901 and 902 with grooves formed by anisotropic wet chemical etching will create electrodes with a diamond-shaped pupil 903 .
- the size of the pupils may be controlled, by varying the width of the initial etched groove either continually or in discrete steps along the axis. It will be appreciated by those skilled in the art that other fabrication methods such as deep reactive ion etching may be used to form U-shaped alignment grooves and electrode grooves, which have greater inherent symmetry.
- the electrodes may be segmented horizontally using additional spacing 904 as shown in FIG. 9 b , or segmented vertically using additional etching 905 as shown in FIG. 9 c . Both methods of segmentation may be combined as shown in FIG. 9 d . Segmented electrodes of this type may be used to provide one- or two-axis electrostatic deflection in addition to focusing. These additional degrees of freedom offer the potential to improve the separation of ions from neutrals, for example by inserting a bend or a dog-leg into the ion path that neutrals cannot follow.
- the ability to provide transverse electrostatic forces using segmented electrodes allows the spray to be deflected in a time-varying manner. If the spray is oscillated using a sinoidally varying lateral force, a periodic perturbation may be induced in the spray flow. If the spatial frequency of this perturbation is chosen to coincide with the spatial frequency of Rayleigh instability in the flow pattern, the flow will be encouraged to fragment into droplets, thus promoting nebulisation.
- MEMS is intended to encompass the terms microengineered or microengineering and is intended to define the fabrication of three dimensional structures and devices with dimensions in the order of microns. It combines the technologies of microelectronics and micromachining. Microelectronics allows the fabrication of integrated circuits from silicon wafers whereas micromachining is the production of three-dimensional structures, primarily from silicon wafers. This may be achieved by removal of material from the wafer or addition of material on or in the wafer.
- microengineering may be summarised as batch fabrication of devices leading to reduced production costs, miniaturisation resulting in materials savings, miniaturisation resulting in faster response times and reduced device invasiveness.
Abstract
Description
- This invention relates to mass spectrometry, and in particular to the use of mass spectrometry in conjunction with liquid chromatography or capillary electrophoresis. The invention particularly relates to a system and method that is implemented in a microengineered configuration.
- Electrospray is a common method of soft ionisation in biochemical mass spectrometry (MS), since it allows the analysis of fluid samples pre-separated by liquid chromatography (LC), the ionization of complex molecules without fragmentation, and a reduction in the mass-to-charge ratio of heavy molecules by multiple charging [Gaskell 1997; Abian 1999]. It may be used in a similar way with fluid samples pre-separated by other methods such as capillary electrophoresis (CE).
- The principle is simple. A voltage is applied between an electrode typically consisting of a diaphram containing an orifice and a capillary needle containing the analyte. Liquid is extracted from the tip and drawn into a Taylor cone, from which large charged droplets are emitted. The droplets are accelerated to supersonic speed, evaporating as they travel. Coulomb repulsion of the charges in the shrinking droplet results in fragmentation to ions when the Rayleigh stability limit is reached. The resulting ions can be multiply charged.
- An electrospray mass spectrometer system contains a number of key elements:
-
- An electrospray ionisation source capable of interfacing to an LC or CE system
- An interface to couple ions (in preference to molecules) into a vacuum chamber
- An alignment and/or observation system capable of maximising the coupling
- A mass filter and detector
- Conventionally, the spray is passed from atmospheric pressure via a chamber held at an intermediate pressure. Several vacuum interfaces that use differential pumping to match flow rates to achievable pressures have been developed [Duffin 1992]. The ion optics normally consist of input and output orifices such as capillaries, capillary arrays and skimmer electrodes, and occasionally also a quadrupole lens operating as an ion guide in all-pass mode. These components are used to maximise the ratio of coupled ions to neutrals, which would otherwise swamp the chamber.
- Various methods are used to promote a well-dispersed spray of small droplets and hence a concentrated flow of analyte ions. Solvent can be preferentially driven off, by direct heating [Lee 1992]. Advantages may be obtained by the use of a sheath gas flow [Huggins 1993], and nebulisation may be enhanced by ultrasound [Hirabayashi 1998].
- Alignment in electrospray is not critical, and the spray may simply be directed towards the MS input. Alternatively, an off-axis spray direction may be used to promote the separation of neutrals. Co-axial lenses mounted directly on the capillary have been developed to focus the spray [U.S. Pat. No. 6,462,337]; however, there are limits to the electrode complexity that can be achieved using such simple mechanical systems.
