(19)
(11)EP 1 688 985 B1

(12)EUROPEAN PATENT SPECIFICATION

(45)Mention of the grant of the patent:
17.09.2014 Bulletin 2014/38

(21)Application number: 06100550.0

(22)Date of filing:  18.01.2006
(51)Int. Cl.: 
H01J 49/16  (2006.01)
H01J 49/00  (2006.01)

(54)

Integrated analytical device

Integriertes analytisches Gerät

Appareil analytique intégré


(84)Designated Contracting States:
AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IS IT LI LT LU LV MC NL PL PT RO SE SI SK TR

(30)Priority: 07.02.2005 GB 0502357

(43)Date of publication of application:
09.08.2006 Bulletin 2006/32

(73)Proprietor: Microsaic Systems PLC
Woking Surrey GU21 5BX (GB)

(72)Inventors:
  • Finlay, Alan
    GU21 5BX, Woking (GB)
  • Wright, Steven
    RH12 3TH, Horsham (GB)
  • Yeatman, Eric
    SW19 7LL, London (GB)

(74)Representative: Moore, Barry et al
Hanna Moore & Curley 13 Lower Lad Lane
Dublin 2
Dublin 2 (IE)


(56)References cited: : 
WO-A-2004/013890
US-A1- 2003 189 170
US-A1- 2004 124 350
US-B1- 6 525 314
US-A- 6 025 591
US-A1- 2004 011 953
US-A1- 2004 222 374
  
      
    Note: Within nine months from the publication of the mention of the grant of the European patent, any person may give notice to the European Patent Office of opposition to the European patent granted. Notice of opposition shall be filed in a written reasoned statement. It shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention).


    Description

    Field of the Invention



    [0001] The present invention relates to analytical devices or instruments and in particular to analytical instrumentation utilising electrospray ionisation spray devices and mass spectrometers. The invention particularly relates to an integrated mass spectrometer and ionisation spray device where the individual components are packaged together and provided as a single unit.

    Background of the Invention



    [0002] Mass spectrometry (MS) is a powerful analytical technique that is used for the qualitative and quantitative identification of organic molecules, peptides, proteins and nucleic acids. MS offers speed, accuracy and high sensitivity. The development of ionisation techniques and mass analysers over the last decade has enables MS to solve a wide variety of problems. The introduction of Electrospray ionisation (ESI) greatly expanded the role of MS in pharmaceutical analysis. One of the characteristic features of ESI is the generation of multiply charged ions for large molecular weight compounds (e.g. proteins, peptides). These differently charged molecules enable accurate determination of the molecular weight of these compounds and their analysis in complex biological media.

    [0003] In ESI, the analyte solution is typically introduced into a capillary which is electrically conductive or has a conductive coating. An electric potential is applied between the capillary and a counter-electrode. The analyte solution extends from the tip of the capillary in a shape known as the Taylor cone. The applied potential accelerates charged droplets from this cone towards the counter-electrode. The droplets reduce by fragmentation or evaporation to individual ions, and these are accelerated, typically through an aperture in the counter-electrode, into the mass analyser.
    Important features of ESI are the simplicity of its source design, and its capability to operate with solutions at atmospheric pressure. This means ESI may be coupled to high performance liquid chromatography (HPLC) for analysis of complex mixtures. The HPLC/MS combination uses the separation of HPLC with the detection of MS. ESI is also extremely sensitive. Furthermore, ESI is a soft ionisation technique that yields a simple, unfragmented and easily interpreted mass spectrum in which molecules typically correspond to the base peak. ESI is the method of choice of the characterisation of drug-bearing compounds and can be applied to over 90% of organic compounds in pharmaceutical research.

    [0004] In the field of compound analysis it is known to use multiplexed, or MUX, systems with for example 4 to 8 channels feeding into a single mass analyser. However 'cross-talk' between the tips is a problem which can result in cross-contamination of sample sprays, thereby limiting the expansion of these systems to high numbers of channels. A further problem arises in the possibility that ions from previous stream are often still present. Furthermore when providing a plurality of channels, a separate bank of binary pump, splitters, LC and UV detector is required for each channel. If the cost and size of the ESI-MS system could be reduced, users could opt for arrays of ESI-MS systems running in parallel with maximum throughput and zero cross-talk.

    [0005] HPLC flow splitters are often used to couple mass spectrometers to liquid chromatographs to reduce the amount and concentration of sample delivered to the mass spectrometers. This is particularly useful in automated systems to avoid unwanted MS inlet overload. Splitting is also required for applications in which a second detector or fraction collection device is used parallel to the MS (e.g. UV detector). HPLC/MS flow splitting is typical in the automated analysis of combinatorial libraries, drug metabolites and the characterisation of impurities.

    [0006] In traditional HPLC/MS systems, the use of a postcolumn splitter decouples the chromatographic and Electrospray flow rates. The column operates at a high flow rate to provide optimal resolution, while the ESI source operates at a lower flow that is compatible with Electrospray or pneumatically assisted Electrospray. However, the integration of the Electrospray electrode with the column narrows the flow range that can be used. Thus, it becomes desirable to use electrodes with as broad a flow as possible.

    [0007] For HPLC/MS with a low flow rate (100 - 200 µL/min), the sample solution can be sprayed directly into the ESI source. However, most samples in the pharmaceutical industry require HPLC separations at high flow rates (0.5 - 2mL/min). A postcolumn split is often used to reduce actual flow rates to the ESI source to 40 - 200 µL/min. HPLC columns with smaller diameters are used for low concentrations of organic compounds and biomolecules and have flow rates of 1 - 40 µL/min. Alternatively, a nanoflow device (e.g. capillary LC) can deliver a sample solution directly to a nanospray source for analysis.

    [0008] High flow rates are important to ensure compatibility with most HPLC systems. To initiate a spray requires very well defined electric fields; therefore factors such as applied voltage, needle diameter and position are critical. However, because electrospray is relatively difficult to achieve and maintain for traditional high flow rate ESI sources, pneumatic, ultrasonic or thermal nebulisation is also required to break up droplets in a process called desolvation. Such desolvation techniques add greatly to source complexity and cost.

    [0009] Operating electrospray at high flow rates is forcing the process into an unnatural state, where stabilisation of what is called the Taylor Cone and formation of aerosol droplets are practically impossible with electric fields alone. To generate stable ion currents one must provide additional energy input, in the form of pneumatic nebulisation and heat, to force droplet formation, leaving the task of droplet charging to the electric field. Proper implementation of this additional energy is of overriding concern in the design of high flow rate systems, far overshadowing in importance other details of the Electrospray process such as Taylor Cone formation and stabilisation. For nanoflow techniques the opposite is true; factors affecting the formation and stabilisation of the Taylor Cone are of paramount concern. Other forms of external energy input to generate charged droplets are not required because the electric field is sufficient to charge the liquid and simultaneously generate an aerosol.

    [0010] Nanospray sources operate in the low microliter per minute flow ranges. Nanospray involves using a low flow rate and a small needle diameter. The spray is introduced directly into the vacuum interface without pneumatic, ultrasonic or thermal nebulisation, reducing system cost and complexity. Nanospray permits the use of low flow techniques like microcapillary liquid chromatography (µLC) and capillary electrophoresis. Very small samples can be separated quickly and efficiently and analysed over a long period of time. Another benefit arises from the reduction in onset potential that comes with decreasing the needle diameter. This facilitates the use of aqueous solutions and reduces the likelihood of corona discharge.

    [0011] The essence of the nanoflow method is to reduce the flow rate of the sprayed sample liquid by orders of magnitude below the microliter per minute regime.
    As stable flows are achieved at lower and lower flow rates, the efficiency of the ionisation process improves approximately in proportion to the flow rate reduction. Even though the sample molecules enter the sprayer at a much lower rate than with the high flow systems, the signal per unit time detected by the MS remains constant and can often be seen to improve by factors of 2 - 3.

