Electrospray apparatus and methods

Abstract

An electrospray apparatus (130) comprises a capillary (102) having an outlet orifice (108) for electrospraying a sample therefrom and a conduit (112) extending into the capillary (102) in a manner such that it is able to deliver said sample into the capillary (102). The apparatus (130) may be configured to supply a pressurising gas into the capillary (102) so as to force said sample within the capillary (102) towards the outlet orifice (108). The apparatus may comprise a sheath member (203) surrounding at least a portion of the capillary (102), wherein the sheath member (102) has one or more apertures (213) located therein for allowing the capillary (102) to be viewed, and the apparatus may comprise a connector element (205) for connecting the sheath member (203) to, in order to position the capillary within the electrospray apparatus (130).

Description

[0001] ELECTROSPRAY APPARATUS AND METHODS

[0002] CROSS-REFERENCE TO RELATED APPLICATION

[0003] This application claims priority from and the benefit of United Kingdom patent application No. 2310641.2 filed on 11 July 2023 and United States of America patent application No. 63 / 611454 filed on 18 December 2023. The entire contents of both of these applications are incorporated herein by reference.

[0004] FIELD

[0005] The present disclosure relates to electrospraying and, in particular, to an electrospray apparatus that uses a capillary to emit a liquid sample.

[0006] BACKGROUND

[0007] Electrospraying is a process that can be used to generate small droplets from liquid samples. Electrospraying can be carried out by liquid forming an interface with air at the tip of an emitter and electrostatic stress generated by electrification of the liquid via an applied voltage causing charged droplets to be emitted from the liquid interface.

[0008] Electrospray ionisation (ESI) is an ionisation technique where ions are generated or released from charged droplets generated via an electrospray process. ESI may be employed as an ionisation technique to generate ions for analysis via mass and / or ion mobility spectrometry.

[0009] ESI can be employed for small sample volumes (e.g. less than 10 pL) in a nanoESI process using an emitter with a suitably small internal tip diameter. Emitters employed for nanoESI are typically pulled glass capillaries that are used for a single sample before being discarded on account of their fragility and potential for inadvertently retaining some portion of a previously sprayed sample that may be carried over and contaminate another sample. Variance in positioning and internal geometry from one emitter to another (for example, the tolerance of the internal diameter at the tip may be at least 20% for pulled glass capillaries) can reduce reproducibility of the resulting ion signal obtainable from a sample using nanoESI. Furthermore, the tip of an emitter suitable for nanoESI may require centrifuging in order to first be wet to allow a liquid sample to be conveyed to its outlet, which can prevent automation of the process and increase the time needed to carry out the process across different samples.

[0010] To automate a nanoESI process, silicon chips etched with an array of holes may be employed as emitters instead of pulled glass capillaries. This can allow a robot pipette to supply successive samples to different etched holes to avoid the need for human intervention between providing different samples. However, each hole of an etched silicon chip may be for single-use, suffer from similar lack of reproducibility due to varying quality of the holes, and is a much more expensive option compared to a pulled glass capillary.

[0011] SUMMARY

[0012] According to a first aspect of the present invention, an electrospray apparatus is provided, comprising: a capillary having an outlet orifice for electrospraying a sample therefrom and a larger drain orifice for flushing out the sample from the capillary; and a conduit extending into the capillary in a manner such that it is able to deliver said sample to the outlet orifice in a first mode of operation, and such that the drain orifice remains open so that the conduit is able to deliver a flushing liquid into the capillary to flush out the sample from the capillary through the drain orifice in a second mode of operation.

[0013] The capillary of the electrospray apparatus acts as an emitter that can, in the first mode of operation, emit a liquid sample via the outlet orifice to electrospray the sample. However, the capillary also comprises a drain orifice (separate to the outlet orifice) and a flushing cycle may be performed for the apparatus to remove, via the drain orifice, substantially all sample remaining in the capillary after the apparatus has been used to electrospray the sample. This can permit the same capillary to be re-used while preventing one sample being carried over and contaminating a next sample supplied into the capillary. The ability to re-use the same capillary can allow for greater reproducibility / consistency of the electrospray process in addition to greater cost efficiency.

[0014] The electrospray apparatus may comprise a voltage supply arranged to electrify said sample.

[0015] The voltage supply may be used to electrify said sample in the first mode of operation to cause sample delivered into the capillary to be electrosprayed via the outlet orifice and thereby form charged droplets.

[0016] The apparatus may be configured for the voltage supply to electrify the sample in any suitable manner. For example, the capillary may comprise an electrically conductive material (e.g. an electrically conductive coating) for electrifying the sample, the conduit may comprise an electrically conductive material (e.g. an electrically conductive coating) for electrifying the sample, and / or an electrode (e.g. wire or plunger) may be inserted into the capillary for electrifying the sample.

[0017] The voltage supply may be able to supply a voltage greater than 100 V, and preferably can supply a voltage greater than 1 kV, for electrospraying said sample.

[0018] The electrospray apparatus may be configured to be able to supply a flushing gas into the capillary via the conduit in a third mode of operation, so as to force the flushing liquid out of the capillary through the drain orifice.

[0019] The apparatus can carry out a flushing cycle by supplying into the capillary via the conduit the flushing liquid in the second mode of operation, optionally followed by a gas in the third mode of operation. Using the same conduit to provide the flushing liquid and the gas as well as sample(s) means that the conduit can also be flushed (as well as the capillary) during a flushing cycle of the apparatus.

[0020] An electrospray capillary emitter would not typically be flushed via its outlet orifice for re-use as this may not reliably ensure removal of the sample from the capillary. In this regard, a liquid within a typical capillary emitter does not readily flow out of the outlet, particularly for a capillary emitter with a small internal diameter that may be used for small sample volumes. For example, a capillary emitter may require centrifuging in order to reliably wet the tip before use, and emission from the tip may only be possible with an applied voltage. The relatively low flow rate out of the outlet would also mean that sufficient flushing of the capillary via the outlet may take excessive time to perform.

[0021] However, the Applicant has found that, by providing a capillary with a drain orifice that is larger than the outlet orifice and configuring the apparatus for removal of a liquid via the drain orifice, a capillary may be suitably re-used as an electrospray emitter, and a flushing cycle may be carried out, optionally without requiring removal of the capillary from the apparatus.

[0022] The drain orifice is larger than the outlet orifice in that it has a larger cross-sectional area, which allows a relatively greater flow rate of a liquid therethrough as compared to the outlet orifice (at a given pressure). Preferably, the drain orifice has a diameter or width that is greater than a diameter or width of the outlet orifice. The drain orifice and outlet orifice may both have circular cross-sections, however, any suitable shape may be used for either one or both of the outlet orifice and the drain orifice.

[0023] The outlet orifice may have a diameter that is less than 100 pm.

[0024] Providing the capillary with a small outlet orifice can allow the capillary to be suitable for use with small sample volumes (e.g. volumes less than 10 pl) and thereby be used for nanoESI. The outlet orifice may have a diameter less than 50 pm, such as less than 25 pm, and preferably between 0.1 pm and 20 pm.

[0025] The drain orifice may have a diameter greater than 25 pm, greater than 50 pm, or greater than 100 pm.

[0026] During a flushing cycle (in the second and / or third mode of operation), some proportion of the liquid within the capillary (the flushing liquid and / or the sample) may be expelled via the outlet orifice. However, the larger size of the drain orifice can result in substantially all of the flushing liquid being expelled via the drain orifice. In this regard, the outlet orifice may resist or reduce flow through the outlet orifice to a greater extent than at the drain orifice, resulting in fluid pressure characteristics that expels liquid within the capillary out of the drain orifice. The flushing gas can optionally be used to expel the flushing liquid out of the drain orifice. However, in embodiments the flushing liquid may flow out of the drain orifice without the use of a gas. For example, the capillary may be orientated such that gravity will cause the flushing liquid to flow out of the drain orifice in the second mode of operation.

[0027] In the first mode of operation, the conduit may, however, supply a liquid sample to the outlet orifice without the liquid sample exiting the capillary at the drain orifice. This may be achieved based on the positioning of the conduit within the capillary, the internal diameter of the capillary, the direction in which the conduit directs a liquid sample into the capillary, and / or the pressure at which the conduit supplies a liquid sample into the capillary.

[0028] The conduit of the electrospray apparatus may be positioned within the capillary to output said sample into the capillary at a position proximate the outlet orifice.

[0029] The outlet of the conduit within the capillary may face towards the outlet orifice.

[0030] A liquid sample may be output from the conduit into the capillary at the outlet of the conduit, and a distance between the outlet of the conduit and the outlet orifice of the capillary may be less than 15 mm, less than 10 mm or less than 5mm.

[0031] A liquid sample supplied into the capillary may be conveyed to the outlet orifice by electrostatic stress and / or by surface tension between the capillary and the liquid sample. The capillary may be orientated, at least in the first mode of operation, such that gravity will assist in conveying a liquid sample towards the outlet orifice, however, this is not essential.

[0032] The orientation of the capillary may be changed after a sample has been electrosprayed such that, in the second mode of operation, gravity will assist in conveying the flushing liquid towards the drain orifice to remove the sample remaining within the capillary. However, this is not essential as the flushing liquid and / or gas may simply be provided in sufficient volume to fill the length of the capillary between the outlet orifice and the drain orifice such that the flushing liquid will be expelled from the drain orifice (as more flushing liquid and / or the gas is supplied into the capillary). Accordingly, the apparatus may be configured such that a relatively smaller volume of a fluid supplied into the capillary does not cause liquid within the capillary to flow out of the drain orifice (and the liquid within the capillary can be emitted out of the outlet orifice) but a relatively larger volume of a fluid supplied into the capillary can cause liquid within the capillary to flow out of the drain orifice.

[0033] The conduit of the electrospray apparatus may be inserted into the capillary through the drain orifice and extends along the capillary from the drain orifice towards the outlet orifice.

[0034] Alternatively, the conduit may be inserted through a separate orifice to the drain (and outlet) orifice. However, in this case, the orifice through which the conduit enters the capillary may be sealed so as to prevent fluid external to the conduit from flowing through this orifice.

[0035] The conduit preferably does not extend the entire length of the capillary. However, the conduit may extend within the capillary so that an outlet of the conduit is proximate to the outlet orifice.

[0036] The capillary may have two opposing ends that are an inlet end at which the drain orifice is located and an outlet end at which the outlet orifice is located. The capillary may be substantially straight or may be curved.

[0037] The capillary may comprise a tip portion at which an internal diameter of the capillary decreases in a direction towards the outlet orifice, and the conduit may extend into the tip portion of the capillary.

[0038] An internal diameter of the capillary may be substantially constant in a direction from the drain orifice towards the outlet orifice until reaching the tip portion.

[0039] The capillary may be a glass capillary, such as a pulled glass capillary. However, this is not essential, and the capillary may be made of another material, such as ceramic or metal. The capillary may be made of a material advantageously selected to be resistant to permanent deformation, so as to reduce the chance of the capillary being damaged throughout its use.

[0040] The electrospray apparatus may comprise a capillary housing that houses the capillary.

[0041] The capillary housing may be configured to secure the conduit within the capillary. For example, the capillary housing may comprise a clamping portion that prevents movement of the conduit therein and can maintain the portion of the conduit downstream of the clamping portion towards the capillary to have a sufficient length for insertion into the capillary (and to the desired position therein).

[0042] The electrospray apparatus may comprise a heater configured for heating the conduit and / or capillary. This can allow a sample to be heated in the conduit and / or capillary before the sample is electrosprayed out of the capillary. The capillary housing may comprise the heater.

[0043] The conduit may be contiguously formed (e.g. provided as a (preferably flexible) tube of material) but may otherwise be formed from separate components secured together. For example, the conduit may comprise a separable portion that is inserted into the capillary and that is removably attachable from another portion of the conduit located within the capillary housing, to thereby allow the capillary and conduit to be removed from the capillary housing together without withdrawing the separable portion of the conduit from the capillary. Removing the capillary and the conduit together may allow the portion of the conduit inserted into the capillary to maintain substantially the same position within the capillary.

[0044] The capillary housing may comprise a housing body and a capillary holder, wherein the capillary holder has the capillary supported therein. The capillary holder may be removably attachable to the housing body, and may be detachable from the housing body without removing the capillary from the capillary holder and optionally without removing the conduit from the housing body.

[0045] The capillary holder may comprise a bore for conveying the conduit into the capillary. The bore may have a conical inlet for guiding the conduit into the bore.

[0046] The capillary housing (for example the capillary holder) may comprise a retractable sheath for protecting the capillary.

[0047] The retractable sheath is movable between an extended position and a retracted position.

[0048] In the extended position, the retractable sheath may at least partially surround the outlet end of the capillary (and optionally the entire length of the capillary that extends out of the capillary holder). Optionally, the retractable sheath has an annular cross-section for entirely surrounding at least the outlet end of the capillary in the extended position.

[0049] In the retracted position, a portion of the capillary (at the outlet end) may extend beyond the retractable sheath (such that at least part of the capillary is not surrounded by the retractable sheath when in the retracted position).

[0050] The retractable sheath may be configured to move from the extended position to the retracted position when inserted into the housing of a mass and / or ion mobility spectrometer. For example, the retractable sheath may comprise one or more engagement structures (e.g. protrusions) for transitioning the retractable sheath from the extended position to the retracted position when the capillary in inserted through an orifice of the housing of the mass and / or ion mobility spectrometer.

[0051] The retractable sheath may be biased towards the extended position. For example, the capillary housing (for example the capillary holder) may comprise a spring arranged to bias the retractable sheath towards the extended position.

[0052] The capillary housing may comprise a counter electrode. In use, a potential difference is maintained between the counter electrode and the sample within the capillary to cause the emission of the sample from the outlet orifice of the capillary.

[0053] The voltage supply may be configured to provide a potential difference between the sample and the counter electrode. The potential difference may be greater than 100 V, such as greater than 1 kV. The potential difference may be between 50 V and 5 kV, such as between 100 V and 3 kV. The potential difference may be provided between the sample and the counter electrode by providing an opposite polarity potential to the counter electrode relative to the sample, by grounding the counter electrode while electrifying the sample, or by applying a lower magnitude potential of the same polarity to the counter electrode relative to the sample.

[0054] The counter electrode may be arranged to control the propagation of a spray of electrified sample when emitted from the capillary (e.g. by effecting the direction of travel and / or spread of the emitted sample droplets). For example, the counter electrode may comprise an aperture downstream from the outlet orifice (and the outlet end) of the capillary, wherein the apparatus is configured for electrified sample emitted from outlet orifice of the capillary to pass through the aperture of the counter electrode. The aperture may be co-axial with the outlet orifice.

[0055] The capillary holder may comprise the counter electrode and the capillary holder may be configured to be attachable and detachable from the housing body of the capillary housing while maintaining the counter electrode at a fixed position relative to the capillary.

[0056] A sheath member may comprise the counter electrode and / or the counter electrode may be provided in the form of a sheath member (as a sheath electrode). Providing the counter electrode in or as a sheath can provide protection to the capillary (and provide protection to a user from the capillary, since the capillary may be sharp and / or contain hazardous material), while also fulfilling the function of the counter electrode in maintaining a potential difference between a region around the outlet end of the capillary and the electrified sample within the capillary. The sheath member may circumferentially surround a portion of the (axial) length of the capillary and the electrode may extend downstream from (have a position axially beyond) the outlet orifice (and the outlet end) of the capillary.

[0057] Thus, in an embodiment, the electrospray apparatus comprises a capillary holder having the capillary supported therein, wherein the capillary holder comprises a sheath member (circumferentially) surrounding at least a portion of the (axial) length of the capillary, and the sheath member comprises an electrode (a counter electrode) that extends downstream from the outlet orifice of the capillary, and wherein the electrospray apparatus is arranged for, in use, providing a potential difference between the sample within the capillary and the electrode to cause droplets of the sample to be electrosprayed from the outlet orifice of the capillary.

[0058] The sheath member may have other optional features, such as one or more side apertures, as described for a sheath member below.