- In a conventional electrospray system, with capillaries of =100 μm internal diameter, flow rates are of the order of 1 μl min−1, and extraction voltages lie in the range 2.5 kV-4 kV. Flow rates and voltages are considerably reduced in so-called “nanospray systems”, based on capillaries having internal diameters ranging down to =10 μm [Wilm 1996]. Such capillaries are relatively easy to fabricate, and are available with a range of diameters and frits. Decreasing the capillary diameter and lowering the flow rate also tends to create ions with higher mass-to-charge ratio, extending the applicability further towards biomolecules.
- Because of the reduced size of the spray cone, alignment of a nanospray source is more critical. Operation typically involves mounting the source on a micropositioner and using a video camera to observe the spray entering the vacuum inlet of an atmospheric pressure ionisation (API) mass spectrometer. Sources are sold customised for most popular brands of mass spectrometer. However, such systems are large, complex and costly.
- To reduce costs, a variety of attempts have been made to integrate some of the components of nanospray ionisation sources. Ramsey and Ramsey [1997] showed that a spray could be drawn from the edge of a glass chip containing an etched capillary. Since then, integrated capillaries with in-plane flow have been demonstrated in many materials, especially plastics [Licklider 2000; Svedberg 2003]. In some cases, the fluid has been extracted from a slot rather than a channel [Le Gac 2003]; in others, from a shaped surface [Kameoka 2002]. Devices have also been formed in one-dimensional arrays. Geometries in which the flow is passed perpendicular to the surface of the chip have also been demonstrated, often by deep reactive ion etching of silicon [Schultz 2000; Griss 2002]. Such devices may be formed into two-dimensional arrays.
- Almost exclusively, the advances above consist of attempts to integrate system sub-components leading up to the ion emitter. They concentrate on the fluidic part of the system, ignoring the problems of separating ions from neutrals, and of aligning the ion spray to the inlet to the vacuum system. As a result, they are not suitable for a low cost nanospray system, because accurate alignment still requires expensive positioning devices.
- There is therefore a need to provide a low cost nanospray system.
- The invention addresses these and other problems by providing a solution to the problems of alignment and electrode mounting in a low-cost nanospray source by using microelectromechanical systems technology to form appropriate mechanical alignment and conducting electrode features on insulating plastic substrates in an integrated manner. The approach also allows integration of features for fluid drainage, spray heating and sheath gas flow.
- This invention provides a method of aligning a nanospray capillary needle, a set of electrodes, and the capillary input to an API mass spectrometer. The electrode system is formed using microelectromechanical systems technology, as an assembly of two separate chips. Each chip is formed on an insulating plastic substrate. The first chip carries mechanical alignment features for the capillary electrospray needle and the API mass spectrometer input, together with a set of partial electrodes. The second chip carries a set of partial electrodes. The complete electrode system is formed when the chips are assembled in a stacked configuration, and consists of an einzel lens capable of initiating a Taylor cone and separating ions from neutrals by focusing.
- Accordingly, the invention provides a system according to
claim 1 with advantageous embodiments provided in the dependent claims thereto. The invention also provides a method of fabricating such a system as detailed in the main independent method claim. - These and other features will be better understood with reference to the following drawings.