    [0012] For a given mass of sample injected, the analyte concentration, [A] is inversely proportional to the square of the column internal diameter, d. As the column diameter is reduced, the optimum flow rate Q also lowers by the same function.

    [0013] Similarly, the ionisation efficiency E increases with lower flows.



    [0014] The outer diameter of the tip at the end of the capillary electrode establishes the minimum voltage required to produce sufficient electric field strength to initiate the Electrospray process. As such, sharper tips can generally be operated closer to the entrance aperture of the mass spectrometer. The taper of the channel leading up to the exit aperture and the restriction to flow it imposes also have an effect; long narrow channel results in flows somewhat lower than expected for a particular diameter.

    [0015] At a lower cone voltage, the multiply charged ions are present at high relative abundances. For example, doubly charged ions of small peptides are intrinsically less stable than their singly charged analogs, and they can easily fragment to form singly charges ions. Low cone voltages can therefore be used to generate multiply charged ions of large molecules, permitting their detection by instruments with limited mass to charge range.

    [0016] Because the spray is generated by strictly electrostatic means, the needle diameter, position and applied potential are critical. The potential Von(kV) required for the onset of electrospray is related to the radius r (µm) of the electrospray needle, the surface tension of the solvent, y (N/m), and the distance d (mm), between the needle tip and the counter electrode, which is sometimes also the vacuum orifice:



    [0017] With methanol as the solvent (y = 0.0226 N/m), a spray needle radius of 50 µm, and a needle-counter electrode distance of 5mm, the onset potential is 1.27 kV. Changing the solvent to water (y = 0.073 N/m) increases the onset potential to 2.29 kV. A possible problem with high applied potentials is that they can cause electric discharge from the capillary tip.

    [0018] One solution to the problem of electric discharge is to reduce the needle diameter. In the pure water example changing the needle diameter from 50 µm to 10 µm decreases the onset potential from 2.29 kV to 1.3 kV. A reduction in the potential required to initiate a spray is one of several benefits of nanospray techniques.

    [0019] Another solution is to reduce the needle-counter electrode distance. For example, for a spray needle radius of 50 µm, reducing the needle-counter electrode distance from 5mm to 100 µm decreases the onset potential from 1.27 kV to 442 V.

    [0020] Both these solutions require accurate alignment of the needle. Today, in order to achieve the necessary alignment, nanospray capillaries are mounted on an assembly of carefully machined stainless steel and ceramic parts, and located using expensive micro-positioners typically costing tens of thousands of dollars. A video camera is often included to help the user find the optimum position for Taylor cone formation, adding yet more cost.

    [0021] There is therefore a need to provide a device and method that can provide for integration and alignment of the necessary components for such analytical instruments.

    [0022] US 6,525,314 discloses a compact high-performance mass spectrometer including an ion source, an ion filter, a collision cell, a fragment filter, and an ion detector, along with one or more ion deflectors and one or more gas removal rings. An ion deflector allows a straight ion filter and a straight collision cell to be coupled in a folded configuration to make a compact design without the loss of performance associated with the use of curved quadrupole components.

    [0023] Particularly, US 6 525 314 discloses an integrated analytical instrument assembly comprising a baseplate and a plurality of components including a mass spectrometer device and an ionisation source. The individual components are precisely aligned on the baseplate by means of a set of precision pins, holes and stops.

    [0024] US Patent 6,025,591 A discloses an integrated analytical instrument assembly comprising a plurality of components including a mass spectrometer device and an ionisation source, the individual components being mounted on an insulating layer over a substrate.

    [0025] WO2004/013890 A2 discloses a monolithic micro-engineered mass spectrometer provided with an embedded electrospray ionisation source.

    [0026] US 2004/124350 A1 discloses a micro-engineered field asymmetric ion mobility spectrometer (FAIMS) comprising either an integrated electrospray tip or an electrospray tip mounted on a mount.

    Summary of the Invention



    [0027] The present invention addresses these and other problems by providing one or more features that precisely locate and align nanospray capillaries, counter electrodes and vacuum interface in a manner that can be reproducibly and cheaply microfabricated from a substrate, thereby eliminating expensive assemblies. Batches of mounting blocks can be produced on wafer, significantly reducing manufacturing and assembly cost.

    [0028] The invention also addresses problems arising from contamination due to neutral solvents which is a problem in many traditional ESI mass spectrometers. Continued cleaning and reconditioning of ion sources and optics and mass analysers is traditionally required which significantly increases after sales costs. The assembly described in this patent could be removed or even potentially disposable, increasing system ease of use, availability and reducing the cost of ownership.

    [0029] Accordingly, a first embodiment of the invention provides for precision alignment of the principal electrospray source elements (i.e. electrospray capillary needle, counter electrode, vacuum inlet, ion optics, mass analyser and ion current detector) relative to features micromachined on a parent substrate as a means of reducing onset potential and cone voltage, increasing transmission, cost and the number of multiply charged ions and therefore boosting analyser mass range.

    [0030] The present invention provides for an assembly as claimed in claim 1. Advantageous embodiments are provided in the dependent claims thereto. The invention also provides, in a further embodiment, a mass spectrometer system as claimed in claim 29. The invention also provides a method of providing a self aligned mass-analysing assembly as detailed in claim 33.

    Brief Description of the Drawings



    [0031] The present invention will now be described with reference to the accompanying drawings in which:

    Figure 1 is a schematic of an analytical instrument assembly according to an illustrated embodiment of the present invention.

    Figure 2 is a side elevation of the assembly of Figure 1.

    Figure 3 is a schematic of alignment features provided on a microbench.

    Figure 4A is a cut-away plan view of a housing for use with the assembly of Figure 1.

    Figure 4B shows the housing of Figure 4A mounted on the microbench substrate.

    Figure 4C is a plan view of the housing of Figure 4A mounted on a microbench with associated submounts assembled.

    Figure 5A shows in plan view an alternative housing to that of Figure 4.

    Figure 5B is a schematic of the housing of Figure 5A enclosing a microbench.

    Figure 5C is a schematic of the housing of Figure 5A enclosing a microbench.

    Figure 5D is a side view of the schematic of Figure 5C.

    Figure 5E is a plan view of a modification of the schematic of Figure 5C so as to provide for an array of capillaries.

    Figure 6 shows an example of a vacuum chamber that may be used with the assembly of the present invention.

    Figure 7 shows the vacuum assembly of Figure 6, enclosing an assembly, and coupled to a vacuum pump combination.

    Figure 8 shows a modification of the system of Figure 7.

    Figure 9 shows a modification of the system of Figure 7.

    Figure 10 shows a modification of the system of Figure 7.


    Detailed Description of the Drawings



    [0032] The present invention will now be described with reference to Figures 1 to 10 As shown in Figure 1, the invention provides an assembly in which a substrate or microbench (1) is used to mount a capillary submount (2), a counter-electrode submount (2A) and a mass spectrometer submount (3) such that all three are firmly co-located and precisely aligned. The capillary submount (2) is dimensioned to support a capillary needle. The counter electrode submount (2A) has provided thereon ring electrodes (7) & (8) and the mass spectrometer submount (3) has provided thereon ion optics (6), ion detector (4) and a mass analyser (5). With regard to the capillary submount and the mass spectrometer submounts, it will be appreciated that the components provided thereon could be formed separately and subsequently bonded to their respective submounts or alternatively integrally formed with the submount. The substrate material can be any suitable metal (e.g. stainless steel), insulator (e.g. PEEK), ceramic (e.g. alumina), glass (e.g. Pyrex), semiconductor (e.g. silicon or bonded silicon on insulator). The microbench is provided with one or more alignment features which are then utilised in the subsequent placing of the submounts on the microbench so as to ensure accurate positioning of each of the components relative to one another. In order to achieve accurate alignment it will be appreciated that a specific feature of each of the submounts needs to be aligned with its respective alignment feature on the microbench. The alignment can be achieved by matching the two together or seating a submount within an alignment feature formed in an upper surface of the microbench.