[0059] The sheath member may be provided in addition to the retractable sheath (wherein the retractable sheath also at least partially surrounds the sheath member to provide protection thereto) or may be provided without the retractable sheath. However, when the sheath member and retractable sheath are both provided, the sheath member is preferably maintained with a portion extending out beyond the outlet end of the capillary when the retractable sheath is in the retracted position (for example, the position of the sheath member may be fixed while the retractable sheath is movable between the extended and retracted positions).

[0060] The electrospray apparatus may be configured to supply a pressurising gas into the capillary in the first mode of operation so as to force the sample within the capillary towards the outlet orifice.

[0061] The pressurising gas may be supplied into the capillary via the drain orifice of the capillary (e.g. from the capillary housing) and may be supplied external to the conduit. For example, the conduit may be inserted through the drain orifice while allowing the pressurising gas to be supplied through the drain orifice around the conduit.

[0062] Any suitable pressurising gas may be used, such as air or an inert gas such as nitrogen. The pressurising gas may or may not have the same composition as the flushing gas that may be supplied into the capillary via the conduit in the third mode of operation.

[0063] The Applicant has recognised that using a gas to force the sample towards the outlet orifice in the manner described herein can remove or reduce any air bubbles present. In this regard, the Applicant has found that air bubbles may otherwise accumulate within the sample and / or at the outlet end of the capillary, and that it is desirable to remove any such air bubbles as they may otherwise detrimentally affect the spray characteristics when the sample is emitted from the outlet orifice.

[0064] However, the apparatus may be configured to reduce a pressure of the pressurising gas within the capillary after forcing the sample towards the outlet orifice so as to prevent the gas from otherwise counteracting the removal of sample and / or flushing liquid out of the drain orifice in the second and / or third modes of operation.

[0065] The pressure of the pressurising gas may be maintained when electrospraying to continue to force the sample towards the outlet orifice for emission therefrom, or the pressure of the pressurising gas may be reduced before electrospraying (after removal of any air bubbles).

[0066] The apparatus may be configured to control a pressure of the pressurising gas within the capillary by controlling a pressure within a chamber of the capillary housing via which the pressurising gas is supplied into the capillary.

[0067] The apparatus may comprise any suitable components for controlling and / or measuring a pressure of gas within the capillary and / or capillary housing. For example, the apparatus may comprise one or more valves (such as pneumatic valves), a pressure gauge, and / or a volumetric flow controller.

[0068] The apparatus may be configured for the pressurising gas to be supplied into the capillary from the chamber of the capillary housing, and the capillary housing may comprise a valve having a closed configuration for preventing the pressurising gas flowing out of the chamber via the valve, and an open configuration for allowing the pressurising gas to flow out of the chamber via the valve.

[0069] The apparatus may be configured for the valve to be switched (e.g. automatically) from the closed configuration to the open configuration such that the valve is in the closed configuration in the first mode of operation and the valve is in the open configuration in the second (and / or third) mode of operation.

[0070] The apparatus may be configured to control a pressure within the chamber of the capillary housing such that, after the pressurising gas is supplied into the capillary to force the liquid sample towards the outlet orifice, pressure within the capillary housing may be released (e.g. by opening the valve) before the sample and flushing liquid flows out of the drain orifice (so that the pressurising gas can flow back out of the capillary and does not counteract the flow of liquid out of the capillary).

[0071] Accordingly, the apparatus may be configured for a pressure of the pressurising gas to be controlled to be: relatively higher in the first mode of operation to force the sample within the capillary towards the outlet orifice; and relatively lower in the second (and / or third) mode of operation so as to allow the sample (and / or flushing liquid) to be flushed out of the drain orifice in the second (and / or third) mode of operation.

[0072] The capillary housing may comprise a gas inlet conduit for supplying the pressurising gas into the capillary via the capillary housing in the first mode of operation.

[0073] The capillary housing may comprise a drain (or drain conduit) for receiving liquid output from the capillary via the drain orifice.

[0074] The valve may be configured to control whether fluid can access the drain from the chamber of the capillary housing.

[0075] For instance, the drain may comprise a conduit comprising the valve to control the pressure of the pressurising gas, such that the valve of the drain may be used to maintain or release pressure within the capillary housing. For example, the valve may be closed to prevent fluid being supplied out of the capillary housing via the drain in the first mode of operation (to maintain a pressure of the pressurising gas in the first mode of operation), and the valve may be opened to allow fluid (e.g. gas, sample and / or flushing liquid) to be received by the drain during the second and / or third modes of operation.

[0076] The drain of the capillary housing may comprise a removable container, such as a bottle, for collecting liquid output from the capillary. The drain may otherwise convey liquid (and / or gas) out of the apparatus entirely (to some other location).

[0077] The gas inlet conduit may comprise a valve for controlling the flow of gas therethrough. The valve of the gas inlet conduit may be opened for supplying the pressurising gas in the first mode of operation and may be optionally closed to stop the flow of pressurising gas (at least initially) in the second and / or third modes of operation. Closing the valve of the gas inlet conduit in the second and / or third modes of operation may assist in reducing the pressure in a chamber of the capillary housing for removal of the sample and / or flushing liquid from the capillary. However, the valve of the gas inlet conduit may otherwise be maintained open (and the pressure released e.g. by opening the valve of the drain) so that the pressurising gas can be continued to be supplied into the capillary housing to assist in flushing the sample and / or flushing liquid out of the drain. Optionally, the valve of the gas inlet conduit may be initially closed in the second and / or third modes of operation and then opened after sample and / or flushing liquid has been supplied out of the capillary into the capillary housing, such that pressurising gas supplied via the gas inlet conduit can then assist in flushing any sample or flushing liquid remaining within the capillary housing into the drain.

[0078] The pressurising gas may be supplied into the capillary (e.g. by opening the valve in the gas inlet conduit) after at least some portion of the sample has been supplied into the capillary from the conduit (and optionally after the sample has finished being supplied into the capillary from the conduit).

[0079] The pressurising gas may be supplied prior to electrification of the sample (e.g. by opening the valve in the gas inlet conduit), so as to remove any air bubbles present before the sample is electrosprayed out of the capillary.

[0080] The apparatus may be suitably configured (e.g. automated) for the relevant steps to be performed in the appropriate sequence. For example, the apparatus may be configured to automatically operate the valve(s), supply the sample, and / or electrify the sample at the appropriate time(s) for achieving the functionality described herein.

[0081] The voltage supply may form part of the capillary housing or the voltage supply may supply a voltage to the sample via the capillary housing.

[0082] The capillary housing may include an electrode configured to supply a voltage to said sample within the capillary to electrify the sample.

[0083] The apparatus may be arranged for the electrode to supply a voltage to said sample directly or to a supply a voltage to said sample via the capillary and / or the conduit.

[0084] The electrospray apparatus may comprise a supply housing for receiving a supply device that can supply a fluid into the conduit for conveying to the capillary.

[0085] The supply housing may be configured for receiving any suitable supply device, such as a syringe, pump, syringe pump, autosampler, or liquid chromatograph.

[0086] The supply device may be configured for preparing the sample that is supplied into the capillary via the conduit (e.g. without being disconnected from the supply housing). For example, the supply device may be configured for converting the sample to a liquid for supplying to the capillary, mixing components to form the sample, and / or to receive a composition comprising the sample and extracting the sample therefrom for supply to the capillary. In this regard, for an electrospray apparatus using a disposable electrospray capillary that needs to be changed between different samples, preparation of the samples may typically be performed “off-line” and separate from the electrospray apparatus. However, for an electrospray apparatus in accordance with the present invention, the Applicant has recognised that as the capillary may be flushed between uses, the continuous use of samples is not prevented by the need to exchange the capillary, and therefore also performing the sample preparation “in-line” with the electrospray apparatus can allow for more continuous / efficient (e.g. automated) use of the electrospray apparatus with extended spraying time and / or reduced down-time.

[0087] For example, biological samples stored in buffer solutions that are not compatible with mass spectrometry require the buffer to be exchanged / removed prior to being electrosprayed for mass analysis. For instance, multiprotein assemblies (e.g. virus capsids) stored in phosphate or trisaminomethane buffer solutions may require the buffer solution to be exchanged for ammonium acetate. This may be achieved by, for example, size-exclusion chromatography (SEC).

[0088] Accordingly, the supply device may comprise a size-exclusion chromatography (SEC) device or other sample extraction or collection device.

[0089] The electrospray apparatus may comprise the supply device. The supply housing may comprise a connector for conveying a sample from a supply device into the conduit. The connector may comprise one or more injector ports (e.g. injector valves), where different injector ports may be able to receive a fluid from a different respective supply device for conveying to the conduit (at an appropriate time).

[0090] The supply housing and the capillary housing may be separated by a flexible connection portion through which the conduit extends from the supply housing to the capillary housing, and that may allow for desired positioning of the capillary and supply housings relative to one another. The flexible connection portion may comprise, for example, a sheath made from a material such as plastic that surrounds the conduit and that can provide additional protection to the conduit. The flexible connection portion may otherwise consist (only) of a portion of the conduit.

[0091] The electrospray apparatus may comprise the supply device, and the supply device may comprise a fluid controller that is configured to control the supply device to supply fluids from different sources into the conduit for conveying to the capillary.

[0092] The electrospray apparatus may comprise said difference sources. The sources may comprise a source of said sample, a source of said flushing liquid and optionally a source of said flushing gas for forcing the flushing liquid out of the capillary.

[0093] The fluid controller may be manually operable to select which source is supplied into the conduit, or it may be programmable for automatically supplying the different sources into the conduit at different respective times.

[0094] Other operations of the apparatus may be automated as desired, for example, the apparatus may comprise a consumable replacing robot for replacing the capillary (when desired).

[0095] The electrospray apparatus may comprise an optical device, such as an imaging device, for example a a camera. The optical device may be configured for observing the position of the conduit and / or capillary within the apparatus. The optical device may be configured for observing whether any bubbles are present within the capillary, such as at the outlet end of the capillary. The apparatus may comprise plural optical devices, such as to allow the capillary to be imaged from different angles. The optical devices may be used together for the same purpose, or different optical devices may be used for different purposes. For example, the apparatus may comprise a first optical device configured for observing whether any bubbles are present within the capillary (such as at the outlet end of the capillary), and a second optical device for observing whether any bubbles are present within the capillary.

[0096] According to a second aspect of the present invention, a mass and / or ion mobility spectrometer is provided comprising an electrospray apparatus as described herein for generating ions via electrospray ionisation.

[0097] The mass and / or ion mobility spectrometer comprises one or more ion analysers, such as a mass analyser and / or an ion mobility analyser, that may analyse ions generated using the electrospray apparatus.

[0098] The liquid sample may comprise analyte that can be ionised to generate analyte ions for analysis by the mass and / or ion mobility spectrometer.

[0099] According to a third aspect of the present invention, a method of electrospraying a liquid sample is provided, the method comprising: providing an electrospray apparatus comprising a capillary and a conduit, wherein the capillary comprises an outlet orifice and a drain orifice, and wherein the conduit extends into and within the capillary; supplying a liquid sample from the conduit into the capillary and to the outlet orifice of the capillary; electrifying the liquid sample so as to electrospray charged droplets of the liquid sample from the outlet orifice of the capillary; and supplying a flushing liquid into the capillary via the conduit, wherein the flushing liquid flows within the capillary and out of the drain orifice so as to remove the liquid sample from the capillary via the drain orifice.

[0100] The electrospray apparatus described above may be used to perform the method. Accordingly, the method may comprise providing an electrospray apparatus having any of the optional features disclosed herein.

[0101] The liquid sample may comprise analyte that is ionised to form analyte ions that are generated or released from the charged droplets, e.g. for analysis via mass spectrometry.

[0102] The method may comprise supplying a flushing gas into the capillary via the conduit so as force the flushing liquid out of the capillary through the drain orifice.

[0103] The flushing liquid may ensure removal of the liquid sample that remains in the capillary after the liquid sample has been electrosprayed. However, the gas may be used to remove substantially all of the flushing liquid from the capillary. A suitable electrospray apparatus for use with the method may be configured for supplying the flushing liquid and the flushing gas, irrespective of whether embodiments of the method may be performed without the use of the flushing gas.

[0104] Any suitable flushing liquid may be used for a particular liquid sample. The flushing liquid employed in aspects of the present invention described above is preferably miscible with the liquid sample to dilute it therein. For example, the flushing liquid may comprise, or consist of, a solvent that dissolves the liquid sample therein and / or that the liquid sample also comprises.

[0105] The flushing liquid may dissolve at least a component of the liquid sample.

[0106] Supplying the flushing liquid into the capillary via the conduit may cause the liquid sample and / or flushing liquid to flow out of the drain orifice prior to the flushing gas being supplied.

[0107] When the flushing liquid is supplied into the capillary, it may form a mixture or solution with the liquid sample. Supplying the flushing liquid in sufficient volume can itself cause the flushing liquid and / or liquid sample to flow away from the outlet orifice towards the drain orifice and out of the capillary via the drain orifice. For example, the method may comprise supplying a greater volume of the flushing liquid than of the liquid sample (to adequately dilute the liquid sample and / or cause it to be expelled from the drain orifice). Thus, the liquid sample may be supplied into the capillary such that the flushing liquid flows within the capillary and out of the drain orifice so as to remove the liquid sample from the capillary via the drain orifice. However, the flushing liquid and / or liquid sample may otherwise not flow out of the drain orifice until the flushing gas is supplied to cause this to happen.

[0108] The volume of the liquid sample supplied into the capillary, prior to supplying any flushing liquid, may be less than 20 pl.

[0109] The volume of the liquid sample supplied into the capillary may be between 1 nL and 20 pL, such as between 100 nL and 15 pL or between 500 nL and 10 pL.

[0110] Supplying a liquid sample from the conduit into the capillary and to the outlet orifice of the capillary may comprise supplying a pressurising gas into the capillary to force the liquid sample towards the outlet orifice.

[0111] The pressurising gas may be supplied into the capillary via the drain orifice and may be supplied external to the conduit. For example, the conduit may extend into the capillary through the drain orifice and the pressurising gas may be supplied into the capillary via the drain orifice and external to (e.g. around) the conduit.

[0112] As described herein, the pressurising gas can force the liquid sample towards the outlet orifice to remove any air bubbles present. The method may comprise supplying the pressurising gas into the capillary from a chamber of a capillary housing that houses the capillary.

[0113] The method may comprise opening a valve in the capillary housing to reduce the pressure of the pressurising gas in the capillary prior to the flushing liquid removing the liquid sample from the capillary via the drain orifice.

[0114] In this regard, after supplying the pressurising gas into the capillary to force the liquid sample towards the outlet orifice, pressure within the chamber of the capillary housing may be reduced before the flushing liquid flows out of the drain orifice so that the pressurising gas can flow back out of the capillary into the chamber and does not counteract the flow of the flushing liquid out of the capillary.

[0115] The pressure of the pressurising gas may otherwise be reduced via any other suitable means besides a valve in the capillary housing.

[0116] The pressure of the pressurising gas may be reduced before or after the liquid sample is electrified so as to electrospray charged droplets of the liquid sample from the outlet orifice of the capillary.

[0117] The valve in the capillary housing may control the flow of fluid into a drain of the capillary housing, for example such that when the valve is open the sample, flushing liquid and gas can all be received by the drain.

[0118] The method may comprise supplying the pressurising gas into the capillary housing via a gas inlet conduit (for supply to the capillary). After supplying the pressurising gas into the capillary to force the liquid sample towards the outlet orifice, the supply of pressurising gas into the capillary housing via the gas inlet conduit may be stopped (e.g. by closing a valve in the gas inlet conduit). However, the supply of pressurising gas into the capillary housing via the gas inlet conduit may otherwise be continued (or may be later resumed, e.g. by opening the valve in the gas inlet conduit) to flush the liquid sample and flushing liquid out of the capillary housing.

[0119] The liquid sample may comprise a protein assembly and / or adduct molecules (e.g. not-volatile salts).

[0120] Electrifying the liquid sample may comprises supplying a voltage greater than 100 V to the liquid sample. For example, a voltage between 200 V and 2 kV may be supplied.