-
FIG. 1 shows in schematic form a microengineered nanospray system aligning a nanospray needle with the capillary input to an atmospheric pressure ionisation mass spectrometer according to an embodiment of the present invention. -
FIG. 2 shows construction of a microengineered nanospray system as a stacked assembly of two chips according to an embodiment of the present invention. -
FIG. 3 is a process flow for construction of a microengineered nanospray chip according to an embodiment of the present invention. -
FIG. 4 a shows the layout of a lower andFIG. 4 b the layout of an upper substrate of a microengineered nanospray chip according to an embodiment of the present invention. -
FIG. 5 shows an assembly of a microengineered nanospray chip according to an embodiment of the present invention. -
FIG. 6 shows electrostatic operation of a microengineered nanospray chip according to an embodiment of the present invention. -
FIG. 7 shows operation of the sheath gas inlet of a microengineered electrospray chip according to an embodiment of the present invention. -
FIG. 8 shows thermal operation of a microengineered electrospray chip according to an embodiment of the present invention. -
FIG. 9 shows electrode configurations realisable using a stacked electrode assembly withFIG. 9 a) being a closed pupil arrangement,FIG. 9 b) a horizontally split pupil,FIG. 9 c) a vertically split pupil andFIG. 9 d) a quadrant pupil arrangement. - The invention will now be described with reference to exemplary embodiments as provided in
FIGS. 1 to 9 . - The present inventor has realised that the benefit of MEMS structures can be extended to nanospray applications. In MEMS, widely used methods of lithographic patterning, oxidation and metallisation are combined with specialised techniques such as anisotropic wet chemical etching [Bean 1978] and deep reactive ion etching [Hynes 1999] to form three-dimensional features in crystalline semiconductors such as silicon. UV exposure of specialised photosensitive polymers such as SU-8 may be used to form three-dimensional features in plastics [Lorenz 1997]. These methods may be used to combine insulating substrates, alignment features and conducting electrodes. The present inventor has realised that at least potentially, they may therefore form an integrated nanospray ionisation source at low cost.
- However, further difficulties remain with the realisation that MEMS technology could be used to provide nanospray devices. The device must typically operate with high voltages, in a wet environment, so that electrical isolation and drainage are both required. The substrate material most commonly used in MEMS, silicon, is therefore not appropriate; however, other insulating materials such as glasses are difficult to micromachine. To obtain a stable spray, an electrode containing an axially aligned orifice is typically required. To obtain efficient ion separation from neutrals, electrostatic deflection or focusing is required. For focusing, further electrodes containing aligned orifices are needed. If the ion path is itself in the plane of a substrate, such orifices are extremely difficult to form by in plane patterning alone. Finally, it is desirable to integrate features capable of providing a sheath gas around the spray, of promoting nebulisation, and of preferentially evaporating solvent. For these and other reasons there has heretofore not been possible an integrated MEMS nanospray system. However, as will be understood from a review of
FIGS. 1 to 9 , the present inventor has addressed these and other issues. -
FIG. 1 illustrates the concept of a microengineered nanospray electrode system. Amass spectrometer 101 is provided in a high-vacuum enclosure 102 pumped (for example) by aturbomolecular pump 103. Ions are channelled into this chamber via afurther chamber 104 held at an intermediate pressure and pumped (again, for example) by arotary pump 105. The inlet to the vacuum system is assumed to be a capillary 106. The exact configuration of these components is not, it will be appreciated, important, apart from the input capillary. For example, the filter element of the mass spectrometer could be an ion trap, a quadrupole, a magnetic sector, a crossed-field or a time of flight device. Equally, the intermediate vacuum chamber could contain a range of components including further capillaries and skimmer electrodes. - The overall input to the system is provided by a
nanospray capillary 107. Alignment between thenanospray capillary 107 and the capillary input to themass spectrometer 106 is provided by amicroengineered chip 108. The chip contains a first set of mechanical alignment features 109 for the nanospray capillary and a second set of alignment features 110 for the capillary input to the mass spectrometer. The chip also contains a set ofelectrodes 111 set up perpendicular to the ion path, which may (for example, but not exclusively) consist of diaphragm electrodes. Other features may be integrated on the chip, including holes for drainage and gas inlet. -
FIG. 2 illustrates the main features of thechip 108. The chip is constructed from two separate substrates, each carrying microengineered features, which are arranged in a stacked assembly. The first substrate consists of a base 201 formed in insulating material and carrying a mechanical alignment feature for the nanospray capillary corresponding to thefeature 109 inFIG. 1 , which may (for example, but not exclusively) consist of agroove 202 etched into a conducting orsemiconducting block 203. This substrate also carries an alignment feature for the capillary input to the mass spectrometer corresponding to thefeature 110 inFIG. 1 , which may again for example consist of afurther groove 204 etched into a block ofsimilar material 205. This substrate also carries a set of electrodes corresponding to part of thefeatures 111 inFIG. 1 and consisting ofgrooves 206 etched into upright plates ofsimilar material 207. - The second substrate again consists of a base 208 formed in insulating material, and carrying a further set of electrodes corresponding to a further part of the
features 111 inFIG. 1 and consisting ofgrooves 209 etched into upright plates of conducting orsemiconducting material 210. When the two substrates are stacked together, the partial electrode sets combine to form complete diaphragm electrodes with closed pupils 211. - Using three such electrodes, a so-called ‘einzel’ or unipotential electrostatic lens is formed. This type of lens allows focusing of ions passing axially through the stack of electrodes in a simple and controlled manner, and hence allows the ion spray to be focused onto the capillary input to the mass spectrometer to present a concentrated stream of analyte ions.