    [0033] In assembly, each of the submounts are positioned relative to a pre-allocated alignment feature on the microbench and then secured in that position. As the alignment is achieved using tolerances based on the ability to accurately define the location of features on the microbench, and these features can be laid down or applied in the same processing step, it is possible using the techniques of the present invention to accurately position each of the submounts relative to one another. In the exemplary embodiments hereinafter described a plurality of alignment features will be described but it will be appreciated that in certain applications and embodiments that one alignment feature may be required which is then used to define a known position on the substrate. Having this known position on the substrate, it is then possible to apply each of the submounts relative to this one alignment feature. As such the term alignment feature when used herein intended to encompass one or more unique features. For example, a plurality of features (e.g. v-grooves) or some fiduciary feature may be found more suitable in certain instances. In the provision of a plurality of alignment features using photolithographic techniques the alignment features are defined with respect to one another during the photolithography. If the alignment features are formed using micromachining lasing techniques, the machined features will typically be machined relative to one selected fiduciary point.

    [0034] The capillary submount (2) desirably includes microfabricated location features (9) for precision alignment of the capillary needle (10) relative to the counter electrodes (8) & (7). The capillary location feature (9) can be microfabricated in several ways including a deep-etched microchannel, or a v-groove wet-etched along crystal planes. The capillary needle may be attached using suitable clips, microsprings, solder or conductive epoxy for electrical connectivity.

    [0035] The mass spectrometer submount (3) includes an ion detector (4), ion optics (6) and mass analyser (5). The ion detector can be an electron multiplier or faraday cup. The mass analyser can be a quadrupole; magnetic sector; quadrupole ion trap; linear ion trap; cyclotron; Fourier transfer; triple quadrupole or tandem mass filter. The ion optics typically form an Einzel lens. Examples of suitable mass spectrometer devices include that described in international application WO2003EP08354.

    [0036] The submounts (2), (2A) & (3) may be integrated into several different combinations in alternative embodiments. The capillary submount (2) may be monolithically integrated with the counter-electrode submount (2A), or the mass spectrometer submount (3) may be monolithically integrated with the counter-electrode submount (2A), or all three may be integrated onto a single substrate. In this last embodiment, all of the components are monolithically formed or integrated onto a single chip, the alignment features for the needle being provided on that chip, and the chip is then subsequently mounted on the substrate microbench.

    [0037] Figure 2 shows a side elevation view of the same assembly of Figure 1 with each of the microfabricated features (12), (12A) and (5), locating each submount, being described in more detail below.

    [0038] Figure 3 is a schematic of alignment features on the bare microbench. The definition of alignment features on the substrate (1) will typically be carried out by the fabrication of a patterned layer using photolithographic methods. This layer may be directly attached to the substrate material or alternatively may be superimposed on additional deposited layers. Alignment features defined in the patterned layer may be fabricated in the substrate or the additional layers through the use of etching techniques such as wet chemical etching or reactive ion etching. The patterned layer may also be used to fabricate alignment features in a subsequently deposited layer by using the lift-off technique as is well known in the art. As an alternative to photolithographic techniques, alignment features may be fabricated using a numerically controlled direct-write process such as laser micromachining, as is known in the art.

    [0039] Alignment features (12), (12A), (15) & (18) are thus provided on the surface (the upper surface) of the substrate (1) for precision co-location of the capillary submount, mass spectrometer submount, counter electrode submount and package housing. These features together with corresponding features provided in the submounts may form references for visual or automated alignment of submounts to the substrate prior to the attachment of the submounts to the substrate by soldering, glueing, anodic bonding or other bonding technique. These features (12), (12A), (15) & (18) may also provide for the mechanical location of submounts, such that correct alignment is obtained by the placement of a submount against such a feature or features. As an example features (12), (12A) and (15) may have the form of precise recessed regions such as v-grooves wet-etched in a silicon substrate along crystal planes. Submounts (2), (2A) & (3) may in such case be provided with protrusions fitting precisely into or against the substrate features (12), (12A) and (15) so providing for the precise location of the submounts prior to bonding them to the substrates. In another embodiment additional parts are used to provide alignment between submounts and substrate. One such embodiment uses glass or other cylindrical rods, fitted in v-grooves or microchannels provided on the surfaces of both substrate (1) and submounts (2), (2A) & (3) to co-align all submounts. These and other techniques are exemplary of the type of techniques that may be used to provide and use alignment features, as will be appreciated by the person skilled in the art, and it is not intended to limit the invention to any one specific technique.

    [0040] The position of alignment features (12), (12A), (15) & (18) is determined by the required position of the electrospray capillary needle necessary to create the optimum electrical field for Taylor cone formation (see Equation 2). In particular, the distance between the nozzle (9) and the counter-electrodes (7) & (8) should be such that the onset potential is easily achieved to ensure reproducible and stable Taylor cones. Furthermore, this distance should also optimise the formation and transmission of multiply charged ions in order to maximise mass analyser (5) sensitivity and mass range.

    [0041] Conductive tracks may be provided on the substrate (1) by use of photolithographic, screenprinting or other techniques known in the art. These tracks may provide electrical connection between individual electrical attachment points for individual submounts and a common interface between the substrate and external systems. The attachment points may comprise bond pads for connection to corresponding bond pads on submounts or submount assemblies. The bonding may be done by wire bonding or by direct bonding methods using for example solder bumps or balls. The common interface may comprise an edge connector (23) or other multi-way electrical connector. The tracks so provided may permit transmission of electrical power; drive signals from external drive electronics to the mass analyser (5); high electrical potentials to the counter electrodes (7) & (8) and ion optics (6); and output signals from the detector (4) to external data acquisition electronics.

    [0042] Figure 4 (a) is a cutaway, in plan view, of a housing (11) which may be used to enclose the microbench (1). This housing serves as a 'lid' or 'package' protecting, encapsulating and partitioning the microbench assembly. The housing material can be any suitable insulator (e.g. PEEK), ceramic (e.g. alumina), glass (e.g. Pyrex), semiconductor (e.g. silicon, bonded silicon on insulator) or metal (e.g. stainless steel).

    [0043] The primary purpose of the enclosure is to create regions of different pressure. In this illustrated embodiment, the capillary needle submount and counter-electrode submount are mounted inside the same region of high to medium vacuum as the mass spectrometer submount. An inlet (17) is designed such that its cross section is greater than that of the capillary needle (10), which can be comfortably fitted or removed. The capillary needle (10) may be inserted into the vacuum through a suitable septum or membrane, which is mounted in the inlet (17). In this way the vacuum in the housing is completely sealed, and the capillary may be easily inserted and removed. A suitable septum is of the type used in gas chromatography inlets, or in solid phase micro-extraction (SPME) applications and these are widely available. A typical material for this septum is silicone rubber. The inlet's cross sectional area, length and conductance may also be designed to realise a steep pressure gradient from an atmospheric pressure at the inlet down to a vacuum pressure at the exit. Inlet (16) is designed so that there is very high conductance to the turbo pump, roughing pump or vacuum system, maximising effective pumping speed.

    [0044] In figure 4 (b), the housing (11) is mounted relative to alignment features (18) on the microbench substrate (1), and permanently attached. In one embodiment, the housing (11) material is selected so that it can be permanently sealed or chemically bonded to the substrate (1). Leak proof seals between the substrate (1) and the housing (11) can be achieved using a variety of techniques such as anodic bonding, a soldering process, or by melting glass frit between two surfaces. Leak-proof, hermetic seals are also possible around the edge connector (23) using anodic bonding, laser bonding, glass frit, solder reflow or glass blown interconnects or ceramic feedthroughs.

