Microengineered nanospray electrode system

Abstract

 This invention provides a method of aligning a nanospray capillary needle, a set of electrodes, and a capillary input to a mass spectrometer. The electrode system is formed using microengineering technologies, 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.

Description

Field of the Invention

[0001] 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.

Background

[0002] 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).

[0003] 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.

[0004] 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

[0005] 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.

[0006] 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].

[0007] 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 [US6462337]; however, there are limits to the electrode complexity that can be achieved using such simple mechanical systems.

[0008] 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.

[0009] 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.

[0010] 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.

[0011] Almost exclusively, the advances above consist of attempts to integrate system subcomponents 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.

[0012] There is therefore a need to provide a low cost nanospray system.

Summary

[0013] 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.

[0014] 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.

[0015] 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.

[0016] These and other features will be better understood with reference to the following drawings.

Brief Description of the Drawing

[0017] 

Figure 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.

Figure 2 shows construction of a microengineered nanospray system as a stacked assembly of two chips according to an embodiment of the present invention.

Figure 3 is a process flow for construction of a microengineered nanospray chip according to an embodiment of the present invention.

Figure 4a shows the layout of a lower and Figure 4b the latout of an upper substrate of a microenginered nanospray chip according to an embodiment of the present invention.

Figure 5 shows an assembly of a microengineered nanospray chip according to an embodiment of the present invention.

Figure 6 shows electrostatic operation of a microengineered nanospray chip according to an embodiment of the present invention.

Figure 7 shows operation of the sheath gas inlet of a microenginered electrospray chip according to an embodiment of the present invention.

Figure 8 shows thermal operation of a microengineered electrospray chip according to an embodiment of the present invention.

Figure 9 shows electrode configurations realisable using a stacked electrode assembly with Figure 9a) being a closed pupil arrangement, Figure 9b) a horizontally split pupil, Figure 9c) a vertically split pupil and Figure 9d) a quadrant pupil arrangement.

Detailed description of the Drawings

[0018] The invention will now be described with reference to exemplary embodiments as provided in Figures 1 to 9.

[0019] 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.

[0020] 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 Figures 1 to 9, the present inventor has addressed these and other issues.

[0021] Figure 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 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.

[0022] 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.

[0023] Figure 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 Figure 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 Figure 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 Figure 1 and consisting of grooves 206 etched into upright plates of similar material 207.

[0024] 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 Figure 1 and consisting of grooves 209 etched into upright plates of conducting or semiconducting material 210. When the two substrates are stacked together, the partial electrode sets combine to form complete diaphragm electrodes with closed pupils 211.

[0025] 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.

[0026] It will be appreciated that the alignment grooves 202 and 204, and the electrode grooves 206 and 209, 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. It will also be appreciated that 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. Finally it will be appreciated that a stacked combination of partial electrodes provides a solution to the problem of forming diaphragm electrodes arranged normal to a substrate.

[0027] 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 Figure 2. Figure 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.

[0028] In step 1, a (100)-oriented silicon substrate 301 is first oxidised to form a SiO₂ layer 302 on both sides. The SiO₂ is patterned and etched to form a channel-shaped opening 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-shaped groove 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.

[0029] 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 any drain holes 307 and gas inlets.

[0030] 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 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. 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 in step 7.

[0031] 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.

[0032] 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.

[0033] 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.

[0034] 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.

[0035] Figure 4 shows the layout of individual substrates that can be realised using the process of Figure 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.

[0036] Figure 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.

[0037] Figure 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. Assuming that the nanospray capillary contains a conducting contact, a large DC voltage V₁ is applied to the nanospray capillary via its associated mount 602. Alternatively the voltage may be applied via a wire passing into the capillary. An intermediate voltage V₂ is applied to the outer electrodes 603, 604 of the lens element and a further voltage V₃ 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 V₁ ― V₂. The ion stream is focused onto the capillary input to the mass spectrometer 607 due to the action of the focus voltage V₃.

[0038] Figure 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. However, 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.

[0039] Figure 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.

[0040] Figures 9a-9d shows different possible electrode cross sections. In the simplest realisation (Figure 9a), 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 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.

[0041] It will also be appreciated by those skilled in the art that the electrodes may be segmented horizontally using additional spacing 904 as shown in Figure 9b, or segmented vertically using additional etching 905 as shown in Figure 9c. Both methods of segmentation may be combined as shown in Figure 9d. 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.

[0042] 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.

[0043] 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.

[0044] 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

[0045] Whereas examples of the latter include:

• Evaporation
• Thick film deposition
• Sputtering
• Electroplating
• Chemical vapour deposition (CVD)
• Epitaxy

[0046] 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.

[0047] 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.

References

[0048] 

Gaskell S.J. "Electrospray: Principles and practice" J. Mass Spect. 32, 677-688 (1997) Abian J. "The coupling of gas and liquid chromatography with mass spectrometry" J. Mass Spectrom. 34, 157-168 (1999)

Duffin K.L., Wachs T., Henion J.D. "Atmospheric-pressure ion-sampling system for liquid-chromatography mass-spectrometry analyses on a benchtop mass-spectrometer" Anal. Chem. 64, 61-68 (1992)

Lee E.D., Henion J.D. "Thermally-assisted electrospray interface for liquid-chromatography mass-spectrometry" Rapid Comm. in Mass Spect. 6, 727-733 (1992)

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)

Li G., Yin H. "Mass spectrometer electrospray ionization" US6462337

Wilm M., Mann M. "Analytical properties of the nanoelectrospray ion source" Anal. Chem. 68,1-8 (1996)