- It will be appreciated that the
alignment grooves electrode grooves - It will be appreciated by those skilled in the art that a variety of materials and processes and may be used to realise structures similar to
FIG. 2 .FIG. 3 shows a process, which is intended to be exemplary rather than exclusive. The materials used are low cost, and only three lithographic steps are required. The process is based on crystalline silicon substrates on which plastic virtual substrates are subsequently formed. The individual process steps are indicated by a set of evolving wafer cross-sections containing typical features. - In
step 1, a (100)-orientedsilicon substrate 301 is first oxidised to form a SiO2 layer 302 on both sides. The SiO2 is patterned and etched to form a channel-shapedopening 303, by (for example) photolithography and reactive ion etching. In step 2, the underlying silicon substrate is anisotropically etched down (111) crystal planes to form a V-shapedgroove 304. Commonly an etchant consisting of potassium hydroxide (KOH), water and isopropanol (IPA) may be used for this purpose. This step defines all capillary-mounting grooves and electrode pupils. The front side oxide is removed, and the wafer is turned over. - In step 3, the wafer is spin coated with a thick layer of the epoxy-based photoresist SU-8 305. This resist may be coated and exposed in layers of at least 0.5 mm thickness, has excellent adhesion, and is extremely rugged after curing, allowing it to be used as a virtual substrate material after processing. The resist is lithographically patterned to form a
dicing groove 306 around each die, together with anydrain holes 307 and gas inlets. - In step 4, the front side of the wafer is metallised to increase conductivity, typically with an adhesion layer of Cr metal and a further thicker layer of
Au 308. In step 5, the front side of the wafer is coated in aphotoresist 309. Since the wafer is non-planar, an electrodeposited resist is used in preference to spin-coated resist for this step. The resist is patterned to define the outlines of all electrode and alignment blocks 310, and the pattern is transferred through the metal. In step 6, the pattern is transferred through the silicon wafer by deep reactive ion etching, to form deep separation features 311 between elements. The photoresist is then removed, and individual dies are separated instep 7. - In step 8, two dies are stacked together to form a complete nanospray chip, by soldering or bonding the metal layers 312 together. Alternatively, a conducting epoxy may be used for this step. The chip is mounted on a carrier circuit board, and
wirebond connections 313 are made to appropriate features on the lower substrate. - It will be appreciated by those skilled in the art that a first alternative process is offered by forming the conducting alignment and electrode elements by electroplating a metal inside a mould, which may itself be formed by a sequence of patterning and etching steps. However, this alternative requires the separate formation of a mould, which is a laborious process.
- It will also be appreciated by those skilled in the art that a second alternative process is offered by forming the alignment and electrode elements by sawing or otherwise eroding a conducting layer attached to an insulating substrate. The substrate bases may be also defined by sawing or by erosion, and the grooves may be formed, by partial sawing. However, this alternative offers less flexibility in the range of structures that may be created.
- It will also be appreciated by those skilled in the art that a third alternative process is offered by forming the substrate bases from glass, which may be patterned by sawing or (in the case of a photosensitive glass) by photopatterning. However, these alternatives again offer less flexibility in the range of structure that may be created. It will be appreciated that regardless of their shortcomings that each of the mentioned alternatives may be considered useful in the context of the present invention for specific applications.