[0121] Electrifying the liquid sample may result in a liquid interface at the outlet orifice being formed between the liquid sample and a fluid (e.g. air) or void (vacuum) external to the capillary. The liquid interface may extend out of the capillary and take the form of, for example, a curved meniscus or a Taylor cone. A portion of the liquid interface may overlap an external surface of the capillary. The charged droplets may be emitted from the liquid interface. The method may comprise heating the sample in the conduit and / or in the capillary.

[0122] The method may comprise supplying a next liquid sample from the conduit into the capillary after supplying the flushing liquid.

[0123] When a flushing gas is used to remove the flushing liquid, the next liquid sample may be supplied after supplying the flushing gas. The entire process may be repeated for the next liquid sample, and so on, as appropriate. For example, it may be repeated such that it is carried out for at least three, four, five, or more than five liquid samples that are supplied at different times into the same capillary.

[0124] The process may be automated such that one or more liquid samples, the flushing liquid, and / or the flushing gas are supplied at programmable times.

[0125] The next liquid sample may be supplied without removing the capillary from a capillary housing that comprises the capillary.

[0126] The method may comprise centrifuging the capillary prior to inserting it into the electrospray apparatus. The centrifuging step is not essential to all embodiments. However, this can allow the outlet end of the capillary (where the outlet orifice is located) to be wet prior to the conduit supplying the sample into the capillary in embodiments where a liquid sample supplied out of the conduit may not otherwise be conveyed to the outlet orifice when the capillary is inserted entirely “dry”, but wetting the outlet end by centrifuging may allow a liquid sample supplied by the conduit to be conveyed to the outlet orifice. However, once the capillary has been inserted into the apparatus after being wet, it may retain some portion of liquid at its outlet end via surface tension such that subsequent centrifuging steps are unnecessary. This may be the case even though contamination of subsequent samples is substantially avoided on account of the small volume of liquid that may be retained after a flushing cycle and / or the use of the flushing liquid to dilute any remaining portion of a previous liquid sample.

[0127] The method can allow the position of the capillary and a voltage applied to the liquid sample to be optimised and remain fixed while one or more successive liquid samples are supplied into the capillary.

[0128] The supply of a voltage from the apparatus to liquid in the capillary may be stopped or maintained during flushing. Maintaining the voltage may cause a portion of the flushing liquid to be expelled via the outlet orifice (and emitted as droplets) to further flush the capillary of the liquid sample.

[0129] The use of a pressurising gas in an electrospray apparatus to removable air bubbles by forcing a sample towards the outlet orifice of a capillary in the manner disclosed herein is believed to be novel and inventive irrespective of whether the sample is flushed out from capillary. Thus, according to a fourth aspect of the present invention, there is provided an electrospray apparatus comprising: a capillary having an outlet orifice for electrospraying a sample therefrom; and a conduit extending into the capillary in a manner such that it is able to deliver said sample into the capillary; wherein the apparatus is configured to supply a pressurising gas into the capillary so as to force said sample within the capillary towards the outlet orifice.

[0130] According to a fifth aspect of the present invention, there is provided a method of electrospraying a liquid sample, the method comprising: providing an electrospray apparatus comprising a capillary and a conduit, wherein the capillary comprises an outlet orifice, and wherein the conduit extends into and within the capillary; supplying a liquid sample from the conduit into the capillary; supplying a pressurising gas into the capillary so as to force said sample within the capillary towards the outlet orifice; and electrifying the liquid sample so as to electrospray charged droplets of the liquid sample from the outlet orifice of the capillary.

[0131] The fourth and fifth aspects of the present invention may comprise any of the features or steps described herein in relation to the first to third aspects and associated embodiments.

[0132] For example, the outlet orifice may have a diameter that is less than 100 pm.

[0133] Optionally a diameter of the outlet orifice is less than 50 pm, such as less than 25 pm, and preferably between 0.1 pm and 20 pm.

[0134] The capillary may comprise an inlet orifice optionally having any of the features or functionality described herein in relation to the drain orifice.

[0135] For example, the conduit may be inserted into the capillary through the inlet orifice, and the apparatus may be arranged for the pressurising gas to be supplied into the capillary via the inlet orifice and external to the conduit.

[0136] The electrospray apparatus may comprise a voltage supply arranged to electrify said sample.

[0137] The voltage supply may be used to electrify said sample to cause sample delivered into the capillary to be electrosprayed via the outlet orifice (and thereby form charged droplets).

[0138] The apparatus may be configured for the voltage supply to electrify the sample in any suitable manner. For example, the capillary may comprise an electrically conductive material (e.g. an electrically conductive coating) for electrifying the sample, the conduit may comprise an electrically conductive material (e.g. an electrically conductive coating) for electrifying the sample, and / or an electrode (e.g. wire or plunger) may be inserted into the capillary for electrifying the sample.

[0139] The voltage supply may be arranged for, and the method may comprise, supplying a voltage greater than 100 V, and preferably can supply a voltage greater than 1 kV, for electrospraying said sample.

[0140] The apparatus may be configured to control a pressure of the pressurising gas within the capillary.

[0141] The pressure of the pressurising gas may be maintained when electrospraying to continue to force the sample towards the outlet orifice for emission therefrom, or the pressure of the pressurising gas may be reduced before electrospraying (after removal of any air bubbles).

[0142] Thus, the method may comprise, and the apparatus may be configured for, reducing the pressure of the pressurising gas in the capillary between the steps of: supplying the pressurising gas into the capillary so as to force said sample within the capillary towards the outlet orifice; and electrifying the liquid sample so as to electrospray charged droplets of the liquid sample from the outlet orifice of the capillary.

[0143] The apparatus may comprise any suitable components for controlling and / or measuring a pressure of gas within the capillary and / or a capillary housing via which the pressurising gas is supplied into the capillary. For example, the apparatus may comprise one or more valves (such as pneumatic valves), a pressure gauge, and / or a volumetric flow controller. For instance, a valve may be opened (e.g. in the capillary housing) to reduce a pressure of the pressurising gas in the capillary.

[0144] The apparatus may comprise a capillary holder (e.g. as a component of the capillary housing) having the capillary supported therein.

[0145] The capillary holder may comprise a retractable sheath for protecting the capillary.

[0146] The capillary holder may comprise a sheath member comprising a (counter) electrode.

[0147] The retractable sheath and sheath member may each have any of the features described herein for a retractable sheath and sheath member respectively.

[0148] In any of the above described aspects of the present invention, the capillary holder may be provided comprising an electrospray emitter assembly that comprises the capillary and the sheath member. The capillary holder may further comprise a connector element, wherein the electrospray emitter assembly is attachable to the connector element and the connector element is attachable to the housing body of the capillary housing. The electrospray emitter assembly may accordingly constitute a consumable (replaceable) part of the electrospray apparatus. For example, such that the electrospray emitter assembly is easily replaceable if blocked or damaged, and / or such that different electrospray emitter assemblies may be provided for different samples and / or with different characteristics / parameters (e.g. different outlet orifice diameters).

[0149] An electrospray apparatus having the features of a capillary holder comprising a connector element and removable electrospray emitter assembly described herein is believed to be novel and inventive itself.

[0150] According to a sixth aspect of the present invention, there is provided an electrospray apparatus, comprising: a capillary holder for holding a capillary for emitting a sample therefrom, the capillary holder comprising; a sheath member for surrounding at least a portion of the capillary, wherein the sheath member has one or more apertures located therein for allowing the capillary to be viewed; and a connector element for connecting the sheath member to in order to position the capillary within the electrospray apparatus.

[0151] The sheath member can protect a capillary and provide protection to a user from the capillary, as well as attaching to the connector element to position the capillary within the electrospray apparatus. In use, a sample can then be provided into the capillary and the sample can be electrosprayed from the capillary.

[0152] The capillary holder may comprise the capillary. In particular, the capillary holder may comprise an emitter assembly comprising the capillary and the sheath member.

[0153] The sheath member may have a connector end for connecting to the connector element and a distal end opposite to the connector end.

[0154] The connector end and distal end may be separated in an axial direction, and the sheath member may comprise one or more apertures for allowing the capillary (such as an outlet orifice of the capillary) to be viewed from a radial direction (perpendicular to the axial direction). For example, the one or more apertures may be located radially outward from the outlet orifice of the capillary and located at a same axial position as the outlet orifice of the capillary.

[0155] In this regard, the sheath member may be elongated between the connector end and the distal end so as to have a longitudinal axis extending between the connector end and the distal end, wherein the axial direction and radial direction are defined relative to the longitudinal axis.

[0156] The sheath member may be removably attachable to the connector element. The capillary may have an outlet orifice for emitting a sample therefrom, and the sheath member may at least partially surround the capillary and (the distal end) extend beyond the outlet orifice of the capillary (i.e. downstream, e.g. in the axial direction).

[0157] The capillary may have a length extending in the axial direction.

[0158] The connector element may comprise a bore for conveying a sample into the capillary when the connector element is connected to the sheath member.

[0159] A conduit as described herein may be inserted through the bore of the connector element and into the capillary to provide a liquid sample and / or gas into the capillary. The emitter assembly and / or connector element may comprise the conduit but preferably the capillary holder can be used independently of the conduit, if desired.

[0160] The sheath member may comprise an electrode for providing a potential difference between the electrode and a sample within the capillary, for example for providing a potential difference between a sample within the capillary and a position (axially) beyond the outlet orifice of the capillary.

[0161] The electrospray apparatus may be arranged for, in use, a potential difference to be provided between a sample within the capillary and the electrode of the sheath member to cause droplets of the sample to be electrosprayed from the outlet orifice of the capillary.

[0162] The electrode of the sheath member may accordingly act as a counter electrode within the electrospray apparatus.

[0163] A voltage may be supplied to the electrode of the sheath member via the connector element.

[0164] The electrode is preferably electrically isolated from the outlet end of the capillary, for example so that different potentials may be applied to the electrode and the capillary.

[0165] The apparatus may be configured to maintain the electrode at a fixed position relative to the outlet orifice of the capillary.

[0166] The electrospray apparatus may comprise a supporting element (e.g. as part of the emitter assembly) for securing the capillary within the sheath member. The securing element may be located radially between the capillary and the sheath member. The supporting element may fix the sheath member to the capillary.

[0167] The supporting element may be or comprise a ferrule.

[0168] The capillary holder may be configured for the supporting element to be inserted into the bore of the connector element while the supporting elements maintain a position of the sheath member relative to the capillary.

[0169] The supporting element may be arranged to form a seal with a circumferential wall of the connector element that surrounds the bore, e.g. such that fluid cannot flow out of the bore other than by passing into the capillary. For example, the connector element and / or supporting element may comprise a sealing element, such as an o-ring, for forming a fluid- tight connection between the emitter assembly and the connector element.

[0170] The sheath member may (circumferentially) surround the axial length of the capillary between the supporting element and the outlet end of the capillary (i.e. the sheath member may extend along the entire axial length of the capillary downstream of the supporting element).

[0171] The sheath member may (also) surround an inlet orifice of the capillary. The inlet orifice of the capillary may be at an upstream end of the capillary opposite to an outlet end at which the outlet orifice is located. This can provide protection to the upstream end of the capillary for example when the emitter assembly is disconnected from other parts of the apparatus. The capillary may optionally be entirely within and between the ends of the sheath member and the sheath member may surround the entire length of the capillary.

[0172] The electrode may extend the entire length of the sheath member.

[0173] The capillary may be entirely within and between the ends of the electrode.

[0174] The sheath member may consist entirely of the electrode, such that the sheath member is provided as a sheath electrode. However, this is not essential and the electrode may only form some portion of the sheath member.

[0175] The supporting element may be bonded (e.g. fixed by adhesive) to the capillary and / or the sheath member.

[0176] However, the supporting element may fix the sheath member to the capillary (so that the sheath member has a fixed position and orientation relative to the capillary) in any other suitable manner.

[0177] The capillary may have any of the features described herein for a capillary of an electrospray apparatus. For example, the capillary may comprise an electrically conductive material, such as a metal, or may comprise an electrically insulative material, such as glass. The capillary may be made of a material advantageously selected to be resistant to permanent deformation, so as to reduce the chance of the capillary being damaged throughout its use.

[0178] The supporting element may electrically isolate the capillary from the electrode (so that different potentials may be applied to the electrode and the capillary).

[0179] The outlet orifice may have a diameter that is less than 100 pm, for example less than 50 pm, such as less than 25 pm, and preferably between 0.1 pm and 20 pm.

[0180] An outer diameter of the emitter assembly may be less than 20 mm, for example less than 15 mm or less than 12 mm. This may be such that the emitter assembly (with the sheath member) can be inserted into standard sized sample tubes (e.g. a sample tube having a volume capacity of 0.1-20 ml) for centrifuging to initially wet the outlet end of the capillary prior to use. However, this is not essential and the emitter assembly may be inserted into the centrifuge directly (e.g. without the sample tube).

[0181] The electrospray apparatus may comprise a cover that the sheath member can be inserted into and removed from. The sheath member may be attachable to the connector element without removing the sheath member from the cover, and the cover can be removed once the emitter assembly is attached to the connector element. The cover may comprise a lid that is closable when the cover is removed from the sheath member, this may substantially seal the cover to prevent any material inadvertently accumulating in the cover when the sheath member is not inserted therein. The cover may be a sample tube having a volume capacity of 0.1-20 ml, and the emitter assembly may be insertable into a centrifuge while the sheath member is located within the sample tube.

[0182] The sheath member may comprise an attachment portion at the connector end for removably attaching the sheath member to the connector element.

[0183] The sheath member may comprise a viewing portion at the distal end, wherein the one or more apertures are located in the viewing portion.

[0184] The sheath member may entirely circumferentially enclose the capillary between the attachment portion and the viewing portion.

[0185] The attachment portion may be a single integral (monolithic) component (instead of being an assembly of separately manufactured components). The attachment portion may also be integral with other components of the emitter assembly. For example, the sheath member may comprise a single integral component that comprises the attachment portion. The single integral component may extend (axially) beyond the outlet orifice of the capillary. The single integral component may be attached to or comprise the electrode of the sheath member.

[0186] The sheath member may (entirely) be a single integral (monolithic) component.

[0187] The Applicant has recognised that providing (at least) an attachment portion of the sheath member as all or part of a single integral component can provide a suitable attachment of the sheath member to the electrospray apparatus while simplifying the manufacture of the assembly and / or electrical connection path to the electrode.

[0188] The sheath member may be configured to attach to the connector element by the sheath member being rotated relative to the connector element.

[0189] The capillary holder may be configured for the sheath member to be rotatable to a predetermined position relative to the connector element.

[0190] The predetermined position may correspond to the sheath member being rotated by less than one complete (360 degrees) turn about its longitudinal axis relative to the connector element. For example, the predetermined position may correspond to a quarter (90 degrees) turn or a half (180 degrees) turn.

[0191] The capillary holder may be configured for a releasable snap fit or interference fit to be provided between the connector element and the sheath member at the predetermined position.

[0192] The Applicant has found that a releasable snap fit or interference fit can provide a “tool-free” connection that a user finds intuitive to operate, and can provide a reproducible connected position for the emitter assembly and may also allow for quick connection and disconnection.

[0193] The sheath member may be configured to provide an audible sound (e.g. “click”) at the predetermined position.

[0194] The sheath member or the connector element may comprise a flexible arm. The flexible arm may be configured to provide a releasable snap fit between the connector element and the sheath member, such as by the sheath member being rotated relative to the connector element.

[0195] The flexible arm may comprise a connected end attached to a supporting structure and a free end opposite to the connected end, wherein the flexible arm is configured for the free end to be displaceable (e.g. in the axial direction) relative to the connected end.

[0196] The free end of the flexible arm may be configured to be movable between a first (rest) position and a second (displaced) position to enable connection of the sheath member to the connector element. During connection, the flexible arm may move from the first position towards the second position and then return from the second position towards the first position. Once connected, the flexible arm may be at the first position or may be at a third (connected) position.

[0197] The free end of the flexible arm may be biased (e.g. by material elasticity) to return to the first position.

[0198] One of the connector element and the sheath member may comprise the flexible arm, and the other of the connector element and the sheath member may comprise an engagement structure.

[0199] The engagement structure may be configured to form a releasable snap fit connection with the flexible arm.