    [0045] Figure 4 (c) is a plan view of the housing (11) attached to the assembled microbench (1) with submounts (2), (2A) and (3) in place. Figure 4 (d) is a cutaway of a side elevation view of the same assembly. The location of critical components is precisely defined; the capillary nozzle (10), counter-electrodes (7) & (8), ion optics (6) and mass analyser (5) are in alignment at specified distances.

    [0046] An alternative housing design, shown in varying degrees of assembly in figures 5(a) to 5(c) provides for two separates areas within the housing by use of a partition (13) with the resultant areas being maintained at different pressures such that there is a steep pressure gradient between the capillary nozzle, counter-electrodes and mass spectrometer submount. In this design, the electrospray source is outside the vacuum and is at atmospheric, or close to atmospheric, pressure in order to promote evaporation of the solvent, droplet formation and reduction of ion energy through collision with atmospheric gas molecules. The two areas are linked by means of an aperture (14) provided in the partition wall (13).

    [0047] As shown, in the embodiment of Figure 5c, the inlet (17) may also support a suitable permeable membrane or septum (17A) to permit a controlled transmission of gases to a first region of high pressure- that area defined between the first aperture (17) and the second aperture (14), so that the electrospray needle tip (10) is at close to atmospheric pressure. The membrane (17A) material may be silicone rubber. This first region of higher pressure may also be connected to a mechanical roughing pump (22) to give greater control over pressure at the needle tip. The second aperture (14) should have a narrow cross sectional area in order to create a pressure drop along its length. Ideally, a rough vacuum of 13332.24 Pa to 133.32 Pa (100 Torr to 1 Torr) is created between the counter electrodes (7) & (8), and a medium vacuum, of between 13 mPa and 1.3 mPa (10-4 Torr and 10-5 Torr), at the ion detector (4), ion optics (6) and mass analyser (5). The dimensions of this aperture (14) must ensure an acceptable response time at the mass analyser. The inlet (14) may also be a glass or stainless steel capillary. Provision may also be required for heating of the aperture (14) to improve response time and ion transmission. However, in every case the inlet is optimally configured so that the pressure at the electrospray nozzle is near atmosphere or rough vacuum, and the pressure at the mass analyser is at medium vacuum.

    [0048] Figure 5 (b) & (c) are schematics of the housing enclosing a microbench (1). In this embodiment, the inlet (14) is positioned such that a counter-electrodes submount (2A) mates with the partition (13), forming part of aperture (14), so that the counter electrodes (7) & (8) are either side of partition (13). Figure 5 (d) is a side elevation of the same schematic. It will be appreciated that the use of micromachined submounts (2), (2A) & (3), located on micromachined alignment features on substrate (1), also provide excellent axial alignment in height.

    [0049] An alternative embodiment is that the counter-electrodes (7) & (8) are permanently attached to the housing wall (13) rather than mounted on submount (2A). In this way metal counter-electrodes with appropriate geometries such as circular apertures may be separately machined and fixed to the housing wall prior to assembly around the capillary and mass spectrometer submounts (2) and (3). Precision alignment of the counter-electrodes (7) and (8) relative to submounts (2) and (3) is achieved through the location of the housing with respect to micromachined features (12), (12A), (15) & (18).

    [0050] In another embodiment it may be desirable to perform several analyses in parallel using an array of capillary sources with corresponding arrays of counter-electrodes and mass analysers. In this embodiment as illustrated in the example of figure 5 (e) as an array of three, submounts are provided for each of a linear array of capillaries, an array of counter-electrodes, and an array of mass analysers. Alignment features (12) (12A) (15) on the substrate provide for the alignment of the corresponding submounts such that each capillary in the array is correctly aligned with its corresponding counter-electrode and mass analyser. In this embodiment, three apertures are also formed in the housing wall, each aperture corresponding to a specific capillary needle.

    [0051] A vacuum chamber (19) is shown in figure 6. This chamber is designed to surround at least a portion of the housing (11) and serves to connect it to the vacuum system, pumps etc. The vacuum chamber may also be sealed by a membrane or septum through which the needle capillary (10) may pass. The septum material may be silicone rubber. The vacuum chamber material may be glass, stainless steel, aluminium or ceramic. The chamber connects the housing assembly (11), shown in figure 7, to the vacuum pump combination and is fully demountable for ease of maintenance. A mounting feature (19A) (e.g. a milled recess) may be machined inside the chamber (19) to accept and securely mount the substrate microbench assembly (1) and housing (11). The chamber is connected to the pump inlet via a standard flange (20) with suitable vacuum fittings, gaskets, o-rings, Viton seals and bolts etc. A suitable vacuum interconnector (24) couples with the edge connector (23) on the microbench substrate (1). In one embodiment this is a 'D-type' vacuum feed-through connector welded into the vacuum chamber side-wall.

    [0052] A typical system configuration is described in figure 7. The vacuum chamber (19), containing an integrated microbench/submount assembly, is connected via a standard flange (20) to a turbo pump (21) and backing pump (22) combination. An alternative configuration uses an ion pump (21) instead of a turbo pump, and a mechanical roughing pump (22) which may also be directly connected to region of higher pressure between (17) and (14). In this alternative embodiment, the flange (20) may also be sealed by a membrane between the chamber (19) and the ion pump (21) to smooth the pumping rate of different gases.

    [0053] A further system based on the technology described here is outlined in figure 8. One application of this system is in the purification and fractionation of compounds by rapid selection of molecular masses. In this illustrated example of the system, the capillary needle is connected via a flow splitter (25) to another flow splitter valve (26) and to a UV detector (27). The UV detector provides additional information on the chemical composition and structure of the analyte which can be used for confirmation purposes. The active flow splitter (26) is connected to a make-up pump (27), a HPLC system (30) and a fraction collector (29). Once a molecular mass of interest is detected at the mass analyser, the active flow splitter (26) may be actuated to siphon off the sample of interest into the fraction collector (29). In this way combinational chemists can save valuable time and effort by rapidly selecting drug-bearing samples and discarding other samples. There is a further significant saving in cost of goods sold through the massive reduction in sample handling, storage, spillage and disposal this system permits.

    [0054] It is known for electrospray ionisation sources to be coupled with two modes of liquid chromatography: microflow (with flow rates of for example 20 µL/min) and nanoflow (with flow rates of for example 20 nl/min). Ultra-high flow rate LC can be used for fast separation. They operate at a pressure of about 30,000 psi. Clearly these pressures and flows are not suitable for direct introduction to a mass spectrometer. Nanoflow LC offers sharper chromatography peaks (e.g. Full width half maximum resolution - 1 second) and therefore faster separation. An example of a nanoflow LC has an internal tube diameter of 50um - 70um. The high back pressure problem has been eliminated through the use of low flow rates. Resolution is excellent, for example in a sample time of 1 min, peak widths of 1 second are achieved. A further advantage of nanoflow is that less solvent is used. This reduces aggregated solvent consumption, handling and waste disposal costs. For a typical nanoflow HPLC system 250 mL of solvent can last months. Therefore, there are significant cost of goods sold (COGS) savings associated with nanoflow LCMS throughout a large enterprise.

    [0055] Splitters are normally used to reduce flow rate down to nanospray flow rates when the HPLC pumps are too fast. Nowadays, the move in nanospray is away from using splitters. Direct flow to the nanospray source is possible with pumps that pump at 200 nL/min down to 5 nL/min. This can be provided by electrokinetic pumps which are available for HPLCs with pump rates down to a few nanoliters and can interface directly with the nanospray source. The low flow rates are possible because good control systems with closed-loop feedback have been developed. Another advantage of low flow rates is that response times are fast. In a transient blockage pressure rises and falls quickly. If nanoflow LC is used with a mass spectrometer, then a direct flow to the nanospray source is possible, eliminating the need for a flow splitter. The dimensions of a nanoflow LC need to be compatible with the desired resolution and flow rate. Tiny beads with a diameter of 1 um down to 0.5 um are used to densely pack the column so that compounds are quickly separated at a very low flow rate.