-
FIG. 4 shows the layout of individual substrates that can be realised using the process ofFIG. 3 . The larger plastic substrate-base 401 carries amounting block 402 for the nanospray capillary, formed in etched, metallised silicon and having an etchedalignment groove 403. The substrate carries asimilar mounting block 404 for the mass spectrometer input capillary, with a similaretched alignment groove 405, and a set ofpartial electrodes 406 with etchedgrooves 407. The electrodes are widened at their extremities to assist in the stacked assembly and to allow bonding. Alarge hole 408 through the plastic substrate-base provides a drain, and asmaller hole 409 provides a channel for sheath gas to flow into an etched plenum chamber 410. The smaller plastic substrate-base 411 carries a further set ofpartial electrodes 412 andfurther features 413 defining the sheath gas plenum. -
FIG. 5 shows assembly. Thesmaller substrate 501 is inverted, aligned on top of thelarger substrate 502, and the electrodes are bonded together. The device is mounted on an external printed circuit board, andwirebond connections 503 are attached to the alignment features and electrodes. The chip is aligned and connected electrically to theinput capillary 504 of the mass spectrometer, and thenanospray capillary 505 is inserted into its input alignment feature and connected electrically. A stop may be provided on each capillary to ensure that it may only be inserted into its alignment groove for a fixed distance. -
FIG. 6 shows electrostatic operation of the device. The capillary input to the mass spectrometer and itsalignment feature 601 both are assumed to be at ground potential. Assuming that the nanospray capillary contains a conducting contact, a large DC voltage V1 is applied to the nanospray capillary via its associatedmount 602. Alternatively the voltage may be applied via a wire passing into the capillary. An intermediate voltage V2 is applied to theouter electrodes centre element 605. Thespray 606 is emitted from a Taylor cone created at the exit of the nanospray capillary due to the potential difference V1−V2. The ion stream is focused onto the capillary input to themass spectrometer 607 due to the action of the focus voltage V3. -
FIG. 7 shows operation of the sheath gas inlet. Sheath gas is passed through the lower substrate-base 701 of the assembly via aninlet hole 702. The gas flows into aplenum 703 formed in thenanospray capillary mount 704. The gas leaks from the plenum around the capillary, because it does not fully seal the orifice formed by the grooves in the upper and lower nanospray capillary mount. However, the natural taper of the capillary 705 ensures that the majority of the leakage takes place in a forwardaxial direction 706, forming a sheath around the spray. -
FIG. 8 shows a mode of thermal operation. A current I is passed through one or more of theelectrodes 801 to provide local heating, which may preferentially evaporate more volatile components in the spray such as a carrier solvent, thus enriching the analyte ion stream. -
FIGS. 9 a-9 d shows different possible electrode cross sections. In the simplest realisation (FIG. 9 a), the assembly of twoplates pupil 903. The edges of the pupil will be defined by the (111) crystal plane angle θ=cos−1(1/√3)=54.73° of silicon. The size of the pupils may be controlled, by varying the width of the initial etched groove either continually or in discrete steps along the axis. It will be appreciated by those skilled in the art that other fabrication methods such as deep reactive ion etching may be used to form U-shaped alignment grooves and electrode grooves, which have greater inherent symmetry. - It will also be appreciated by those skilled in the art that the electrodes may be segmented horizontally using
additional spacing 904 as shown inFIG. 9 b, or segmented vertically usingadditional etching 905 as shown inFIG. 9 c. Both methods of segmentation may be combined as shown inFIG. 9 d. Segmented electrodes of this type may be used to provide one- or two-axis electrostatic deflection in addition to focusing. These additional degrees of freedom offer the potential to improve the separation of ions from neutrals, for example by inserting a bend or a dog-leg into the ion path that neutrals cannot follow. - It will also be appreciated that the ability to provide transverse electrostatic forces using segmented electrodes allows the spray to be deflected in a time-varying manner. If the spray is oscillated using a sinoidally varying lateral force, a periodic perturbation may be induced in the spray flow. If the spatial frequency of this perturbation is chosen to coincide with the spatial frequency of Rayleigh instability in the flow pattern, the flow will be encouraged to fragment into droplets, thus promoting nebulisation.
- What has been described herein is a microengineered nanospray device. While advantageous embodiments have been described it will be appreciated that certain integers and components are used to illustrate exemplary embodiments and it is not intended to limit the invention in any way except as may be deemed necessary in the light of the appended claims. Furthermore where the invention is described with reference to specific figures it will be appreciated that components or features of one figure can be freely interchanged with those of other figures without departing from the scope of the invention.