Ramsey R., Ramsey J."Generating electrospray from microchip devices using electro-osmotic pumping" Anal. Chem. 69, 1174-1178 (1997)

Licklider L., Wang X.Q., Desai A., Tai Y.C., Lee T.D. "A micromachined chip-based electrospray source for mass spectrometry" Anal Chem. 72, 367-75 (2000)

Svedberg M., Petterson A., Nilsson S., Bergquist J., Nyholm L., Nikolajeff F., Markides K. "Sheathless electrospray from polymer microchips" Anal Chem. 75, 3934-3940 (2003)

Le Gac S., Arscott S., Rolando C. "A planar microfabricated nanoelectrospray emitter tip based on a capillary slot" Electrophoresis 24, 3640-3647 (2003)

Kameoka J., Orth R., Czaplewski D., Wachs T., Craighead H.G. "An electrospray ionization source for integration with microfluidics" Anal. Chem. 74, 5897-5901 (2002)

Schultz G.A., Corso T.N., Prosser S.J., Zhang S. "A fully integrated monolithic microchip electrospray device for mass spectrometry" Anal. Chem. 72, 4058-4063 (2000)

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

1. A microengineered nanospray ionisation device provided on a single chip for coupling between a nanospray source and a mass spectrometer, the device including a first alignment feature for cooperating with a capillary input, a second alignment feature for cooperating with a capillary output and a orifice defining an ion path between the capillary input and capillary output, the device further including at least one conducting electrode provided in an orientation substantially perpendicular to the ion path, and wherein each of the first alignment feature, the second alignment feature, the orifice and the at least one electrode are integrally formed in the chip.

2. The device as claimed in claim 1 wherein the chip is constructed from two substrates, the substrates being combined in a stack configuration so as to form the chip,

3. The device as claimed in claim 2 wherein each of the two substrates are provided with an insulating base, the substrates being stacked relative to one another such that the resultant chip has an insulating portion on an outer surface thereof.

4. The device as claimed in claim 2 or 3 wherein each of the two substrates are formed with individual features, the features being configured such that when the two substrates are brought together the resultant combination of features define the first alignment feature, the second alignment feature, the orifice and the at least one electrode.

5. The device as claimed in claim 4 wherein a first substrate is defines a first grooved alignment feature for the capillary input and a second grooved alignment feature for the capillary output, the substrate additionally having provided thereon the at least one conducting electrode with a grooved upright edge arranged normal to the substrate.

6. The device as claimed in claim 5 wherein the second substrate has provided thereon at least one conducting electrode with a grooved upright edge arranged normal to the substrate

7. The device as claimed in claim 6 wherein on stacking the first and second substrates relative to one another the at least one electrodes provided on the first and second substrates form a contiguous electrode and the electrode grooves combine to form orifices.

8. The device as claimed in any preceding claim where the capillary input is a nanospray capillary.

9. The device as claimed in claim 8, where the nanospray capillary input provides a fluid, the fluid being derivable from a liquid chromatography system.

10. The device as claimed in Claims 8, where the nanospray capillary input provides a fluid, the fluid being derivable from a capillary electrophoresis system.

11. The device as claimed in any preceding claim wherein the electrode nearest to the input capillary is used first to create a Taylor cone and then to extract ions from liquid contained in the input capillary.

12. The device as claimed in any preceding claim wherein the capillary output forms the input to a mass spectrometer.

13. The device as claimed in any preceding claim including at least two electrodes and wherein at least a second electrode is used to focus ions onto the output capillary.

14. The device as claimed in any preceding claim where at least one electrode is electrically heated and used to remove solvent preferentially.

15. The device as claimed in any one of claims 1 to 13, where at least one electrode is segmented and used to provide a deflecting lateral electric field to assist in separating ions from neutrals.

16. The device as claimed in claim 15, where the deflecting lateral field is time varying and used to promote nebulisation.

17. The device as claimed in any preceding claim wherein the chip contains at least one drain hole for fluids.

18. The device as claimed in claim 3, in which at least a first substrate base contains at least one inlet hole for gases and a plenum chamber surrounding the capillary input.

19. The device as claimed in claim 18, in which the plenum chamber is arranged to create an axial flow of gas arranged as a sheath to the spray.

20. The device as claimed in claim 3 wherein the insulating base is formed in a photo-patternable polymer.

21. The device as claimed in claim 18 in which the substrate-base perimeter, drain holes and gas inlets are defined by photopatterning.

22. The device as claimed in any preceding claim, in which the alignment features and electrodes are formed in a semiconductor.

23. The device as claimed in claim 22, in which the semiconductor is silicon.

24. The device as claimed in claim 22, in which the semiconductor is grooved by anisotropic wet chemical etching down crystal planes.

25. The device as claimed in claim 22, in which the semiconductor is grooved by deep reactive ion etching.

26. The device as claimed in claim 22, in which either the alignment features or the electrodes are formed using deep reactive ion etching.

27. The device as claim in claim 3, in which the electrodes, grooves or substrate-bases are formed by sawing.

28. The device as claimed in any preceding claim, in which the alignment features and electrodes are formed in a metal.

29. The device as claimed in claim 28, in which the metal is deposited by electroplating.

30. The device as claimed in claim 3, in which the substrate-bases are formed in glass.

31. The device as claimed in claim 30 in which the glass is photopatternable.

32. An integrated package including a nanospray source having a capillary needle at an output thereof, a mass spectrometer having a capillary needle at an input thereof and a nanospray ionisation device as claimed in any preceding claim provided between the source and the mass spectrometer, the alignment features of the device providing connection ports for the capillary needles so as to enable a fluid originating from the source to be ionised and passed to the mass spectrometer.

Drawing