    [0056] However in such systems, valves and capillary connectors are a limiting factor as they add dead volume. The more dead volume, the more peak tailing and deteriorating resolution is observed. A typical valve has a dead volume of more than 25mL. Therefore minimising the number of valves and connections will improve LC resolution and separation efficiency.

    [0057] The integrated analyser of the present invention can be used to address these problems and a modification to that described here before is shown in figure 9. This arrangement avoids the use of a splitter and limits the number of connections and valves by permitting direct connection of the nanospray source to the HPLC system. Direct connection of the LC column to nanospray source at flow rates of 200 nL/min down to 5 nL/min is possible with commercially available electrokinetic pumps. A simple connector (31) directly connects the nanospray capillary to a nanoflow LC column (32). The LC column length and internal diameter are selected such that its flow rate is compatible with that required by the nanospray nozzle. Typical flow rates are 800 nL/min down to 1 nL/min. The LC column is in turn connected to a controllable pump (33), preferably of the type known as an electrokinetic pump, which in turn draws on reservoirs of solvent and sample (34).

    [0058] Yet another alternative system combination which avoids the use of a splitter and a controllable nanoflow pump is described in figure 10. This system would have significant cost advantages over those described above. A simple connector (31) directly connects the nanospray capillary to a nanoflow LC column (32). The LC column length and internal diameter are selected such that there is a hydrostatic pressure gradient between the reservoir (34) and the nanospray capillary needle (10), which may be mounted inside or outside the vacuum region as describer above. When carefully selected, the length and diameter of the LC column, and difference in hydrostatic pressure between the reservoir (34) at atmosphere and the nanospray capillary needle tip (10) at vacuum, creates a certain flow rate to the nanospray tip which promotes nebulisation and evaporation of droplets, and a flow through the LC column.

    [0059] It will be appreciated that what has been described herein is an analytical instrument assembly comprising a microbench substrate on which is mounted a plurality of individual components. Each of these components may be provided on an individual submounts or more than one may be provided on a common submount. The alignment of the components relative to a desired position on the substrate is achieved by the use of one or more alignment features provided on the substrate. The location can be such as to co-locate the component with its respective alignment feature or alternatively the alignment feature is used as a fiduciary point or locator on the substrate and the component is located relative to that point. Where a plurality of submounts are provided, each of these is assembled relative to the others on the microbench which has previously been provided with a plurality of alignment features - each of the alignment features being specifically positioned relative to its intended submount. Semiconductor 'microbench' technology is commonly used in the optoelectronics industry to cheaply align optical components where semiconductor laser sources are aligned on microbenches with optical fibres, detectors, and other components to maximise optical transmission and reduce assembly cost. This approach is applied in this patent to the problem of initiation of electrospray using a very well defined electric field, where factors such as applied voltage, needle diameter and needle position relative to the counter electrode and vacuum inlet are crucial. Furthermore, microbenches should permit the formation of an electrospray with very low cone voltages, increasing the number of multiply charged ions and boosting the mass range of cheaper mass analysers with a limited mass to charge range. Although the invention has been described with regard to specific embodiments and arrangements, It will , be appreciated that numerous modifications can and may be made without departing from the scope of the invention which is not intended to be limited in any way except as may be deemed necessary in the light of the appended claims.

    [0060] 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.


    Claims

    1. An integrated analytical instrument assembly comprising a plurality of components including a mass spectrometer device (5) and an electrospray ionisation source (9, 10), a microbench (1) and plurality of submounts (2, 2A, 3) each having at least one of the components mounted thereon, wherein individual components are initially provided on the submounts of the assembly, each submount being subsequently mountable on the microbench such that each component of the instrument assembly is mounted on at least one of the submounts, the location of the submounts on the microbench being defined relative to at least one micromachined alignment feature (12, 12a, 15, 18) provided on the microbench, so as to provide a self aligned instrument assembly.
     
    2. The assembly as claimed in claim 1 wherein the individual submounts are mountable on the microbench at locations defined by the at least one micromachined alignment feature, the at least one micromachined alignment feature determining the relative positioning of the mounted submounts relative to one another.
     
    3. The assembly as claimed in claim 2 wherein a plurality of micromachined alignment features are provided on the microbench, each of the plurality of micromachined alignment features being associated with a specific individual submount, the submount being located on the microbench coincident with the location of its respective micromachined alignment feature.
     
    4. The assembly as claimed in any preceding claim wherein the electrospray ionisation source includes an electrospray capillary needle and counter electrodes, the needle being provided on a capillary submount, the capillary submount including at least one microfabricated location feature configured to provide for an accurate alignment of the needle relative to the counter electrodes.
     
    5. The assembly as claimed in claim 4 wherein the location feature is selected from one of:

    a) an etched microchannel, or

    b) a v-groove provided along crystal planes of the submount.


     
    6. The assembly of claim 5 wherein the capillary needle is coupled to its location feature using one or more of:

    a) clips,

    b) microsprings,

    c) solder,

    d) electrically conductive epoxy or other glue.


     
    7. The assembly as claimed in any preceding claim wherein the mass spectrometer device includes an ion detector, ion optics and a mass analyser.
     
    8. The assembly as claimed in any preceding claim wherein the electrospray ionisation source is provided on a plurality of submounts, individual submounts being used for needle and electrode components of the source.
     
    9. The assembly as claimed in claim 8, wherein the mass spectrometer submount is monolithically integrated with the counter-electrode submount such that the two components are provided on the same submount.
     
    10. The assembly as claimed in any preceding claim wherein the at least one micromachined alignment feature provided on the microbench is a feature formed subsequent to a patterning of the microbench.
     
    11. The assembly as claimed in any preceding claim wherein the microbench is provided with a plurality of conductive tracks, the tracks being configured to enable electrical connection to individual components on the submounts.
     
    12. The assembly as claimed in claim 11 wherein the tracks provide for a transmission of power control or drive signals from external electronics or for transmission of signals to external electronics or for connection between individual components.
     
    13. The assembly as claimed in any preceding claim further including a housing, the housing being positioned relative to the microbench so as to encapsulate at least some of the components of the assembly.
     
    14. The assembly as claimed in claim 13 wherein the housing is dimensioned so as to provide for regions of differing pressure within the housing.
     
    15. The assembly as claimed in claim 13 or 14 wherein a mounting of the housing to the microbench is at a location defined by alignment features provided on the microbench.
     
    16. The assembly as claimed in any one of claims 13 to 15 wherein the housing is permanently bonded to the microbench.
     
    17. The assembly as claimed in any one of claims 13 to 16 wherein the housing defines two regions, a first region defining a first pressure area and a second region defining a second pressure region, the two areas being in communication with one another through an aperture.
     
    18. The assembly as claimed in any one of claims 13 to 17 wherein side walls of the housing are configured to receive counter electrode components of the electrospray.
     
    19. The assembly as claimed in any one of claims 13 to 18 further including a vacuum chamber, the vacuum chamber encapsulating at least a portion of the assembly and being coupled to a pump.
     
    20. The assembly as claimed in claim 19 wherein the vacuum chamber and/or housing include a sealable inlet, the inlet being dimensioned to enable insertion of an electrospray needle into the vacuum chamber.
     
    21. The assembly as claimed in claim 20 wherein the electrospray source is mounted to the microbench within the area defined by the vacuum chamber, the sealable inlet enabling a replacement of the needle.
     
    22. The assembly as claimed in claim 20 wherein at least a portion of the electrospray source is located externally of the vacuum chamber, the inlet enabling a passing of the needle through walls of the vacuum chamber into the vacuum chamber.
     