- While the reference to the miniature nature of the device of the present invention has been made with reference to MEMS technology it will be appreciated that within the context of the present invention that the term MEMS is intended to encompass the terms microengineered or microengineering and is intended to define the fabrication of three dimensional structures and devices with dimensions in the order of microns. It combines the technologies of microelectronics and micromachining. Microelectronics allows the fabrication of integrated circuits from silicon wafers whereas micromachining is the production of three-dimensional structures, primarily from silicon wafers. This may be achieved by removal of material from the wafer or addition of material on or in the wafer. The attractions of microengineering may be summarised as batch fabrication of devices leading to reduced production costs, miniaturisation resulting in materials savings, miniaturisation resulting in faster response times and reduced device invasiveness. Wide varieties of techniques exist for the microengineering of wafers, and will be well known to the person skilled in the art. The techniques may be divided into those related to the removal of material and those pertaining to the deposition or addition of material to the wafer. Examples of the former include:
- Wet Chemical Etching (Anisotropic and Isotropic)
-
- Electrochemical or photo assisted electrochemical etching
- Dry plasma or reactive ion etching
- Ion beam milling
- Laser
Whereas examples of the latter include: - Evaporation
- Thick film deposition
- Sputtering
- Electroplating
- Chemical vapour deposition (CVD)
- Epitaxy
- These techniques can be combined with wafer bonding to produce complex three-dimensional, examples of which are the interface devices provided by the present invention.
- The words comprises/comprising when used in this specification are to specify the presence of stated features, integers, steps or components but does not preclude the presence or addition of one or more other features, integers, steps, components or groups thereof.
-
- Gaskell S. J. “Electrospray: Principles and practice” J. Mass Spect. 32, 677-688 (1997)
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- Huggins T. G., Henion J. D. “Capillary electrophoresis mass-spectrometry determination of inorganic ions using an ion spray-sheath flow interface electrophoresis” 14, 531-539 (1993)
- Hirabayashi A., de la Mora J. F. “Charged droplet formation in sonic spray” Int. J. Mass Spect. 175, 277-282 (1998)
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- Wilm M., Mann M. “Analytical properties of the nanoelectrospray ion source” Anal. Chem. 68, 1-8 (1996)
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- Griss P., Melin J., Sjödahl J., Roeraade J., Stemme G. “Development of micromachined hollow tips for protein analysis based on nanoelectrospray ionization mass spectrometry” J. Micromech. Microeng. 12, 682-687 (2002)
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Claims (32)
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GBGB0514843.2A GB0514843D0 (en) | 2005-07-20 | 2005-07-20 | Microengineered nanospray electrode system |
GB0519439A GB2428514B (en) | 2005-07-20 | 2005-09-23 | Microengineered nanospray electrode system |
GB0519439.4 | 2005-09-23 |
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US20090127481A1 (en) * | 2007-11-02 | 2009-05-21 | Richard Syms | Mounting arrangement |
US8379392B2 (en) | 2009-10-23 | 2013-02-19 | Qualcomm Mems Technologies, Inc. | Light-based sealing and device packaging |
US8766177B2 (en) | 2010-10-11 | 2014-07-01 | University Of North Texas | Nanomanipulation coupled nanospray mass spectrometry (NMS) |
DE102013004871A1 (en) * | 2013-03-21 | 2014-09-25 | Bruker Daltonik Gmbh | Multi-nozzle chip for electrospray ionization in mass spectrometers |
US20150028221A1 (en) * | 2013-07-23 | 2015-01-29 | Hamilton Sundstrand Corporation | Methods of ion source fabrication |
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GB0514843D0 (en) | 2005-07-20 | 2005-08-24 | Microsaic Systems Ltd | Microengineered nanospray electrode system |
GB2445016B (en) | 2006-12-19 | 2012-03-07 | Microsaic Systems Plc | Microengineered ionisation device |
US7960711B1 (en) | 2007-01-22 | 2011-06-14 | Chem-Space Associates, Inc. | Field-free electrospray nebulizer |
GB2451239B (en) | 2007-07-23 | 2009-07-08 | Microsaic Systems Ltd | Microengineered electrode assembly |
DE202009002192U1 (en) * | 2009-02-16 | 2009-04-23 | Thermo Fisher Scientific (Bremen) Gmbh | Electrode for influencing ion motion in mass spectrometers |
US8242441B2 (en) * | 2009-12-18 | 2012-08-14 | Thermo Finnigan Llc | Apparatus and methods for pneumatically-assisted electrospray emitter array |
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Also Published As
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GB0514843D0 (en) | 2005-08-24 |
GB0519439D0 (en) | 2005-11-02 |
US7615744B1 (en) | 2009-11-10 |
GB2428514B (en) | 2010-10-06 |
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