[0200] The apparatus may be configured for the engagement structure to displace the free end of the flexible arm (e.g. to the second and / or third position) during attachment of the sheath member to the connector element, for example when the sheath member is rotated relative to the connector element. The flexible arm may comprise a protrusion (e.g. at the free end), and the apparatus may be configured for the protrusion to abut a surface of the engagement structure when the connector element is attached to the sheath member. For example, the apparatus may be configured for the engagement structure to be located between the supporting structure and the protrusion when the sheath member is attached to the connector element.

[0201] The protrusion may have a curved or sloped portion (e.g. a chamfer or bevel) to allow the flexible arm to be displaced by the engagement structure for detaching the sheath member from the connector element, for example, when the sheath member is rotated relative to the connector element in an opposite direction to a direction that the sheath member is rotated to attach the sheath member to the connector element.

[0202] The engagement structure may comprise a curved or sloped surface that contacts the protrusion when the sheath member is rotated relative to the connector element, which may allow the flexible arm to be gradually displaced in a controlled manner based on the curvature or gradient of the slope.

[0203] The connector element may comprise a circumferential wall surrounding the bore.

[0204] The sheath member may comprise a collar portion arranged to at least partially surround the circumferential wall of the connector element when the connector element and the sheath member are connected to one another. The collar portion may be provided as the supporting structure that the flexible arm is connected to.

[0205] The engagement structure may be provided on a circumferential wall of the connector element that surrounds the bore, for example the engagement structure may protrude radially outward from the circumferential wall of the connector element.

[0206] The collar portion may comprise a circumferential slot for receiving the engagement member therein.

[0207] The slot may have a first portion for allowing the engagement structure to slide within the slot in the axial direction relative to the sheath member, and a second portion for allowing the sheath member to be rotated relative to the engagement structure while retaining the engagement structure within the slot. During connection the engagement structure may travel within the first portion and then the second portion.

[0208] The slot may be partially bordered by the flexible arm.

[0209] The sheath member may comprise a circumferential wall for surrounding (at least a portion of the axial length of) the capillary.

[0210] When the sheath member and connector element are connected, axial ends of the circumferential wall of the sheath member and the circumferential wall of the connector element may abut one another. The circumferential wall of the sheath member may comprise the one or more apertures, for example so that the circumferential wall encloses the perimeter(s) of the one or more apertures. The apertures may otherwise be open at the distal end of the sheath member rather than being enclosed, for example in arrangements where the sheath member comprises prongs as described below.

[0211] The sheath member may comprise an outlet aperture for a sample emitted from the capillary to pass therethrough. The outlet aperture may be axially beyond (downstream from) the outlet orifice of the capillary when the capillary is located within the sheath member.

[0212] The outlet aperture may be contiguous or non-contiguous with the one or more apertures for viewing the capillary.

[0213] The electrode may comprise the outlet aperture.

[0214] The electrode may extend along (at least a portion of) the circumferential wall of the sheath member.

[0215] The electrode may comprise the one or more (side) apertures for viewing the capillary. For example, the electrode may comprise a mesh or cage structure that surrounds a portion of the (axial) length of the capillary (and that comprises the side apertures).

[0216] The one or more (side) apertures may allow the position of the capillary within the sheath member to be viewed during assembly to allow the position of the capillary to be more easily set / verified.

[0217] The one or more apertures may allow the sample at the outlet end of the capillary to be viewed optically (e.g. with a camera), which may allow for verification / assessment of aspects of the electrospray process, such as the wetting of the outlet end of the capillary, the lack of presence of any air bubbles, and the formation of a Taylor cone. Having side apertures in the counter electrode may also be used to control / set the shape of the electric field at the outlet end of the capillary to set an appropriate electric field for the desired propagation of the spray of droplets emitted from the capillary.

[0218] The apparatus may accordingly comprise one or more cameras for viewing the capillary via the one or more apertures in the sheath electrode.

[0219] The sheath member may comprise prongs (at the distal end). The prongs may extend axially (downstream) from the circumferential wall of the sheath member.

[0220] The prongs may extend beyond (to a position downstream from) the outlet orifice of the capillary. The one or more apertures may be plural apertures, and the prongs may circumferentially separate the apertures from one another (the apertures may be gaps that are open at the distal end and located circumferentially between respective pairs of prongs).

[0221] Accordingly, the prongs may be spaced apart in a circumferential direction around a longitudinal axis of the sheath member (and / or capillary) so as to define the apertures (gaps) therebetween.

[0222] The apertures (gaps) may be located at a same axial position as the outlet orifice of the capillary.

[0223] The prongs may extend from a (axial) position upstream of the outlet orifice of the capillary to a (axial) position downstream of the outlet orifice of the capillary. For example, the sheath member may comprise a wall circumferentially surrounding at least a portion of the axial length of the capillary upstream of the outlet orifice, and the prongs may extend from the circumferential wall to a position downstream of the outlet orifice of the capillary.

[0224] The prongs may have any suitable size and shape. The prongs may be of a same size (and shape) as one another or different sized / shaped prongs may be provided. The prongs may be equally spaced in the circumferential direction around the longitudinal axis of the capillary. The gaps between the prongs may be of a same size (and shape) as one another.

[0225] The electrode may extend along one or more of the prongs. For example, the electrode may extend along a plurality of (and optionally each of) the prongs, in which case the portions of the electrode provided on different ones of the prongs may merge upstream of the prongs (for example, as discussed above, the sheath member may consist entirely of the electrode).

[0226] There may otherwise be a plurality of electrodes where different ones of the electrodes are provided on different ones of the prongs, and each electrode may be in accordance with the electrode described herein for the sheath member. In use, the electrodes on the different prongs may each have an equal electric potential applied thereto (but this is not essential). The sheath member may be manufactured from an electrically conductive material such as a metal, may comprise an electrically conductive coating (e.g. paint) applied to an electrically insulating material such as a plastic material, or may comprise an electrically insulating material filled with an electrically conductive powder (e.g. carbon powder, metal powder) dispersed therein. For example, the sheath member may comprise a (electrically insulating) plastic material such as polypropylene, polyether ether ketone (PEEK) or polyimide. Electrically conductive material located / dispersed within the sheath member may form the electrode. The one or more apertures for viewing the capillary may be devoid of any solid material or a solid material that is optically transparent and / or electrically insulative may be located in the one or moreapertures.

[0227] The sheath member or electrospray emitter assembly may be attachable to the connector element while maintaining the position of the electrode (and optionally the entire sheath member) relative to the capillary.

[0228] When the electrospray emitter assembly is attached to the connector element, the sheath member may extend outward from the connector element to beyond the outlet end of the capillary (the sheath member may circumferentially surround the entire axial length of the capillary extending out of the connector element).

[0229] The electrospray emitter assembly may comprise any suitable means for attaching the electrospray emitter assembly to the connector element. For example, the electrospray emitter assembly may be attachable to the connector element using one or more springs (e.g. an annular canted spring between the connector element and the sheath member), using a press-fit, a snap fit, a bayonet connection, or using a threaded connection. The connector element may be attachable to, or integral with, apparatus (e.g. a housing body as described herein) for supplying a sample into the capillary.

[0230] As discussed above, the connector element may comprise a bore for conveying a sample and / or conduit into the capillary. The bore in the connector element may have a conical inlet for guiding a conduit into the capillary.

[0231] The downstream end of the connector element and the upstream end of the emitter assembly may form a fluid-tight connection with one another. For example, the connector element and / or the electrospray emitter assembly may comprise one or more sealing elements, such as an “o-ring”, to provide a fluid-tight connection between the emitter assembly and the connector element.

[0232] It is believed that an electrospray emitter assembly comprising a sheath member and a capillary may be novel and inventive itself independent of the connector element.

[0233] Thus, according to a seventh aspect of the present invention, there is provided an electrospray emitter assembly comprising a capillary and a sheath member surrounding at least a portion of the (length of the) capillary.

[0234] The sheath member and / or capillary may have any of the optional features for an electrospray apparatus described herein.

[0235] In an embodiment, the capillary has an outlet orifice at an outlet end of the capillary for emitting a sample therefrom, the sheath member comprises an electrode that extends downstream from the outlet orifice of the capillary, and the electrospray emitter assembly is arranged for, in use, a potential difference to be provided between the sample within the capillary and the electrode of the sheath member to cause droplets of the sample to be electrosprayed from the outlet orifice of the capillary.

[0236] As described above, the sheath member can provide protection to the capillary and provide protection to a user from the capillary, and may also fulfil the function of a counter electrode in providing a potential difference between an electrified sample within the capillary and a region external to the outlet end of the capillary.

[0237] The assembly may maintain the counter electrode at a fixed position relative to the capillary.

[0238] According to an eight aspect of the present invention, a method of electrospraying a liquid sample is provided, the method comprising: providing an electrospray apparatus comprising a capillary having an outlet orifice at an outlet end of the capillary and a sheath member (circumferentially) surrounding at least a portion of the (axial) length of the capillary, wherein the sheath member comprises an electrode that extends downstream from (has a position axially beyond) the outlet orifice of the capillary; supplying a liquid sample into the capillary; and providing a potential difference between the liquid sample within the capillary and the electrode of the sheath member to electrospray charged droplets of the liquid sample from the outlet orifice of the capillary.

[0239] Providing the electrospray apparatus may comprise providing an electrospray in accordance with any aspects or embodiments described above. For example, providing the electrospray apparatus may comprise providing an electrospray emitter assembly comprising the capillary and the sheath member, and attaching the electrospray emitter assembly to a housing of the electrospray apparatus (e.g. via a capillary holder) while maintaining the position of the sheath member fixed relative to the capillary.

[0240] The electrospray emitter assembly and the capillary holder may have any of the respective optional features described herein. For example, the capillary holder may comprise the connector element for attaching the electrospray emitter assembly to the capillary housing.

[0241] Supplying the liquid sample into the capillary may comprise supplying the liquid sample through a bore in the capillary holder into the capillary.

[0242] The liquid sample may be supplied to the outlet end of the capillary via a conduit inserted into the capillary through an inlet orifice of the capillary.

[0243] The conduit may be inserted through the bore in the capillary holder. Providing a potential difference between the liquid sample within the capillary and the electrode may comprise electrifying the liquid sample by applying a voltage to the liquid sample via the conduit.

[0244] Any other suitable means of providing the potential difference may otherwise be used and it is not essential that the voltage is applied to the liquid sample via the conduit. For example, the voltage may be applied to the liquid sample via the capillary or an electrode within the capillary.

[0245] The potential difference may be greater than 100 V, such as greater than 1 kV. The potential difference may be between 50 V and 5 kV, such as between 100 V and 3 kV. The potential difference may be provided between the sample and the electrode by providing an opposite polarity potential to the electrode relative to the sample, by grounding the electrode while electrifying the sample, or by applying a lower magnitude potential of the same polarity to the electrode relative to the sample.

[0246] The method may comprise supplying a flushing liquid into the capillary via the conduit, wherein the flushing liquid flows within the capillary and out of the inlet orifice so as to remove the liquid sample from the capillary via the inlet orifice.

[0247] Any of the other optional steps or features described herein in relation to flushing the liquid sample and / or flushing liquid out of the capillary may be provided.

[0248] The method may comprise supplying a pressurising gas into the capillary so as to force said sample within the capillary towards the outlet orifice.

[0249] Any of the other optional steps or features described herein in relation to forcing the sample towards the outlet orifice using a pressurising gas may be provided.

[0250] The method may comprise centrifuging the electrospray emitter assembly (comprising the sheath member and the capillary) to wet the outlet end of the capillary prior to attaching the electrospray emitter assembly to the capillary holder. Liquid sample may then be subsequently supplied into the capillary via the conduit.

[0251] The sheath member may consist entirely of the electrode, such that the sheath member is provided as a sheath electrode. However, this is not essential and the electrode may only form some portion of the sheath member.

[0252] According to a ninth aspect of the present invention, a method of providing an electrospray apparatus is provided, the method comprising: providing a sheath member surrounding at least a portion of a capillary, wherein the sheath member has one or more apertures located therein for allowing the capillary to be viewed; and connecting the sheath member to a connector element in order to position the capillary for electrospraying a sample therefrom. The method may comprise any of the steps or features for an electrospray apparatus or method described above.

[0253] For example, the sheath member may be connected to the connector element while maintaining the capillary in a fixed position relative to the sheath member.

[0254] The connector element may comprise a bore for conveying a sample into the capillary when the connector element is connected to the sheath member.

[0255] A supporting element may secure the capillary within the sheath member, and the supporting element may be inserted into the bore of the connector element when the sheath member and connector element are connected to one another.

[0256] The sheath member may comprise an electrode for a potential to be applied to for causing the sample to be electrosprayed from the capillary.

[0257] The sheath member may be attached to the connector element by the sheath member being rotated relative to the connector element.

[0258] The sheath member may be rotated to a predetermined position relative to the connector element, and a releasable snap fit or interference fit may be provided between the connector element and the sheath member at the predetermined position.

[0259] The sheath member may be a single integral component.

[0260] The sheath member may comprise prongs, the one or more apertures may be plural apertures, and the prongs may circumferentially separate the plural apertures from one another.

[0261] According to an tenth aspect of the present invention, a method of electrospraying a liquid sample from an emitter is provided, the method comprising: providing an emitter having a flushing liquid therein and an orifice; transferring a liquid sample into the emitter via the orifice, wherein the flushing liquid is immiscible with the liquid sample such that the liquid sample is located within the emitter between the flushing liquid and the orifice; generating charged droplets of the liquid sample by electrifying the liquid sample to emit the liquid sample via the orifice; and causing the flushing liquid to displace the liquid sample out of the emitter via the orifice.

[0262] Using a flushing liquid that is immiscible with the liquid sample in the manner disclosed herein can allow the flushing liquid to be used to displace the liquid sample out of the emitter, thereby avoiding a “dead volume” of liquid sample that could otherwise be inadvertently retained within the emitter. An immiscible flushing liquid may, for example, be an oil. However, any liquid suitably immiscible with a particular liquid sample may be used as the flushing liquid in such a method. The ability to remove or at least substantially reduce any dead volume of the liquid sample allows for the method to be suitably used for small liquid samples. For example, a volume of the liquid sample transferred into the emitter may be less than 5 pL, less than 1 pl or less than 500 nL.

[0263] The orifice may have a diameter less than 100 pm, less than 50 pm, less than 25 pm, and preferably between 0.1 pm and 20 pm.

[0264] The emitter may comprise a capillary, such as a glass capillary, having the orifice. The liquid sample and flushing liquid may be held entirely within the capillary when in the emitter.

[0265] Providing the emitter having the flushing liquid therein may comprise transferring the flushing liquid into the emitter via the orifice prior to transferring the liquid sample into the emitter via the orifice.

[0266] The flushing liquid and / or liquid sample can be transferred into the emitter from any suitable supply of the flushing liquid and liquid sample respectively. For example, the emitter may be immersed in a supply of flushing liquid / liquid sample when transferring it therein.

[0267] The flushing liquid may be caused to displace the liquid sample out of the emitter in any suitable manner. For example, the emitter may comprise a displacement device (e.g. a plunger) that is used to displace the flushing liquid (located between the displacement device and the liquid sample) to thereby displace the liquid sample out of the emitter via the orifice.

[0268] The displacement device may be used to transfer the liquid sample and / or flushing liquid into the emitter.

[0269] The emitter may comprise a displacement device for varying the quantity of a volume of fluid that can be held within the emitter, and the method may comprise: transferring the liquid sample into the emitter via the orifice by moving the displacement device to increase the volume of fluid that can be held within the emitter to thereby aspirate the liquid sample through the orifice into the emitter; and causing the flushing liquid to displace the liquid sample out of the emitter via the orifice by moving the displacement device to decrease the volume of fluid that can be held within the emitter.

[0270] Transferring the flushing liquid into the emitter via the orifice may comprise, before transferring the liquid sample into the emitter, moving the displacement device to increase the volume of fluid that can be held within the emitter to thereby aspirate the flushing liquid through the orifice into the emitter. After the flushing liquid is used to displace the liquid sample out of the emitter via the orifice, the method may be repeated any number of times for subsequent liquid samples. Thus, the method may comprise transferring a next liquid sample into the emitter via the orifice, repeating the process to generate charged droplets of the next liquid sample and displace it out of the emitter using the flushing liquid, and so on.