    23. The assembly as claimed in any one of claims 20 to 22 wherein the inlet is sealable with a septum or membrane, the septum being dimensioned to seal around an inserted needle, thereby preventing a leak from an interior portion of the assembly to an exterior portion.
     
    24. The assembly as claimed in claim 19 wherein the electrospray components are coupled to a flow splitter, the flow splitter being coupled to a fraction collector, the flow splitter being configured, in response to a detection of a sample of interest by the mass spectrometer, to siphoning off a portion of the sample of interest to the fraction collector.
     
    25. The assembly as claimed in claim 19 wherein the pump is an ion pump.
     
    26. The assembly as claimed in any preceding claim wherein an array of mass spectrometer devices and associated electrospray ionisation sources are provided, the array being configured to provide for a plurality of analyses to be conducted in parallel.
     
    27. The assembly as claimed in any preceding claim wherein the mass spectrometer is formed as a MEMS device.
     
    28. The assembly as claimed in any preceding claim wherein the microbench is formed from a silicon substrate.
     
    29. A liquid chromatography mass spectrometer system including reservoir of solvent and sample to be analysed in fluid communication with a nanoflow chromatography column, and an assembly as claimed in any preceding claim, the electrospray ionisation source of the assembly being a nanospray ionisation source and being configured to provide a mount for a nanospray capillary needle which may be coupled to the nanoflow chromatography column.
     
    30. The mass spectrometer system as claimed in claim 29 wherein the flow of solvent and sample through the chromatography column to the nanospray ionisation source is maintained by a hydrostatic pressure difference between the reservoir and the nanospray capillary needle.
     
    31. The mass spectrometer system as claimed in claim 30 wherein the reservoir is maintained at atmospheric pressure and the nanospray capillary needle is maintained within a vacuum.
     
    32. The mass spectrometer system as claimed in claim 29 further including an electrokinetic pump, the pump being configured to provide a flow of sample from the reservoir to the nanospray capillary needle.
     
    33. A method of providing a self aligned mass-analysing assembly, the assembly including at least an electrospray ionisation source (9, 10) and a mass spectrometer (5), the method including the steps of:

    Providing a substrate (1),

    Providing at least one micromachined alignment feature (12, 12a, 15, 18) on the substrate (1),

    Providing a plurality of submounts (2, 2A, 3), each submount having mounted thereon selected ones of the electrospray ionisation source and the mass spectrometer,

    Mounting the assembled submounts on the substrate, the relative position of the submounts on the substrate being determined with respect to the at least one micromachined alignment feature.


     


    Ansprüche

    1. Integrierte Anordnung analytischer Instrumente, umfassend mehrere Komponenten, einschließlich eines Massenspektrometergeräts (5) und einer Elektrosprayionisationsquelle (9, 10), eine Mikrobank (1) und mehrere Hilfsträger (2, 2A, 3), die jeweils zumindest eine der Komponenten auf sich angebracht aufweisen, wobei anfangs individuelle Komponenten auf den Hilfsträgern der Anordnung bereitgestellt sind, wobei anschließend jeder Hilfsträger auf der Mikrobank so anbringbar ist, dass jede Komponente der Instrumentanordnung auf zumindest einem der Hilfsträger angebracht ist, wobei die Position der Hilfsträger auf der Mikrobank relativ zu zumindest einem auf der Mikrobank vorgesehenen mikrogefertigten Ausrichtungsmerkmal (12, 12a, 15, 18) festgelegt ist, um eine selbstausgerichtete Instrumentanordnung bereitzustellen.
     
    2. Anordnung nach Anspruch 1, wobei die individuellen Hilfsträger auf der Mikrobank anbringbar sind an mittels des zumindest einen mikrogefertigten Ausrichtungsmerkmals festgelegten Positionen, wobei das zumindest eine mikrogefertigte Ausrichtungsmerkmal die relative Positionierung der angebrachten Hilfsträger relativ zueinander bestimmt.
     
    3. Anordnung nach Anspruch 2, wobei mehrere mikrogefertigte Ausrichtungsmerkmale auf der Mikrobank vorgesehen sind, wobei jedes der mehreren mikrogefertigten Ausrichtungsmerkmale zu einem spezifischen individuellen Hilfsträger gehört, wobei sich der Hilfsträger auf der Mikrobank in Übereinstimmung mit der Position seines jeweiligen mikrogefertigten Ausrichtungsmerkmals befindet.
     
    4. Anordnung nach einem der vorstehenden Ansprüche, wobei die Elektrosprayionisationsquelle eine Elektrospray-Kapillarnadel und Gegenelektroden beinhaltet, wobei die Nadel auf einem Kapillarhilfsträger vorgesehen ist, wobei der Kapillarhilfsträger zumindest ein mikrogefertigtes Positionsmerkmal beinhaltet, das dazu ausgebildet ist, eine akkurate Ausrichtung der Nadel relativ zu den Gegenelektroden zu gewährleisten.
     
    5. Anordnung nach Anspruch 4, wobei das Positionsmerkmal gewählt ist aus einem von:

    a) einem geätzten Mikrokanal, oder

    b) einer v-Vertiefung, die entlang Kristallflächen des Hilfsträgers vorgesehen ist.


     
    6. Anordnung nach Anspruch 5, wobei die Kapillarnadel an ihr Positionsmerkmal gekoppelt ist unter Verwendung eines oder mehrerer von:

    a) Clips,

    b) Mikrofedern,

    c) Lötmittel,

    d) elektrisch leitendem Epoxid oder anderem Klebstoff.


     
    7. Anordnung nach einem der vorstehenden Ansprüche, wobei das Massenspektrometergerät einen Ionendetektor, Ionenoptik und einen Massenanalysator beinhaltet.
     
    8. Anordnung nach einem der vorstehenden Ansprüche, wobei die Elektrosprayionisationsquelle auf mehreren Hilfsträgern vorgesehen ist, wobei für Nadel- und Elektrodenkomponenten der Quelle individuelle Hilfsträger verwendet werden.
     
    9. Anordnung nach Anspruch 8, wobei der Massenspektrometer-Hilfsträger mit dem Gegenelektroden-Hilfsträger monolithisch integriert ist, so dass die beiden Komponenten auf dem selben Hilfsträger vorgesehen sind.
     
    10. Anordnung nach einem der vorstehenden Ansprüche, wobei das zumindest eine mikrogefertigte Ausrichtungsmerkmal, das auf der Mikrobank vorgesehen ist, ein im Anschluss an eine Strukturierung der Mikrobank gebildetes Merkmal ist.
     
    11. Anordnung nach einem der vorstehenden Ansprüche, wobei die Mikrobank mit mehreren Leiterbahnen versehen ist, wobei die Bahnen dazu ausgebildet sind, elektrische Verbindung mit individuellen Komponenten auf den Hilfsträgern zu ermöglichen.
     
    12. Anordnung nach Anspruch 11, wobei die Bahnen für eine Übertragung von Leistungssteuerungs- oder Ansteuersignalen aus externer Elektronik oder für eine Übertragung von Signalen an externe Elektronik oder für eine Verbindung zwischen individuellen Komponenten sorgen.
     
    13. Anordnung nach einem der vorstehenden Ansprüche, die weiterhin ein Gehäuse beinhaltet, wobei das Gehäuse relativ zur Mikrobank positioniert ist, um zumindest ein paar der Komponenten der Anordnung einzukapseln.
     
    14. Anordnung nach Anspruch 13, wobei das Gehäuse so dimensioniert ist, dass es Regionen unterschiedlichen Drucks innerhalb des Gehäuses gewährleistet.
     
    15. Anordnung nach Anspruch 13 oder 14, wobei eine Anbringung des Gehäuses an der Mikrobank an einer Position ist, die durch auf der Mikrobank vorgesehene Ausrichtungsmerkmale festgelegt ist.
     
    16. Anordnung nach einem der Ansprüche 13 bis 15, wobei das Gehäuse dauerhaft mit der Mikrobank verbunden ist.
     
    17. Anordnung nach einem der Ansprüche 13 bis 16, wobei das Gehäuse zwei Regionen festlegt, wobei eine erste Region einen ersten Druckbereich festlegt und eine zweite Region einen zweiten Druckbereich festlegt, wobei die beiden Bereiche durch eine Öffnung in Kommunikation miteinander sind.
     
    18. Anordnung nach einem der Ansprüche 13 bis 17, wobei seitliche Wände des Gehäuses dazu ausgebildet sind, Gegenelektrodenkomponenten des Elektrosprays aufzunehmen.
     
    19. Anordnung nach einem der Ansprüche 13 bis 18, die weiterhin eine Vakuumkammer beinhaltet, wobei die Vakuumkammer zumindest einen Abschnitt der Anordnung einkapselt und an eine Pumpe gekoppelt ist.
     
    20. Anordnung nach Anspruch 19, wobei die Vakuumkammer und/oder das Gehäuse einen abdichtbaren Einlass beinhalten bzw. beinhaltet, wobei der Einlass so dimensioniert ist, dass er eine Einführung einer Elektrospraynadel in die Vakuumkammer ermöglicht.
     
    21. Anordnung nach Anspruch 20, wobei die Elektrosprayquelle an der Mikrobank innerhalb des durch die Vakuumkammer festgelegten Bereichs angebracht ist, wobei der abdichtbare Einlass einen Austausch der Nadel ermöglicht.
     
    22. Anordnung nach Anspruch 20, wobei sich zumindest ein Abschnitt der Elektrosprayquelle außerhalb der Vakuumkammer befindet, wobei der Einlass ein Dringen der Nadel durch Wände der Vakuumkammer in die Vakuumkammer ermöglicht.
     
    23. Anordnung nach einem der Ansprüche 20 bis 22, wobei der Einlass mit einem Septum oder einer Membran abdichtbar ist, wobei das Septum so dimensioniert ist, dass es um eine eingeführte Nadel herum abdichtet, wodurch einem Lecken von einem inneren Abschnitt der Anordnung zu einem äußeren Abschnitt vorgebeugt wird.
     
    24. Anordnung nach Anspruch 19, wobei die Elektrospraykomponenten an einen Flussteiler gekoppelt sind, wobei der Flussteiler an einen Fraktionssammler gekoppelt ist, wobei der Flussteiler dazu ausgebildet ist, in Reaktion auf eine Detektion einer interessierenden Probe durch das Massenspektrometer, einen Teil der interessierenden Probe zum Fraktionssammler abzuleiten.
     
    25. Anordnung nach Anspruch 19, wobei die Pumpe eine Ionenpumpe ist.
     
    26. Anordnung nach einem der vorstehenden Ansprüche, wobei ein Array von Massenspektrometergeräten und zugehörigen Elektrosprayionisationsquellen vorgesehen ist, wobei der Array ausgebildet ist zur Gewährleistung, dass mehrere Analysen parallel durchgeführt werden.
     
    27. Anordnung nach einem der vorstehenden Ansprüche, wobei das Massenspektrometer als MEMS-Gerät gebildet ist.
     
    28. Anordnung nach einem der vorstehenden Ansprüche, wobei die Mikrobank aus einem Siliziumsubstrat gebildet ist.
     
    29. Flüssigchromatographie-Massenspektrometer-System einschließlich eines Behälters mit Lösungsmittel und zu analysierender Probe in fluider Kommunikation mit einer Nanofluss-Chromatographiesäule, und einer Anordnung nach einem der vorstehenden Ansprüche, wobei die Elektrosprayionisationsquelle der Anordnung eine Nanosprayionisationsquelle ist und dazu ausgebildet ist, eine Halterung für eine Nanospray-Kapillarnadel bereitzustellen, die an die Nanofluss-Chromatographiesäule gekoppelt werden kann.
     
    30. Massenspektrometersystem nach Anspruch 29, wobei der Fluss von Lösungsmittel und Probe durch die Chromatographiesäule zur Nanosprayionisationsquelle durch eine hydrostatische Druckdifferenz zwischen dem Behälter und der Nanospray-Kapillarnadel aufrechterhalten wird.
     
    31. Massenspektrometersystem nach Anspruch 30, wobei der Behälter auf Atmosphärendruck gehalten wird und die Nanospray-Kapillarnadel innerhalb eines Vakuums gehalten wird.
     
    32. Massenspektrometersystem nach Anspruch 29, das weiterhin eine elektrokinetische Pumpe beinhaltet, wobei die Pumpe dazu ausgebildet ist, einen Probenfluss aus dem Behälter zur Nanospray-Kapillarnadel bereitzustellen.
     
    33. Verfahren zur Bereitstellung einer selbstausgerichteten Massenanalyseanordnung, wobei die Anordnung zumindest eine Elektrosprayionisationsquelle (9, 10) und ein Massenspektrometer (5) beinhaltet, wobei das Verfahren die Schritte beinhaltet:

    Bereitstellen eines Substrats (1),

    Bereitstellen zumindest eines mikrogefertigten Ausrichtungsmerkmals (12, 12a, 15, 18) auf dem Substrat (1),

    Bereitstellen mehrerer Hilfsträger (2, 2A, 3), wobei jeder Hilfsträger Ausgewählte von der Elektrosprayionisationsquelle und dem Massenspektrometer auf sich angebracht aufweist,

    Anbringen der zusammengebauten Hilfsträger auf dem Substrat, wobei die relative Position der Hilfsträger auf dem Substrat in Bezug auf das zumindest eine mikrogefertigte Ausrichtungsmerkmal bestimmt wird.


     


    Revendications

    1. Ensemble d'instrument analytique intégré comprenant une pluralité de composants comprenant un dispositif de spectrométrie de masse (5) et une source d'ionisation par électropulvérisation (9, 10), un micro-banc (1) et une pluralité de montages secondaires (2, 2A, 3) ayant chacun au moins l'un des composants monté sur celui-ci, dans lequel des composants individuels sont prévus initialement sur les montages secondaires de l'ensemble, chaque montage secondaire pouvant par la suite être monté sur le micro-banc de sorte que chaque composant de l'ensemble d'instrument soit monté sur au moins l'un des montages secondaires, l'emplacement des montages secondaires sur le micro-banc étant défini par rapport à au moins une caractéristique d'alignement micro-usinée (12, 12a, 15, 18) prévue sur le micro-banc, de manière à réaliser un ensemble d'instrument auto-aligné.
     
    2. Ensemble selon la revendication 1, dans lequel les montages secondaires individuels peuvent être montés sur le micro-banc à des emplacements définis par ladite au moins une caractéristique d'alignement micro-usinée, ladite au moins une caractéristique d'alignement micro-usinée déterminant le positionnement relatif des montages secondaires les uns par rapport aux autres.
     
    3. Ensemble selon la revendication 2, dans lequel une pluralité de caractéristiques d'alignement micro-usinées sont prévues sur le micro-banc, chacune de la pluralité de caractéristiques d'alignement micro-usinées étant associée à un montage secondaire individuel spécifique, le montage secondaire étant situé sur le micro-banc en coïncidence avec l'emplacement de sa caractéristique d'alignement micro-usinée respective.
     
    4. Ensemble selon l'une quelconque des revendications précédentes, dans lequel la source d'ionisation par électropulvérisation comprend une aiguille capillaire d'électropulvérisation et des contre-électrodes, l'aiguille étant prévue sur un montage secondaire de capillaire, le montage secondaire de capillaire comprenant au moins une caractéristique de positionnement micro-fabriquée configurée pour réaliser un alignement précis de l'aiguille par rapport aux contre-électrodes.
     