[0271] Different liquid sample volumes separated by flushing liquid may also be held within the emitter by alternating between transferring a flushing liquid into the emitter and transferring a liquid sample into the emitter any number of times such that a volume of liquid sample is located within the emitter between a volume of flushing liquid and the orifice and one or more other volumes of liquid sample (either the same sample or differing samples) are each located within the emitter between volumes of flushing liquid. The different volumes of liquid sample may then be emitted in turn by a respective volume of liquid sample being emitted once any volumes of flushing liquid and other volumes of liquid sample that were held within the emitter between the respective volume of liquid sample and the orifice have been displaced out of the orifice.

[0272] The liquid sample may be electrified in any suitable manner. For example, a voltage may be supplied to the liquid sample from the emitter via the flushing liquid, via the displacement device, via a conductive coating on the emitter, and / or via an electrode (e.g. a wire) within the emitter.

[0273] In an embodiment, the method comprises electrifying the liquid sample by supplying a voltage to the liquid sample via the flushing liquid and / or via the displacement device.

[0274] According to an eleventh aspect of the present invention, a method of mass and / or ion mobility spectrometry is provided, comprising providing ions from charged droplets generated using a method of electrospraying a liquid sample as described herein, and mass and / or ion mobility analysing said ions or ions derived from said ions.

[0275] Ions generated from the charged droplets may be conveyed into an inlet of a mass and / or ion mobility spectrometer and analysed in any suitable manner. The ions generated from the charged droplets may comprise analyte ions generated from an analyte within the sample.

[0276] BRIEF DESCRIPTION OF THE DRAWINGS

[0277] Various embodiments will now be described, by way of example only, and with reference to the accompanying drawings in which:

[0278] Fig. 1A shows an electrospray apparatus in accordance with an embodiment of the present invention; Fig. 1 B shows an electrospray apparatus in accordance with another embodiment of the present invention;

[0279] Fig. 1C shows an enlarged view of certain components of the electrospray apparatus of Fig. 1 B;

[0280] Fig. 1 D shows an electrospray apparatus in accordance with another embodiment of the present invention, the apparatus has a retractable sheath shown in an extended position;

[0281] FIG. 1 E shows the electrospray apparatus of Fig. 1 D with the retractable sheath in a retracted position;

[0282] Fig. 1 F shows an electrospray apparatus in accordance with another embodiment of the present invention, the apparatus has a sheath electrode surrounding the capillary;

[0283] Fig. 1G shows a cross-sectional view of the electrospray apparatus of Fig. 1 F;

[0284] Fig. 1 H shows a sample being electrosprayed from the outlet end of the capillary of the electrospray apparatus of Fig. 1 F and Fig. 1G;

[0285] Fig. 11 shows an electrospray apparatus in accordance with another embodiment of the present invention, wherein the apparatus has a pronged sheath member;

[0286] Fig. 1J shows the electrospray apparatus of Fig. 11 when the sheath member is attached to a connector element;

[0287] Fig. 1 K shows the electrospray apparatus of Fig. 11 and Fig. 1J with a sample tube covering the sheath member;

[0288] Fig. 1 L shows the electrospray apparatus of Fig. 1 K when the sheath member is attached to a connector element;

[0289] Fig. 1 M shows a cross-sectional view of the electrospray apparatus of Fig. 11 and Fig. 1 J when the sheath member is attached to the connector element, and the connector element is attached to a housing body;

[0290] Fig. 1 N shows a back view of the electrospray apparatus of Fig. 1M and indicates the cutting plane for Fig. 1 M;

[0291] Fig. 10 shows an offset sectional view of the electrospray apparatus of Fig. 1M and Fig. 1 N;

[0292] Fig. 1P shows a back view of the electrospray apparatus of Fig. 10 and indicates the cutting plane for Fig. 10;

[0293] Fig. 2 shows a method of electrospraying a sample in accordance with embodiments of the present invention;

[0294] Figs. 3A-C show plots of data demonstrating the re-usability of a capillary of an electrospray apparatus in accordance with embodiments of the present invention;

[0295] Fig. 4 shows an electrospray apparatus in accordance with other embodiments of the present invention.

[0296] DETAILED DESCRIPTION

[0297] Figure 1A shows an electrospray apparatus 100 in accordance with an embodiment of the present invention. The apparatus 100 comprises a capillary 102 housed within a capillary housing 104. The capillary 102 is configured to act as an emitter that, in use, will emit charged droplets 106 of a sample via an electrospray process when the sample is provided to an outlet orifice 108 of the capillary 102 and the sample is electrified.

[0298] The outlet orifice 108 is located at an outlet end of the capillary 102 and may be sized to allow the capillary 102 to be suitable for use in a nano electrospray ionisation (NanoESI) process. For example, a diameter of the outlet orifice 108 at the downstream end may be less than 100 pm, less than 50 pm, or less than 25 pm and is preferably between 0.1 pm and 20 pm.

[0299] In use, a meniscus of the sample can form extending out of the capillary 102 at the outlet orifice 108 (e.g. in the form of a Taylor cone) and electrostatic stress within the sample resulting from its electrification can cause charged droplets 106 to be emitted from the meniscus. Successively smaller droplets may then be created from the charged droplets, e.g. by evaporation of the sample causing the droplets to decrease in size and burst into smaller droplets as a result of increasing electrostatic forces within the charged droplets 106 as they decrease in size. In an electrospray ionisation technique, this process can lead to gaseous phase ions emitted from the droplets being obtained for use, e.g. by entering the inlet 110 of a mass spectrometer for analysis.

[0300] The capillary 102 may be a pulled glass capillary comprising an electrically conductive (e.g. metallic) coating and the capillary housing may be configured to provide a voltage received from a voltage source 111 to the conductive surface of the capillary 102 to electrify the sample at the tip thereof. However, this is not essential, and in other embodiments the capillary 102 itself may be made from an electrically conductive material such that a coating is not required, or the capillary 102 may not have an electrically conductive surface and other means for electrifying the sample may be provided, such as by providing an electrode (e.g. wire, rod or needle) located within, upstream or downstream of the capillary 102.

[0301] Any suitable voltage for electrospraying a particular sample may be used. However, a voltage greater than 100 V is preferably supplied to the sample to electrospray it. For example, the voltage may be between 100 V and 10kV and is preferably between 200 V and 2 kV. The apparatus 100 comprises a conduit 112 configured to internally fill the capillary 102 with a sample to be emitted from the outlet 108 at the outlet end of the capillary 102. The conduit 112 enters the capillary 102 through a drain orifice 114 at an inlet end of the capillary 102 (the opposing end to the outlet end) and the conduit 112 extends within the capillary 102 from the inlet end towards the outlet end. The outlet of the conduit 112 may be arranged within the capillary 102 and proximate to the outlet end of the capillary 102, such that a sample can be supplied by the conduit to the outlet end of the capillary 102 without it being required to wet the entire length of the capillary 102. For example, an outlet 116 of the conduit 112 from which a sample can be supplied into the capillary 102 may be located at least 60%, 70%, 80% or 90% of the distance from the inlet end towards the outlet end of the capillary 102. In this regard, the conduit 112 preferably does not extend the entire length of the capillary 102 to enter into the outlet orifice 108. However, the conduit 112 extends within the capillary so that an outlet 116 of the conduit is proximate to the outlet orifice 108 of the capillary 102.

[0302] Locating an outlet 116 of the conduit 112 near to the outlet orifice 108 of the capillary 102 may more efficiently and reliably supply the outlet end of the capillary 102 with small sample volumes for electrospraying via the outlet orifice 108. For example, the apparatus 100 may be operable with sample volumes less than 10 pL.

[0303] The inlet end of the capillary 102 is open at the drain orifice 114 for receiving the conduit therein, and the drain orifice 114 is larger in size than the outlet orifice 108 (e.g. has a greater area or diameter). The capillary 102 may be substantially straight, with the drain orifice 114 and the outlet orifice 108 at the two opposing ends, and an internal diameter of the capillary 102 may be substantially constant in a direction from the inlet end towards the outlet end until reaching a tip portion of the capillary 118 at which point the internal diameter may decrease towards the outlet orifice 108, and the conduit 112 extends into the tip portion 118 of the capillary.

[0304] In use, surface energy / tension between the internal walls of the capillary 102 and a sample supplied into the capillary 102 can cause the sample to flow towards the outlet orifice 108 of the capillary 102. Other forces may also be employed as appropriate if required. For example, a pressure may be provided (e.g. with a pump) to convey the sample towards the outlet orifice 108 and / or at least during the supply of a sample into the capillary 102, the capillary 102 may be orientated so that gravity will assist the supply of sample to the outlet orifice 108 of the capillary 102. However, itis is not essential for the sample to require some external force or pressure to wet the tip of the capillary 102.

[0305] With continued reference to Figure 1A, the apparatus 100 comprises a supply housing 120 and a syringe pump 122 that can supply a sample to be electrosprayed into a portion of the conduit 112 that is housed within the supply housing 120. The supply housing 120 comprises a sample connector 124 that is adapted and configured for conveying a sample from the syringe pump 122 into the conduit 112. The sample connector 124 is shown in Figure 1A as a separate component connected to the conduit 112 but may otherwise be integral with the conduit 112. The sample connector 124 may be made of a thermoplastic such as PEEK. The conduit 112 extends from the supply housing 120 to the capillary housing 104 and into the capillary 102 for supplying a sample supplied from the syringe pump 122 to the outlet orifice 108 of the capillary 102. The supply housing 120 and the capillary housing 104 are separated by a flexible connection portion 126 through which the conduit 112 extends and that can allow for desired positioning of the capillary housing 104 and supply housing 120 in use. The flexible connection portion 126 may comprise, for example, a sheath made from a material such as plastic or other electrically insulating material that surrounds the conduit 112 and that can provide additional protection to the conduit 112. The flexible connection portion 126 may otherwise consist (entirely) of a portion of the conduit 112 alone. The flexible connection portion 126 may electrically isolate the supply housing 120 from a voltage applied downstream from the supply housing 120. This can ensure that a voltage applied to the sample does not pass to a user or some other upstream fluidic component.

[0306] The apparatus 100 is configured for the capillary 102 to be re-useable with different samples that are electrosprayed at different times. Between different samples, the apparatus 100 can flush the capillary 102 to remove previous sample remaining in the capillary 102. The apparatus 100 can flush the capillary 102 by supplying a flushing liquid into the capillary 102 via the conduit 112 and then optionally supplying a flushing gas into the capillary 102 via the conduit 112 to remove the flushing liquid.

[0307] The same syringe pump 122 may optionally be used to provide the sample, flushing liquid and gas. For example, to supply the flushing liquid into the conduit 112, the syringe pump 122 may be withdrawn from the sample housing 120, re-filled with the flushing liquid, and re-inserted into the sample housing 12 for supplying the flushing liquid via the sample connector 124 into the conduit 112. This may then be repeated to supply the flushing gas from the syringe pump 122 into the conduit 112 for conveying to the capillary 102.

[0308] However, any suitable supply device(s) may be used in place of the syringe pump 122. Optionally, one supply device capable of sequentially supplying different fluids into the conduit 112 without being withdrawn from the sample housing 120 may be used to supply at least two of the sample, flushing liquid and gas (and optionally all three). Different syringe pumps or other supply devices may otherwise be used for respectively supplying the sample, flushing liquid and gas into the conduit The capillary housing 104 comprises a drain 128 for receiving the flushing liquid from the capillary drain 114, and the apparatus 100 is configured for the flushing liquid to flow into the drain 128 via the drain orifice 114 of the capillary 102, e.g. when a flushing gas is supplied into the capillary 102 via the conduit 112. The capillary 102 may then be re-supplied with (another) sample via the conduit 112 for electrospraying. A bottle or other storage device (not shown) may be connected to the drain 128 for collecting fluid that has been flushed out of the capillary 102.

[0309] The flushing gas supplied into the capillary 102 may cause some portion of flushing liquid to flow out of the outlet orifice 108 of the capillary. As discussed below, this may also or otherwise occur due to an applied voltage being maintained to the capillary 102 during flushing. However, it is not essential that flushing liquid flows out of the outlet orifice 108, and fluid pressure characteristics on account of the larger size of the drain orifice 114 compared to the outlet orifice 108 of the capillary can result in flushing gas supplied into the capillary 102 forcing substantially all of the flushing liquid to flow out of the drain orifice 114 of the capillary 102.

[0310] The voltage supplied by the apparatus 100 for electrospraying may be stopped while the capillary 102 is flushed. However, in embodiments, the voltage may be supplied while the capillary contains flushing liquid, which may result in a portion of the flushing liquid being electrosprayed via the outlet orifice 108 of the capillary 102. This can allow the same voltage to be maintained throughout use, if desired, and may ensure the outlet end of the capillary 102 has any sample remaining therein removed.

[0311] Any suitable flushing liquid may be used, and a particular flushing liquid may be selected for a particular sample. The flushing liquid is preferably miscible with the previously used (sprayed) sample and may be a solvent for the sample. For example, the flushing liquid may comprise or consist of a solvent that the sample also comprises, e.g. where the sample (but not the flushing liquid) contains an analyte dissolved in the solvent. Any suitable flushing gas may be used, such as air or an inert gas such as nitrogen.

[0312] Using the apparatus 100 to flush and re-fill the capillary 102 with sample via the conduit in the manner disclosed herein may allow the capillary 102 and capillary housing 104 to remain in a fixed position while it is flushed and re-filled with (another) sample. This avoids the capillary 102 needing to be removed from the capillary housing 104 in order to be re-filled (or discarded) after use with a first sample.

[0313] However, nevertheless, the capillary 102 is preferably removable from the capillary housing 104. This can allow for replacement of the capillary 102 when appropriate (e.g. if the capillary 102 becomes damaged). Furthermore, in particular embodiments the outlet end of the capillary 102 may be wet with a fluid by other means, such as via centrifuging, before the capillary 102 is inserted into the capillary housing 104. For example, this may be performed before that capillary 102 is first used in the apparatus 100. Once the outlet end has been wet by a fluid, the outlet orifice 108 may retain some small portion of a fluid (e.g. sample and / or flushing liquid) throughout its use (including when flushed) that will allow a next sample to be more reliably conveyed to the outlet orifice 108 of the capillary when supplied via the conduit 112. This may be achieved without significantly affecting the composition of samples emitted via the outlet orifice 108 the capillary 102 on account of the small quantity size of any fluid that remains at the outlet orifice 108 of the capillary 102 after flushing.

[0314] Figure 1B shows an electrospray apparatus 130 in accordance with another embodiment of the present invention. The electrospray apparatus 130 comprises a capillary housing 134 having a different structure to the capillary housing 104 of the electrospray apparatus 100 of Figure 1A. However, other components and functionality of the electrospray apparatus 100 of Figure 1A may be used with the electrospray apparatus 130 of Figure 1 B (such as the sample housing 120 and the capillary 102) and like reference numerals are used for like components in the following description of Figure 1 B.

[0315] The capillary housing 134 comprises a housing body 136 and a capillary holder 138 removably attached to the housing body 136. The capillary holder 138 secures the capillary 102 therein and can be removed from the housing body 136 without removing the capillary 102 from the capillary holder 138. The capillary holder 138 may comprise a removable cap or sheath (not shown) for enclosing (and thereby protecting) the outlet end of the capillary when not in use. The capillary holder 138 comprises a conical inlet 140 for guiding the conduit 112 into the drain orifice 114 of the capillary 102. Gas and liquid may flow through the conical inlet 140 external to the conduit 112 and into and out of the capillary 102 via the drain orifice 114.

[0316] The capillary housing 134 comprises a chamber 142 therein and a gas inlet conduit 144 having a valve 146 (e.g. pneumatic valve) for controlling the supply of a pressurising gas into the chamber 142 from the gas inlet conduit 144. The capillary housing also comprises a drain conduit 148 having a valve 150 (e.g. pneumatic valve) for controlling the flow of fluid out of the chamber 142 via the drain conduit 148.