    5. Ensemble selon la revendication 4, dans lequel la caractéristique de positionnement est sélectionnée parmi :

    a) un micro-canal gravé, ou

    b) une rainure en V prévue le long des plans cristallins du montage secondaire.


     
    6. Ensemble selon la revendication 5, dans lequel l'aiguille capillaire est accouplée à sa caractéristique de positionnement en utilisant un ou plusieurs des éléments suivants :

    a) des agrafes,

    b) des micro-ressorts,

    c) une soudure,

    d) de la colle époxy ou une autre colle électriquement conductrice.


     
    7. Ensemble selon l'une quelconque des revendications précédentes, dans lequel le dispositif de spectrométrie de masse comprend un détecteur d'ions, une optique d'ions et un analyseur de masse.
     
    8. Ensemble selon l'une quelconque des revendications précédentes, dans lequel la source d'ionisation par électropulvérisation est prévue sur une pluralité de montages secondaires, les montages secondaires individuels étant utilisés pour les composants d'aiguille et d'électrode de la source.
     
    9. Ensemble selon la revendication 8, dans lequel le montage secondaire de spectromètre de masse est intégré de manière monolithique avec le montage secondaire de contre-électrode de sorte que les deux composants soient prévus sur le même montage secondaire.
     
    10. Ensemble selon l'une quelconque des revendications précédentes, dans lequel ladite au moins une caractéristique d'alignement micro-usinée prévue sur le micro-banc est une caractéristique formée à la suite d'une structuration du micro-banc.
     
    11. Ensemble selon l'une quelconque des revendications précédentes, dans lequel le micro-banc est pourvu d'une pluralité de pistes conductrices, les pistes étant configurées pour permettre une connexion électrique à des composants individuels sur les montages secondaires.
     
    12. Ensemble selon la revendication 11, dans lequel les pistes permettent une transmission de signaux de contrôle ou de commande de puissance à partir d'une électronique externe ou une transmission de signaux à une électronique externe ou une connexion entre des composants individuels.
     
    13. Ensemble selon l'une quelconque des revendications précédentes, comprenant en outre un logement, le logement étant positionné par rapport au micro-banc de manière à encapsuler au moins certains des composants de l'ensemble.
     
    14. Ensemble selon la revendication 13, dans lequel le logement est dimensionné de manière à obtenir des régions de pression différente dans le logement.
     
    15. Ensemble selon la revendication 13 ou la revendication 14, dans lequel un montage du logement sur le micro-banc est effectué à un emplacement défini par des caractéristiques d'alignement prévues sur le micro-banc.
     
    16. Ensemble selon l'une quelconque des revendications 13 à 15, dans lequel le logement est relié en permanence au micro-banc.
     
    17. Ensemble selon l'une quelconque des revendications 13 à 16, dans lequel le logement définit deux régions, une première région définissant une première zone de pression et une deuxième région définissant une deuxième zone de pression, les deux zones étant en communication l'une avec l'autre à travers une ouverture.
     
    18. Ensemble selon l'une quelconque des revendications 13 à 17, dans lequel les parois latérales du logement sont configurées pour recevoir des composants de contre-électrode du dispositif d'électropulvérisation.
     
    19. Ensemble selon l'une quelconque des revendications 13 à 18, comprenant en outre une chambre à vide, la chambre à vide encapsulant au moins une partie de l'ensemble et étant accouplée à une pompe.
     
    20. Ensemble selon la revendication 19, dans lequel la chambre à vide et/ou le logement comprennent une entrée pouvant être fermée hermétiquement, l'entrée étant dimensionnée pour permettre l'insertion d'une aiguille d'électropulvérisation dans la chambre à vide.
     
    21. Ensemble selon la revendication 20, dans lequel la source d'électropulvérisation est montée sur le micro-banc dans la zone définie par la chambre à vide, l'entrée pouvant être fermée hermétiquement permettant le remplacement de l'aiguille.
     
    22. Ensemble selon la revendication 20, dans lequel au moins une partie de la source d'électropulvérisation est située à l'extérieur de la chambre à vide, l'entrée permettant un passage de l'aiguille à travers les parois de la chambre à vide dans la chambre à vide.
     
    23. Ensemble selon l'une quelconque des revendications 20 à 22, dans lequel l'entrée peut être fermée hermétiquement par un septum ou une membrane, le septum étant dimensionné pour se fermer autour d'une aiguille insérée, empêchant de ce fait une fuite d'une partie intérieure de l'ensemble vers une partie extérieure.
     
    24. Ensemble selon la revendication 19, dans lequel les composants d'électropulvérisation sont accouplés à un diviseur d'écoulement, le diviseur d'écoulement étant accouplé à un collecteur de fraction, le diviseur d'écoulement étant configuré pour, en réponse à une détection d'un échantillon d'intérêt par le spectromètre de masse, siphonner une partie de l'échantillon d'intérêt vers le collecteur de fraction.
     
    25. Ensemble selon la revendication 19, dans lequel la pompe est une pompe à ions.
     
    26. Ensemble selon l'une quelconque des revendications précédentes, dans lequel un agencement de dispositifs de spectrométrie de masse et de sources d'ionisation par électropulvérisation associées est prévu, l'agencement étant configuré pour réaliser une pluralité d'analyses à effectuer en parallèle.
     
    27. Ensemble selon l'une quelconque des revendications précédentes, dans lequel le spectromètre de masse est formé en tant que dispositif MEMS.
     
    28. Ensemble selon l'une quelconque des revendications précédentes, dans lequel le micro-banc est formé à partir d'un substrat en silicium.
     
    29. Système de chromatographie en phase liquide-spectrométrie de masse et comprenant un réservoir de solvant et d'échantillon à analyser en communication fluidique avec une colonne de chromatographie à nano écoulement et un ensemble selon l'une quelconque des revendications précédentes, la source d'ionisation par électropulvérisation de l'ensemble étant une source d'ionisation à nano pulvérisation et étant configurée pour réaliser un montage pour une aiguille capillaire de nano pulvérisation qui peut être accouplée à la colonne de chromatographie à nano écoulement.
     
    30. Système de spectrométrie de masse selon la revendication 29, dans lequel l'écoulement de solvant et d'échantillon à travers la colonne de chromatographie vers la source d'ionisation à nano pulvérisation est maintenu par une différence de pression hydrostatique entre le réservoir et l'aiguille capillaire de nano pulvérisation.
     
    31. Système de spectrométrie de masse selon la revendication 30, dans lequel le réservoir est maintenu à la pression atmosphérique et l'aiguille capillaire de nano pulvérisation est maintenue dans un vide.
     
    32. Système de spectrométrie de masse selon la revendication 29, comprenant en outre une pompe électrocinétique, la pompe étant configurée pour réaliser un écoulement de l'échantillon du réservoir vers l'aiguille capillaire de nano pulvérisation.
     
    33. Procédé pour réaliser un ensemble d'analyse de masse auto-aligné, l'ensemble comprenant au moins une source d'ionisation par électropulvérisation (9, 10) et un spectromètre de masse (5), le procédé comprenant les étapes :

    de fourniture d'un substrat (1),

    de fourniture d'au moins une caractéristique d'alignement micro-usinée (12, 12a, 15, 18) sur le substrat (1),

    de fourniture d'une pluralité de montages secondaires (2, 2A, 3), l'un sélectionné de la source d'ionisation par électropulvérisation et du spectromètre de masse étant monté sur chaque montage secondaire,

    de montage des montages secondaires assemblés sur le substrat, la position relative des montages secondaires sur le substrat étant déterminée en relation avec ladite au moins une caractéristique d'alignement micro-usinée.


     




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    REFERENCES CITED IN THE DESCRIPTION



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    Patent documents cited in the description