[0317] A bottom wall 151 of the chamber 142 is angled to remove liquid from the chamber 142 into the drain conduit 148 (and the capillary 102 is also angled downwards when secured within the capillary housing 134 to assist in the flow of sample to the outlet orifice 108). The capillary housing 134 further comprises a conduit holder 152 for securing the conduit 112 within the capillary housing 134 so that the conduit 112 is at a fixed location within the capillary 102 (when the capillary 102 and capillary holder 138 are attached to the housing body 136). The conduit holder 152, gas inlet conduit 144 and drain conduit 148 are all removably attachable from the housing body 134 (but this is not essential). The conduit holder 152 may retain the conduit 112 secured therein when the conduit holder 152 is removed from the housing body 136.

[0318] The conduit 112 comprises an electrically insulating conduit portion 112a extending into the conduit holder 152 and that is joined to an electrically conductive conduit portion 112b of the conduit 112 at a joint 154 within capillary housing 134. The electrically insulating conduit portion 112a may, for example, comprise a flexible tube (e.g. made of plastic material, for example a thermoplastic material such as PEEK) and the electrically conductive conduit portion 112b may comprise a (rigid) metal (e.g. stainless steel) tube for insertion into the capillary 102. An electrically conductive tube 155 surrounds the joint 154 between the electrically insulating conduit portion 112a and the electrically conductive conduit portion 112b and the electrically conductive tube 155 extends downstream from the joint 154. The electrically conductive tube 155 does not extend upstream out of the conduit holder 152 to avoid external components from being electrified and reduce the possibility of a user suffering an electric shock. Downstream of the joint 154, the electrically conductive tube 155 has tabs 156 extending inwards and making electrical contact with the electrically conductive conduit portion 112b within the capillary housing 134. Upstream from the joint 154 a ferrule 158 is in electrical contact with the electrically conductive tube 155 and in use a voltage may be applied to the ferrule and conveyed to the sample to electrify the sample via the electrically conductive tube 155 and the electrically conductive conduit portion 112b.

[0319] An enlarged view of a section of the electrically conductive tube 155 and sections of the electrically conductive conduit portion 112b and electrically insulative conduit portion 112a is shown in Figure 1 C, that also best shows the structure of the tabs 156 that contact the electrically conductive conduit portion 112b.

[0320] As shown in Figure 1 C, the conductive tube 155 comprises a fluid bleed hole 160 so that if the joint 154 fails fluid flowing into the electrically conductive tube 155 from the joint 154 can leak out into the chamber 142 via the fluid bleed hole (160) rather than potentially leaking out of the capillary housing 134 via the conduit holder 152 which could potentially pose a hazard to users.

[0321] These means of electrifying the sample described in connection with Figures 1B and 1C are not essential and alternative electrodes / means may be provided. However, when the conduit 112 is used to electrify the sample, the electrically conductive conduit portion 112b of the conduit 112 preferably does not extend out of the capillary housing 134 such that it can not pose an electrical hazard to users.

[0322] In use, a sample is supplied into the capillary 102 through the electrically conductive conduit portion 112b. A pressurising gas may be supplied into the chamber 142 via the gas inlet conduit 144 (through the open valve 146 of the gas inlet conduit 144) and the valve 150 of the drain conduit 148 may be maintained closed so that the pressure of the pressurising gas within the chamber 142 increases as the amount of gas supplied into the chamber 142 increases. The pressurising gas is supplied into the capillary 102 from the chamber 142 via the drain orifice 114 and forces the sample towards the outlet orifice 108. Forcing the sample towards the outlet orifice 108 in this manner can reduce any air bubbles present within the portion of the capillary 102 intended to be occupied by the sample. After the sample has been forced towards the outlet orifice 108 by the pressurising gas, the valve 150 of the drain conduit 148 may be opened (and the valve 146 of the gas inlet conduit 144 optionally closed) to allow pressurising gas to be released therethrough and thereby reduce the pressure of the pressurising gas within the capillary 102. This may be done before or after the sample is emitted from the outlet orifice 108 by electrospraying. To electrospray the sample, the sample is electrified by a voltage being applied to the electrically conductive conduit portion 112b (via the ferrule 158 and conductive tube 155). Electrifying the sample causes charged droplets of a sample to be emitted from the outlet orifice 108. To flush the sample out of the capillary 102, a flushing liquid is supplied into the capillary 102 via the conduit 112 to flush out the sample from the capillary 102 through the drain orifice 114, optionally followed by a flushing gas being supplied into the capillary 102 via the conduit 112 so as to force the flushing liquid out of the capillary 102 through the drain orifice 114. The valve 150 of the drain conduit 148 is opened prior to the sample being flushed out of the capillary 102 so as to reduce the pressure of the pressurising gas to prevent this from otherwise counteracting the flow of liquid out of the capillary 102. The valve 150 of the drain conduit 148 is maintained open during flushing to allow the sample and flushing liquid to be removed from the chamber 142 via the drain conduit 148. The valve 146 of the gas inlet conduit 144 may be maintained open (or re-opened if earlier closed) to allow gas to (continue to) flow into the chamber 142 from the gas inlet conduit 144 to assist in flushing liquid out of the chamber 142 and into the drain conduit 148. When a next sample is to be, or has been, supplied into the capillary 102 (after the previous sample has been flushed into the drain), the valve 150 of the drain conduit 148 may be closed so that pressurising gas supplied into the chamber 142 can again be supplied into the capillary 102 at an appropriate pressure to force the next sample towards the outlet orifice 108. Although the gas inlet conduit 144 is described as having a valve 146 this is not essential, and the pressure within the chamber 142 can be controlled while gas continues to be supplied into the chamber 142 using the opening or closing of the valve 150 of the drain conduit 148 and / or the flow of gas into the chamber 142 may otherwise be stopped or started using some other upstream component that supplies the pressurising gas.

[0323] Although the capillary housing 104 of Figure 1A is not described as having certain components of the capillary housing 134 of Figure 1 B, any of the components of the capillary housing 134 of Figure 1 B may be provided to the capillary housing 104 of Figure 1A, such as the capillary holder 138, conduit holder 152, gas inlet conduit 144 and / or drain conduit 148.

[0324] Optionally, the gas inlet conduit 144 and / or drain conduit 148 may connect to (or be integral with) the conduit holder 152 instead of being separately attachable to the housing body 136.

[0325] The flushing of sample(s) from the capillary 102 is described further below with reference to Figure 2.

[0326] Figures 1D and 1 E show an electrospray apparatus 160 in accordance with another embodiment of the present invention. The electrospray apparatus 160 is shown inserted into an orifice 162 of a mass and / or ion mobility spectrometer 163. The electrospray apparatus 160 comprises a capillary housing 164 having a different structure to the capillary housing 104 of the electrospray apparatus 130 of Figure 1B. However, other components and functionality of the electrospray apparatus of Figures 1 A and 1 B may be used with the electrospray apparatus 160 of Figures 1D and 1 E (such as the sample housing 120 and the capillary 102) and like reference numerals are used for like components in the following description of Figures 1 D and 1E.

[0327] The capillary housing 164 comprises a housing body 166 and a capillary holder 168. The capillary holder 168 differs from the capillary holder 138 of Figure 1B in that it comprises a sheath assembly 170, however, the capillary holder 168 of Figures 1D and 1 E may be used with the housing body 136 of Figure 1 B.

[0328] With continued reference to Figures 1 D and 1E, the capillary holder 168 supports a capillary 102 therein surrounded by the sheath assembly 170. The capillary housing 164 secures a conduit 112 therein, optionally in the same manner as the capillary housing 134 of Figure 1B.

[0329] The sheath assembly 170 comprises a supporting body 172 that surrounds a portion of the capillary 102 and a retractable sheath 174 that surrounds the supporting body 172 and is movable relative to the supporting body 172. The retractable sheath 174 is movable between an extended position (shown in Figure 1 D) and a retracted position (shown in Figure 1E). In the extended position, the retractable sheath 174 surrounds the outlet end of the capillary 102 to protect the capillary when not in use. In the retracted position, the capillary extends through an orifice 176 in the retractable sheath 174 such that the outlet end of the capillary 102 extends outward beyond the retractable sheath 174. The capillary holder 168 comprises a sealing element 177 to prevent liquid flushed out of the capillary from leaking out through the sheath assembly 170.

[0330] The retractable sheath 174 is biased towards the extended position by a first (longitudinal) spring 178 that co-axially surrounds the capillary 102 inside the retractable sheath 174. A second (annular) spring 180 is located between the supporting body 172 and the retractable sheath 174 with the axis of the second spring 180 curved around the supporting body 172. In the extended position, the second spring 180 is contracted within a first annular recession 182a in the supporting body 172 in contact with a flat wall of the first annular recession 182a to prevent further extension of the retractable sheath 174. As the retractable sheath 174 is retracted away from the outlet end of the capillary by sliding along the supporting body 172, the second spring 180 is forced to expand as it travels along a sloped wall of the first annular recession 182. The supporting body 172 comprises a second annular recession 182b to limit the extent to which the retractable sheath can slide along the supporting body 172 away from the outlet end of the capillary 102. The retractable sheath 174 comprises a protruding rim 184 extending radially outward to engage a surface of the mass and / or ion mobility spectrometer as the capillary 102 is inserted through the orifice 162 of the mass and / or ion mobility spectrometer 163, such that the protruding rim 184 will contact the surface of the spectrometer 163 and cause the sheath 174 to retract (and the first spring 180 to contract) as the capillary is inserted further into the spectrometer 163. Alternative arrangements for biasing the retractable sheath 174 towards the extended position and limiting the extent to which the retractable sheath can slide relative to the capillary 102 may be provided. Alternative means for causing the sheath 174 to retract may also be provided.

[0331] The capillary holder 168 comprises a bore 186 for conveying the conduit 112 into the capillary 102. The bore 186 has a conical inlet for guiding the conduit 112 into the bore 186. The capillary holder 168 is detachable from the housing body 166 without removing the capillary 102 from the capillary holder 168 and without removing the conduit 112 from the housing body 166. The capillary holder 168 and housing body 166 comprise respective threads for connecting one to the other, however, any other suitable means of attachment may alternatively be provided.

[0332] Figures 1F, 1G and 1H show an electrospray apparatus 190 in accordance with another embodiment of the present invention. Figure 1G shows a cross-sectional view of the apparatus 190, and Figure 1H shows an enlarged view of a sample being electrosprayed from an outlet orifice 108 of a capillary 102 of the apparatus 190.

[0333] The electrospray apparatus 190 comprises a capillary holder 191 that differs from the capillary holder 138 of Figure 1 B and the capillary holder 168 of Figure 1 D and 1 E in that it comprises an electrospray emitter assembly 192 having a sheath electrode 193. However, other components and functionality of the electrospray apparatus of Figures 1A- 1E may be used with the electrospray apparatus 190 of Figures 1 F-1 H. For example, a capillary 102 secured within the capillary holder 191 may be in accordance with the capillary described in relation to any of Figures 1A-1 E, a sample housing 120 in accordance with Figure 1 A may be provided, and like reference numerals are used for like components in the following description of Figures 1F-1 H.

[0334] The electrospray emitter assembly 192 comprises a sheath member in the form of a sheath electrode 193 (though in other embodiments an electrode may from only part of the sheath member). The capillary 102 (e.g. a glass capillary), and a ferrule 194 fixed to the capillary 102 and the sheath electrode 193 such that the ferrule 194 supports the sheath electrode in a co-axial arrangement with the capillary and such that the sheath electrode

[0335] 193 surrounds the capillary 102 along the axial length of the capillary 102.

[0336] The capillary holder 191 further comprises a connector element 195 that the electrospray emitter assembly 192 is attached to. The connector element 195 is attached to the electrospray emitter assembly 192 using a canted spring 195a between the connector element 195 and sheath electrode 193, and an o-ring 195b between the ferrule

[0337] 194 and the connector element 195 forms a fluid-tight seal. However, any alternative or additional attachment or sealing means may be provided, such as a threaded fitting, snap fit or press-fit mechanism.

[0338] The electrospray emitter assembly 192 is attachable to (and removable from) the connector element 195 while maintaining the sheath electrode 193 in a fixed position relative to the capillary 102. The electrospray emitter assembly 192 can therefore be provided as an easy to fit consumable without requiring subsequent alignment of the sheath electrode 193 relative to the capillary 102.

[0339] The connector element 195 may be operable with different electrospray emitter assemblies, such as that have capillaries of differing dimensions (e.g. different outlet orifice diameters) or different electrode arrangements. The connector element 195 is optionally compatible with a sheath assembly having a retractable sheath, such as the sheath assembly 170 described above in relation to Figures 1D and 1 E. The capillary holder 191 may be attachable to a housing body 166 of a capillary housing having features in accordance with that of the capillary housing 134 of Figure 1 B, or the capillary housing 164 of Figures 1 D and 1E.

[0340] The electrospray emitter assembly 190 further comprises a conduit 112 that extends through a bore 195c in the connector element 195 to the capillary 102, and is inserted into the capillary 102 via a drain orifice 114 of the capillary. As described above in relation to Figure 1A and Figure 1B, the conduit can supply a sample to the outlet orifice 108 of the capillary, and the drain orifice 114 may be used to supply a pressurising gas to force the sample within the capillary 102 towards the outlet orifice 108 and / or to allow the sample to be flushed out of the capillary (in which case the pressurising gas and / or sample flushed out of the capillary also passes through the bore 195c in the connector element 195). The bore 195c has a conical inlet for guiding the conduit 112 into the capillary 102.

[0341] The sheath electrode 193 protects the capillary 102 from accidentally being collided with another object during assembly of the apparatus, and can protect a user from being accidentally stabbed by the capillary 102. However, the sheath electrode 193 also acts as a counter electrode that can provide a potential difference between electrified sample 196 within the capillary 102 and a region external to the outlet end of the capillary 102, so as to cause charged droplets 106 to be emitted from the outlet orifice 108 of the capillary 102.

[0342] The sheath electrode 193 extends axially outward beyond (and downstream from) the outlet orifice 108 of the capillary and comprises an outlet aperture 197 (shown in Figure 1H) that the apparatus 190 is configured for charged droplets 106 emitted from the outlet orifice 108 of the capillary 102 to pass through.

[0343] The sheath electrode 193 further comprises a plurality of side apertures 198 that surround (and have a same axial position as) the outlet orifice 108 of the capillary 102. The side apertures 198 allow the outlet end of the capillary 102 to be viewed so as to monitor the electrospray process when in use (e.g. to verify the removal of any air bubbles present at the outlet end of the capillary 102). The outlet aperture 197 and side apertures 198 also define the electric field shape in the region external to the outlet end of the capillary 102 for controlling the emission and propagation of charged droplets electrosprayed from the capillary 102.

[0344] Figures 11 and 1J show a capillary holder 201 in accordance with another embodiment of the present invention. The capillary holder 201 comprises an electrospray emitter assembly 202 comprising a sheath member in the form of a pronged sheath electrode 203. Other components and functionality of the electrospray apparatus of Figures 1A-1 E may be used with the capillary holder 201 of Figures 11 and 1 J. For example, a capillary (not shown) secured within the capillary holder 201 may be in accordance with the capillary 102 described in relation to any of Figures 1A-1 H, a sample housing 120 in accordance with Figure 1A may be provided, and the capillary holder 201 can form part of a capillary housing, such as the capillary housing 134 of Figure 1 B, or the capillary housing 164 of Figures 1 D and 1E, such as by attachment to a housing body 166 described in relation to Figure 1B.

[0345] A ferrule 204 is fixed within the sheath electrode 203. The ferrule 204 can support a capillary in a co-axial arrangement with the sheath electrode 203, such that ferrule 204 is located radially between the capillary and the sheath electrode 203. The ferrule 204 may be in accordance with the ferrule 194 described in Figures 1F-1 H.

[0346] The capillary holder 201 further comprises a connector element 205 that the electrospray emitter assembly 202 is removably attachable to. Figure 11 shows the electrospray emitter assembly 202 disconnected from the connector element 205, whereas Figure 1 J shows the connector element 205 and electrospray emitter assembly 202 connected to one another.

[0347] The electrospray emitter assembly 202 is attachable to (and removable from) the connector element 205 while maintaining the sheath electrode 203 in a fixed position relative to a capillary secured therein. The electrospray emitter assembly 202 can therefore be provided as an easy to fit consumable without requiring subsequent alignment of the sheath electrode 203 relative to the capillary.

[0348] The connector element 205 may be operable with different electrospray emitter assemblies, for example that have capillaries of differing dimensions (e.g. different outlet orifice diameters) or different electrode arrangements.

[0349] The sheath electrode 203 extends in an axial direction 207 between a connector end 203a and a distal end 203b. Between the connector end 203a and distal end 203b the sheath electrode 203 comprises a circumferential wall 209 for surrounding a portion of the axial length of a capillary when the capillary is held within the ferrule 204. The sheath electrode 203 further comprises four prongs 211 (though other numbers of prongs may be provided) that extend axially downstream from the circumferential wall 209. The prongs 211 are spaced apart in a circumferential direction 212 to define gaps 213 therebetween. When a capillary is located within the sheath electrode 203 (and ferrule 204), the prongs 211 may extend axially downstream from the outlet orifice of the capillary, such that the outlet orifice of the capillary can be viewed from a radial direction via the gaps 213, and such that the sheath electrode 203 can provide a potential difference between a sample within the capillary and a position downstream of the outlet orifice of the capillary (by applying an electrical potential to the prongs). By applying such a potential difference, the sheath electrode 203 can act as a counter electrode and cause the sample to be electrosprayed from the capillary.

[0350] To attach the sheath electrode 203 to the connector element 205, and thereby position the capillary within the capillary holder 201 , the sheath electrode 203 comprises a collar portion 215 and a flexible arm 217 connected to the collar portion 215. The collar portion 215 is arranged to fit over a circumferential wall 219 of the connector element 205 that surrounds a bore 221 for supplying a sample into the capillary. During connection of the sheath electrode 203 to the connector element 205, the ferrule 204 is inserted into the bore 221, and the ferrule 204 comprises a sealing element 204a for forming a fluid tight seal with the circumferential wall 219 to prevent sample leaking out of the capillary holder 201 when the sample is supplied into the capillary.

[0351] When the ferrule 204 is inserted into the bore 219, the collar portion 215 surrounds the circumferential wall 219 of the connector element 205 and an engagement structure 223 protruding from the circumferential wall 219 of the connector element 205 is slid (axially) into a circumferential slot 225 within the sheath electrode 203. The sheath electrode 203 is then rotated relative to the connector element 205 which causes the flexible arm 217 to be displaced away from the distal end 203b of the sheath electrode 203 by the engagement structure 223 contacting a protrusion 217a at a free end of the flexible arm 217. When the protrusion 217a passes the end of the engagement structure 223, the flexible arm returns towards the distal end 203b of the sheath electrode 203 so that a snap fit connection is formed with the engagement structure 223 held between the protrusion 217a and the collar portion 215. This secures the sheath electrode 203 and capillary (within the ferrule 204) at a predetermined position relative to the connector element 205.

[0352] To disconnect the sheath electrode 203 from the connector element 205, the sheath electrode 203 can be rotated in a reverse direction to that used to connect the two components, which cases the flexible arm 217 to be displaced and the engagement structure 223 released so that it can be removed from the circumferential slot 225.

[0353] Although Figures 11 and 1 J show a sheath electrode 203 with both prongs and a flexible arm 217, this combination is not essential and other means of connection may be provided for a pronged sheath electrode, and a snap fit connection may be used to connect a sheath electrode that does not comprise prongs.

[0354] Figures 1K and 1L show the capillary holder 201 of Figures 11 and 1J with a cover 227 surrounding the distal end 203b of the sheath electrode 203. Figure 1K shows the sheath electrode 203 disconnected from the connector element 205 whereas Figure 1L shows the sheath electrode 203 connected to the connector element 205. Like reference numerals are used for like components. The cover 227 may be in the form of a standard sample tube and extends to the collar portion 215 of the sheath electrode 203. By providing the cover 227 in the form of a standard sample tube, the capillary and sheath electrode 203 can be together conveniently inserted into a centrifuge (to wet the end of the capillary) by surrounding the sheath member 203 with the cover 227 and inserting the cover 227 into the centrifuge. The sheath member 203 can be connected to the connector element 205 while surrounded by the cover 227, and the cover 227 can then be removed once the sheath member 203 and connector element 205 are connected to one another. The cover 227 comprises a lid 229, and when the cover has been removed from the sheath member 203 the lid 229 may be closed to seal the cover 227 and reduce the risk of contamination.

[0355] Figure 1M shows, in cross-section, an electrospray apparatus 230 comprising a capillary housing 231. the capillary housing 231 comprises the capillary holder 201 of Figures 11 and 1 J and a housing body 232. The housing body 232 comprises some of the same features as the housing body 136 of Fig. 1B, and like reference numerals are used for like components in the following description of Figure 1M.

[0356] The capillary holder 201 comprises an emitter assembly 202 and a connector element 205. The capillary holder 201 is removably attached to the housing body 232 via fasteners 233 that secure the connector element 205 to the housing body 232. The emitter assembly 202 secures a capillary 102 therein and is removably attached to the connector element 205 via a collar portion 215 that surrounds a circumferential wall 219 of the connector element 205 and engages the engagement structure 223 of the connector element 205. The emitter assembly 202 can be removed from the connector element 205 without removing the capillary 102 from the emitter assembly 202. As described above, the capillary holder 202 comprises a pronged sheath electrode 203 and the sheath electrode comprises gaps 213 between the prongs 211 for viewing the capillary 102. The emitter assembly also comprises a ferrule 204 that fixes the position of the capillary 102 relative to the sheath electrode 203. The ferrule 204 is inserted into a bore 221 of the connector element 205 and a sealing element 204a forms a fluid tight seal with the circumferential wall 219 to prevent fluid leaking out of the capillary holder 201. The bore 221 has a conical inlet for guiding a conduit 112 into the capillary 102. Gas and liquid may flow through the bore 221 external to the conduit 112 and into and out of the capillary 102.

[0357] The housing body 232 comprises a chamber 234 therein and a drain conduit 148. The drain conduit 148 may have a valve 150 for controlling the flow of fluid out of the chamber 234 via the drain conduit 148. The capillary housing 232 further comprises a conduit holder 152 for securing the conduit 112 within the capillary housing 232, and the conduit holder 152 and conduit 112 are described above in relation to Figure 1 B and Figure 1C. An insulating portion 112a of the conduit 112 has, at an upstream end of the conduit 112, a connector 235 for connection to a sample housing (such as the sample housing 120 described above in relation to Figure 1A).

[0358] The conduit holder 152 can electrify a sample within the capillary 102 by a voltage being supplied to a first electrical terminal 236, and the first electrical terminal 236 supplying the voltage to the sample via the conduit 112, for example in the same manner as described above in relation to Figure 1 B and Figure 1C. The capillary housing 231 also comprises a second electrical terminal 237 for supplying a voltage to the sheath electrode 203 via the connector element 205. Accordingly, by supplying different voltages to the first electrical terminal 236 and the second electrical terminal 237, a potential difference can be maintained between a sample in the capillary 102 and the sheath electrode 203, such that the sheath electrode 203 can act as a counter electrode 203 to cause the sample to be electrosprayed out of the capillary 102.

[0359] Figure 1N shows a back view of the apparatus of Figure 1M, and like reference numerals are used for like components. Figure 1N shows the cutting plane 238 for the cross-sectional view of Figure 1M. As shown in Figure 1 N (but not visible in Figure 1M), the capillary housing 231 comprises a gas inlet conduit 144 described above in relation to Figure 1B, and the gas inlet conduit 144 can supply a pressurising gas into the chamber 234. The pressurising gas can then be supplied into the capillary 102 from the chamber 234 to force the sample towards the outlet of the capillary 102.

[0360] Figure 10 shows a sectional view of the apparatus of Figure 1M and Figure 1 N, where the path for the pressurising gas to be supplied into the chamber 234 via the gas inlet conduit 144 is better shown.

[0361] Figure 1 P shows a back view of the apparatus of Figure 1 M, Figure 1 N and Figure 10, and shows the cutting plane for the sectional view of Figure 10.

[0362] Figure 2 shows a flow diagram of a method 240 of electrospraying a sample in accordance with an embodiment of the present invention. The method can be performed using the apparatus 100 shown in any of Figures 1A-1P, and will be described with refence to the same components described above in relation to Figures 1A and 1 B.

[0363] When the capillary 102 contains a sample for electrospraying (step 241), a voltage is supplied to the sample to emit the sample via the outlet orifice 108 of the capillary 102 (step 242). After the sample has been emitted via the outlet orifice 108 of the capillary 102, the capillary 102 may then be flushed (step 243). To flush the capillary 102, a flushing liquid is supplied into the capillary 102 via the conduit 112 (step 243a) before a flushing gas is supplied into the capillary 102 via the conduit 112 (step 243b) to remove the flushing liquid from the capillary 102. The flushing liquid may cause sample remaining in the capillary 102 after the electrospraying step to be flushed out of the capillary 102 via the drain orifice 114 of the capillary. The flushing gas supplied into the capillary 102 via the conduit 112 can then expel the flushing liquid through the drain orifice 114 of the capillary 102 to render the capillary 102 substantially empty of any liquid and ready to receive a next sample. After flushing liquid has been removed from the capillary 102 using the flushing gas, a next sample to be electrosprayed can be supplied into the capillary 102 via the conduit 112 (step 244) and the process may be repeated until all of the desired samples have been electrosprayed. As sample, flushing liquid and gas are all supplied into the capillary via the (same) conduit 112, the flushing liquid can also remove residual sample from the conduit 112 via the capillary 102, and the flushing gas can also expel flushing liquid residing in the conduit 112 out in the capillary 102, and then out of the drain orifice 114 of the capillary 102, to thereby avoid or reduce contamination of a next sample from occurring within the conduit 112 (and any other part of the electrospray apparatus 100; 130 upstream of the capillary 102).

[0364] Figures 3A-C show plots of data demonstrating that flushing a capillary in the manner disclosed herein can remove substantially all of a sample previously supplied into the capillary. The plots of data were obtained by analysing ions obtained via electrospray ionisation using an electrospray apparatus 100 described above in relation to Figure 1A.

[0365] Figure 3A shows a mass spectrum acquired by analysing ions obtained from a solution of Bovine Serum Albumin (BSA). The mass spectrum was acquired for 1 minute for a 10 pl sample of 10 pM BSA dissolved in 150 mM Ammonium Acetate.

[0366] Figure 3B shows a mass spectrum acquired by analysing ions generated using the electrospray apparatus 100 with the same capillary 102 and conduit 112 but following a flushing cycle to remove the solution of BSA from the capillary 102. The mass spectrum was acquired for 1 minute following a flushing cycle using 250 pL of 150 mM Ammonium Acetate as a flushing liquid, followed by 250 pL of air.

[0367] The mass spectra of Figures 3A and 3B are shown with relative ion intensities based on different respective absolute intensities representing the 100% relative intensity value for the two plots. Comparison of the absolute ion signal for the mass spectrum in Figure 3A and the mass spectrum in Figure 3B indicates that the proportion of ions from the sample measured after the flushing cycle compared to before the flushing cycle is approximately 0.08%. Correspondingly, the number of ions from the sample detected after flushing is more than 1000 times lower compared to before flushing. This shows that substantially all of the sample is removed from the capillary 102 of the electrospray apparatus 100 after a flushing cycle. Figure 3C shows a plot of relative intensity against time measured by analysing ions obtained across sample injections and flushing cycles of the electrospray apparatus. The y-axis shows combined relative intensity of ions in the m / z range 3700-5200. Periods 301a and 301b are each during injection of the same BSA sample into the electrospray apparatus. Periods 302a and 302b are each during a flushing cycle. It can be seen that the ion signal intensity for the second injection of the sample (during period 301 b) is of an amount similar to that of the first injection of the sample (during period 301a), demonstrating that reasonably reproducible signals may be obtained before and after a flushing cycle.

[0368] Figures 4A-B show an electrospray apparatus 400 in accordance with another embodiment of the present invention.

[0369] Figure 4A shows the apparatus 400 when receiving a liquid sample 401. The apparatus 400 comprises an emitter 404 comprising a capillary 402. A flushing liquid 406 that is immiscible with the sample 401 is held within the capillary 402 between a displacement device 408 and an orifice 410 of the conduit via which the sample 401 may be transferred into the capillary 402 from a sample container 412 (e.g. a vial or plate having the liquid sample stored thereon e.g. as part of tissue or an individual cell). The displacement device 408 may be, for example, a syringe plunger. The flushing liquid 406 may, for example, be an oil. The displacement device 408 may be in the form of a plunger and, prior to transferring the sample 401 into the capillary 402, the flushing liquid 406 may be transferred into the capillary 402 by moving the displacement device 408 in a first direction 414 while immersing the orifice 410 in an external volume of the flushing liquid. Moving the displacement device 408 in the first direction 114 increases the volume of fluid that can be held within the capillary 402 to thereby aspirate the flushing liquid 406 through the orifice 410 into the capillary 402. After the flushing liquid 406 has been transferred into the capillary 402, a sample 401 can then be transferred into the capillary 402 in the same manner as the flushing liquid 406, by moving the displacement device 414 further in the first direction 114 while the orifice 410 is immersed in a volume of the sample 401 stored by the sample container 412, to increase the volume of fluid that can be held within the capillary 402 and thereby aspirate the sample 401 into the capillary 402.

[0370] Figure 4B shows the apparatus 400 being used to generate droplets 416 by electrospraying a sample 401 that has been transferred into the capillary 402 via the orifice 410. When the sample 401 is transferred into the capillary 402, the sample 401 is located in the capillary 402 between the orifice 410 and the flushing liquid 406, and the flushing liquid 406 is located in the capillary 402 between the displacement device 408 and the sample 401. To electrospray droplets of the sample 401 a voltage supplied from a voltage source 411 is applied to electrify the sample 401. The voltage source 411 may be contained within the emitter 404 or may be a separate component connected to the emitter 404. Any suitable voltage for electrospraying a particular sample may be used. However, a voltage greater than 100 V is preferably supplied to electrospray a sample. For example, the voltage may be between 100 V and 10kV and is preferably between 200 V and 2 kV. The apparatus is configured to electrify the sample 401 using the voltage in any suitable manner. For example, the flushing liquid 406 and or displacement device 408 may be electrified to electrify the sample 401 by transferring charge thereto, or the sample 401 may be electrified without electrifying the flushing liquid 406 (or at least without requiring flushing liquid 406 to be electrified to electrify the sample 401). The capillary 402 may comprise an electrically conductive surface configured for conveying the voltage to the sample 402. The conductive surface may be a coating, in which case the capillary 402 may comprise a non-conductive material, for example the capillary 402 may be a pulled glass capillary or a ceramic capillary. However, the conductive surface may otherwise be provided by the capillary 402 being manufactured out of a conductive material e.g. a metal.

[0371] Electrification of the sample 401 may be sufficient by itself to cause the sample to be emitted from the capillary 402 by the orifice 410 and form droplets 416. However, the displacement device 408 may be operated to decrease the volume of fluid that can be held within the capillary 402 to displace the liquid sample 401 within the capillary 402 towards the orifice 410 and thereby assist with the wetting of the orifice 410 and emission of the sample 401 therefrom. The displacement device 418 can be operated to decrease the volume of fluid that can be held within the capillary 402 by being moved in a second direction 418 that is opposite to the first direction 414.

[0372] When performing ESI (or nanoESI), the droplets emitted by the apparatus 400 may generate or release ions that can be transferred into the inlet 420 of a mass spectrometer for analysis in any suitable manner.

[0373] The displacement device 418 may continue to be operated during electrospraying, and / or may be operated after electrospraying, to decrease the volume of fluid that can be held within the capillary 402. This can result in sample 401 remaining inside the capillary 402 being expelled from the orifice 410 (either via electrospray or being discarded) by operating the displacement device to displace the flushing liquid 406 towards and orifice 410 and thereby displace the remaining sample 401 towards and out of the orifice 410. The displacement may take place until (only) a portion of the flushing liquid 406 is expelled from the orifice 410. This can avoid any “dead volume” of liquid sample 401 remaining inside the capillary 402 before another sample may be transferred into the capillary 402 (e.g. in the same manner as for the previous sample).

[0374] Thus, the apparatus 400 is reusable with the same capillary 402 of the emitter 404 being operable to be used with different samples. Furthermore, eliminating the dead volume can allow the apparatus 400 to be used with small volumes of liquid sample. For example, the volume transferred into the capillary 402 may be less than 1 pL, or may be less than 500 nL.

[0375] Although the present invention has been described with reference to preferred embodiments, it will be understood by those skilled in the art that various changes in form and detail may be made without departing from the scope of the invention as defined by the accompanying claims.

Claims

163189-03v3Claims1. An electrospray apparatus, comprising: a capillary having an outlet orifice for electrospraying a sample therefrom; and a conduit extending into the capillary in a manner such that it is able to deliver said sample into the capillary; wherein the apparatus is configured to supply a pressurising gas into the capillary so as to force said sample within the capillary towards the outlet orifice.

2. The electrospray apparatus of claim 1 , wherein the outlet orifice has a diameter that is less than 100 pm.

3. The electrospray apparatus of claim 1 or 2, wherein the capillary comprises an inlet orifice, the conduit is inserted into the capillary through the inlet orifice, and the apparatus is arranged for the pressurising gas to be supplied into the capillary via the inlet orifice and external to the conduit.

4. The electrospray apparatus of claim 1 , 2 or 3, comprising a voltage supply arranged to electrify said sample to cause sample delivered into the capillary to be electrosprayed via the outlet orifice.

5. The electrospray apparatus of any preceding claim, comprising a capillary holder having the capillary supported therein, wherein the capillary holder comprises a retractable sheath for protecting said capillary.

6. The electrospray apparatus of any one of claims 1-4, comprising a capillary holder having the capillary supported therein, wherein the capillary holder comprises a sheath member surrounding at least a portion of the length of the capillary, and the sheath member comprises an electrode that extends downstream from the outlet orifice of the capillary; and wherein the electrospray apparatus is arranged for, in use, providing a potential difference between the sample within the capillary and the electrode to cause droplets of the sample to be electrosprayed from the outlet orifice of the capillary.

7. A method of electrospraying a liquid sample, the method comprising: providing an electrospray apparatus comprising a capillary and a conduit, wherein the capillary comprises an outlet orifice, and wherein the conduit extends into and within the capillary; supplying a liquid sample from the conduit into the capillary; supplying a pressurising gas into the capillary so as to force said sample within the capillary towards the outlet orifice; and electrifying the liquid sample so as to electrospray charged droplets of the liquid sample from the outlet orifice of the capillary.

8. A method of electrospraying a liquid sample as claimed in claim 7, comprising reducing a pressure of the pressurising gas in the capillary between the steps of: supplying the pressurising gas into the capillary so as to force said sample within the capillary towards the outlet orifice; and electrifying the liquid sample so as to electrospray charged droplets of the liquid sample from the outlet orifice of the capillary.

9. An electrospray apparatus, comprising a capillary holder for holding a capillary for emitting a sample therefrom, the capillary holder comprising: a sheath member for surrounding at least a portion of the capillary, wherein the sheath member has one or more apertures located therein for allowing the capillary to be viewed; and a connector element for connecting the sheath member to, in order to position the capillary within the electrospray apparatus.

10. The electrospray apparatus of claim 9, wherein the sheath member has a connector end for connecting to the connector element and a distal end opposite to the connector end, the connector end and distal end being separated in an axial direction, and wherein the one or more apertures allow the capillary to be viewed from a radial direction.

11. The electrospray apparatus of claim 9 or 10, wherein the connector element comprises a bore for conveying a sample into the capillary when the connector element is connected to the sheath member.

12. The electrospray apparatus of claim 11 , wherein the electrospray apparatus comprises a supporting element for securing the capillary within the sheath member, and wherein the capillary holder is configured for the supporting element to be inserted into thebore of the connector element while the supporting element maintains a position of the sheath member relative to the capillary.

13. The electrospray apparatus of any one of claims 9 to 12, wherein the sheath member comprises an electrode for providing a potential difference between the electrode and a sample within the capillary.

14. The electrospray apparatus of any one of claims 9 to 13, wherein the sheath member is configured to attach to the connector element by the sheath member being rotated relative to the connector element.

15. The electrospray apparatus of claim 14, wherein the capillary holder is configured for the sheath member to be rotatable to a predetermined position relative to the connector element, and wherein the capillary holder is configured for a releasable snap fit or interference fit to be provided between the connector element and the sheath member at the predetermined position.

16. The electrospray apparatus of any one of claims 9 to 15, wherein the sheath member is a single integral component.

17. The electrospray apparatus of any one of claims 9 to 16, wherein the sheath member comprises prongs, the one or more apertures are plural apertures, and the prongs circumferentially separate the plural apertures from one another.

18. The electrospray apparatus of any one of claims 9 to 17, further comprising the capillary, wherein the capillary has an outlet orifice for emitting a sample therefrom, and the sheath member at least partially surrounds the capillary and extends beyond the outlet orifice of the capillary.

19. An electrospray emitter assembly comprising a capillary and a sheath member surrounding at least a portion of the capillary.

20. The electrospray emitter assembly of claim 19, wherein: the capillary has an outlet orifice at an outlet end of the capillary for emitting a sample therefrom;the sheath member comprises an electrode that extends downstream from the outlet orifice of the capillary; and the electrospray emitter assembly is arranged for, in use, a potential difference to be provided between the sample within the capillary and the electrode of the sheath member to cause droplets of the sample to be electrosprayed from the outlet orifice of the capillary.

21. The assembly of claim 19 or 20, comprising a supporting element located radially between the capillary and the sheath member, wherein the supporting element fixes the sheath member to the capillary.

22. The assembly of claim 21 , wherein the sheath member surrounds the length of the capillary between the supporting element and the outlet end of the capillary.

23. The assembly of claim 21 or 22, wherein the supporting element is bonded to the capillary and / or the sheath member.

24. The assembly of any one of claims 20-23, wherein the outlet orifice has a diameter that is less than 100 pm.

25. The assembly of any one of claims 20-24, wherein the electrode comprises an outlet aperture downstream from the outlet orifice of the capillary, wherein the assembly is configured for the droplets electrosprayed from the outlet orifice of the capillary to pass through said outlet aperture.

26. The assembly of any one of claims 20-25, wherein the sheath member comprises a wall circumferentially surrounding at least a portion of the axial length of the capillary, and the wall comprises one or more apertures located at a same axial position as the outlet orifice of the capillary; or the sheath member comprises prongs that extend to a position downstream from the outlet orifice of the capillary, wherein the prongs are spaced apart in a circumferential direction around a longitudinal axis of the capillary so as to define gaps therebetween, and wherein the gaps are located at a same axial position as the outlet orifice of the capillary.

27. The assembly of any one of claims 20-26, wherein the electrode extends the entire length of the sheath member.

28. The assembly of any one of claims 20-27, wherein the capillary is entirely within and between the ends of the electrode.

29. A method of electrospraying a liquid sample, the method comprising: providing an electrospray apparatus comprising a capillary having an outlet orifice at an outlet end of the capillary and a sheath member surrounding at least a portion of the length of the capillary, wherein the sheath member comprises an electrode that extends downstream from the outlet orifice of the capillary; supplying a liquid sample into the capillary; and providing a potential difference between the liquid sample within the capillary and the electrode of the sheath member to electrospray charged droplets of the liquid sample from the outlet orifice of the capillary.

30. The method of claim 29, wherein the liquid sample is supplied to the outlet end of the capillary via a conduit inserted into the capillary through an inlet orifice of the capillary.31 . The method of claim 30, wherein providing a potential difference between the liquid sample within the capillary and the electrode of the sheath member comprises electrifying the liquid sample by applying a voltage to the liquid sample via the conduit.

32. The method of claim 30 or 31 , comprising supplying a flushing liquid into the capillary via the conduit, wherein the flushing liquid flows within the capillary and out of the inlet orifice so as to remove the liquid sample from the capillary via the inlet orifice.

33. The method of any one of claims 29 to 32, comprising supplying a pressurising gas into the capillary so as to force said sample within the capillary towards the outlet orifice.

34. A method of mass and / or ion mobility spectrometry, comprising providing ions from charged droplets generated using the method of any one of claims 7, 8 or 29-33, and mass and / or ion mobility analysing said ions or ions derived from said ions.

35. A method of providing an electrospray apparatus, comprising: providing a sheath member surrounding at least a portion of a capillary, wherein the sheath member has one or more apertures located therein for allowing the capillary to be viewed; andconnecting the sheath member to a connector element in order to position the capillary for electrospraying a sample therefrom.

36. The method of claim 35, wherein the sheath member is connected to the connector element while the capillary remains fixed relative to the sheath member.

37. The method of claim 35 or 36, wherein the connector element comprises a bore for conveying a sample into the capillary when the connector element is connected to the sheath member.

38. The method of claim 37, wherein a supporting element secures the capillary within the sheath member, and the supporting element is inserted into the bore of the connector element when the sheath member and connector element are connected to one another.

39. The method of any one of claims 35-38, wherein the sheath member comprises an electrode for a potential to be applied to for causing the sample to be electrosprayed from the capillary.

40. The method of any one of claims 35-39, wherein the sheath member is attached to the connector element by the sheath member being rotated relative to the connector element.

41. The method of any one of claims 35-40, wherein the sheath member is rotated to a predetermined position relative to the connector element, and a releasable snap fit or interference fit is provided between the connector element and the sheath member at the predetermined position.

42. The method of any one of claims 35-41 , wherein the sheath member is a single integral component.

43. An electrospray apparatus, comprising: a capillary having an outlet orifice for electrospraying a sample therefrom and a larger drain orifice for flushing out the sample from the capillary; and a conduit extending into the capillary in a manner such that it is able to deliver said sample to the outlet orifice in a first mode of operation, and such that the drain orificeremains open so that the conduit is able to deliver a flushing liquid into the capillary to flush out the sample from the capillary through the drain orifice in a second mode of operation.

44. The electrospray apparatus of claim 43, comprising a voltage supply arranged to electrify said sample.

45. The electrospray apparatus of claim 43 or 44, wherein the apparatus is configured to be able to supply a flushing gas into the capillary via the conduit in a third mode of operation, so as to force the flushing liquid out of the capillary through the drain orifice.

46. The electrospray apparatus of claim 43, 44 or 45, wherein the outlet orifice has a diameter that is less than 100 pm.

47. The electrospray apparatus of any one of claims 43-46, wherein the conduit is positioned within the capillary to output said sample into the capillary at a position proximate the outlet orifice.

48. The electrospray apparatus of any one of claims 43-47, wherein the conduit is inserted into the capillary through the drain orifice and extends along the capillary from the drain orifice towards the outlet orifice.

49. The electrospray apparatus of any one of claims 43-48, wherein the apparatus is configured to supply a pressurising gas into the capillary in the first mode of operation so as to force the sample within the capillary towards the outlet orifice.

50. The electrospray apparatus of claim 49, wherein the apparatus is configured to supply the pressurising gas into the capillary via the drain orifice and external to the conduit.

51. The electrospray apparatus of claim 49 or 50, comprising a capillary housing that houses the capillary, wherein the apparatus is configured for the pressurising gas to be supplied into the capillary from a chamber of the capillary housing, and the capillary housing comprises a valve having a closed configuration for preventing the pressurising gas flowing out of the chamber via the valve, and the valve has an open configuration for allowing the pressurising gas to flow out of the chamber via the valve.

52. The electrospray apparatus of claim 51, wherein the electrospray apparatus is configured for the valve to be switched from the closed configuration to the open configuration such that the valve is in the closed configuration in the first mode of operation and the valve is in the open configuration in the second mode of operation.

53. The electrospray apparatus of claim 51 or 52, wherein the capillary housing comprises a drain for receiving liquid output from the capillary via the drain orifice.

54. The electrospray apparatus of claim 53, wherein the valve is configured to control whether fluid can access the drain from the chamber of the capillary housing.

55. The electrospray apparatus of any one of claims 43-54, comprising a supply housing for receiving a supply device that can supply a fluid into the conduit for conveying to the capillary.

56. The electrospray apparatus of claim 55, wherein the apparatus comprises the supply device, and wherein the supply device comprises a fluid controller that is configured to control the supply device to supply fluids from different sources into the conduit for conveying to the capillary.

57. The electrospray apparatus of any one of claims 43-56, comprising a capillary holder having the capillary supported therein, wherein the capillary holder comprises a retractable sheath for protecting said capillary.

58. The electrospray apparatus of any one of claims 43-56, comprising a capillary holder having the capillary supported therein, wherein the capillary holder comprises a sheath member surrounding at least a portion of the length of the capillary, and the sheath member comprises an electrode that extends downstream from the outlet orifice of the capillary; and wherein the electrospray apparatus is arranged for, in use, providing a potential difference between the sample within the capillary and the electrode to cause droplets of the sample to be electrosprayed from the outlet orifice of the capillary.

59. A mass and / or ion mobility spectrometer comprising the electrospray apparatus of any one of claims 1-6, 9-18 and 43-58 for generating ions via electrospray ionisation.

60. A method of electrospraying a liquid sample, the method comprising: providing an electrospray apparatus comprising a capillary and a conduit, wherein the capillary comprises an outlet orifice and a drain orifice, and wherein the conduit extends into and within the capillary; supplying a liquid sample from the conduit into the capillary and to the outlet orifice of the capillary; electrifying the liquid sample so as to electrospray charged droplets of the liquid sample from the outlet orifice of the capillary; and supplying a flushing liquid into the capillary via the conduit, wherein the flushing liquid flows within the capillary and out of the drain orifice so as to remove the liquid sample from the capillary via the drain orifice.

61. The method of claim 60, comprising supplying a flushing gas into the capillary via the conduit so as force the flushing liquid out of the capillary through the drain orifice.

62. The method of claim 60 of 61 , comprising supplying a next liquid sample from the conduit into the capillary after supplying the flushing liquid without removing the capillary from a capillary housing that comprises the capillary.

63. The method of claim 60, 61 or 62, wherein supplying a liquid sample from the conduit into the capillary and to the outlet orifice of the capillary comprises supplying a pressurising gas into the capillary so as to force the liquid sample supplied into the capillary towards the outlet orifice.

64. The method of claim 63, wherein the conduit extends into the capillary through the drain orifice and the pressurising gas is supplied into the capillary via the drain orifice and external to the conduit.

65. The method of claim 63 or 64, comprising: supplying the pressurising gas into the capillary from a chamber of a capillary housing that houses the capillary; and opening a valve in the capillary housing to reduce the pressure of the pressurising gas in the capillary prior to the flushing liquid removing the liquid sample from the capillary via the drain orifice.

66. A method of electrospraying a liquid sample from an emitter, comprising:providing an emitter having a flushing liquid therein and an orifice; transferring a liquid sample into the emitter via the orifice, wherein the flushing liquid is immiscible with the liquid sample such that the liquid sample is located within the emitter between the flushing liquid and the orifice; generating charged droplets of the liquid sample by electrifying the liquid sample to emit the liquid sample via the orifice; and causing the flushing liquid to displace the liquid sample out of the emitter via the orifice.

67. The method of claim 66, wherein providing the emitter having the flushing liquid therein comprises transferring the flushing liquid into the emitter via the orifice prior to transferring the liquid sample into the emitter via the orifice.

68. The method of claim 66 or 67, wherein the emitter comprises a displacement device for varying the quantity of a volume of fluid that can be held within the emitter, and wherein the method comprises: transferring the liquid sample into the emitter via the orifice by moving the displacement device to increase the volume of fluid that can be held within the emitter to thereby aspirate the liquid sample through the orifice into the emitter; and causing the flushing liquid to displace the liquid sample out of the emitter via the orifice by moving the displacement device to decrease the volume of fluid that can be held within the emitter.

69. A method of mass and / or ion mobility spectrometry, comprising providing ions from charged droplets generated using the method of any one of claims 60-68, and mass and / or ion mobility analysing said ions or ions derived from said ions.

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