Electrospray apparatus and method

Abstract

An electrospray device (130) includes a capillary tube (102) having an outlet orifice (108) for electrospraying a sample therefrom, and a conduit (112) extending into the capillary tube (102) in a manner that enables delivery of the sample into the capillary tube (102). The apparatus (130) may be configured to supply pressurized gas into the capillary tube (102) so as to force the sample within the capillary tube (102) toward the outlet orifice (108). The apparatus may include a sheath member (203) surrounding at least a portion of the capillary tube (102), where the sheath member (102) has one or more apertures (213) therein to permit observation of the capillary tube (102), and may include a connector element (205) for connecting the sheath member (203) to position the capillary tube within the electrospray apparatus (130).

Description

Cross-references to related applications

[0001] This application claims priority and benefit to UK Patent Application No. 2310641.2, filed July 11, 2023, and U.S. Patent Application No. 63 / 611454, filed December 18, 2023. The entire contents of both applications are incorporated herein by reference. Technical Field

[0002] This disclosure relates to electrospraying, and more particularly to an electrospraying device that uses a capillary to eject a liquid sample. Background Technology

[0003] Electrospraying is a process used to generate small droplets from liquid samples. Electrospraying is achieved by creating an interface between the liquid and air at the tip of the emitter, and by using electrostatic stress generated by energizing the liquid with an applied voltage to eject charged droplets from the liquid interface.

[0004] Electrospray ionization (ESI) is an ionization technique in which ions are generated or released from charged droplets produced via an electrospray process. ESI can be used as an ionization technique to generate ions for analysis via mass spectrometry and / or ion mobility spectrometry.

[0005] In nano-ESI processes using emitters with appropriately small internal tip diameters, ESI can be used for small sample volumes (e.g., less than 10 µL). Emitters used for nano-ESI are typically drawn glass capillaries used for a single sample and then discarded due to their fragility and the possibility of inadvertently retaining portions of previously sprayed sample, which could be carried over and contaminate another sample. Variance in the positioning and internal geometry from one emitter to another (e.g., for drawn glass capillaries, the tolerance for the inner diameter at the tip can be at least 20%) can reduce the reproducibility of the resulting ion signal obtainable from the sample using nano-ESI. Furthermore, the tips of emitters suitable for nano-ESI may need to be centrifuged to first wet them to allow liquid sample to be delivered to their outlet, which can hinder process automation and increase the time required to perform the process across different samples.

[0006] To automate the nano-ESI process, an etched silicon chip with an array of holes can be used as the emitter instead of a drawn glass capillary. This allows robotic pipettes to continuously supply samples to different etched holes, avoiding the need for human intervention between serving different samples. However, each hole in the etched silicon chip can be single-use, similarly lacking reproducibility due to varying hole quality, and is a much more expensive option compared to drawn glass capillaries. Summary of the Invention

[0007] According to a first aspect of the present invention, an electrospraying device is provided, the electrospraying device comprising:

[0008] A capillary having an outlet orifice for electrospraying a sample from it and a larger discharge orifice for flushing the sample out of the capillary; and

[0009] The conduit extends into the capillary in such a way that it can deliver the sample to the outlet orifice in a first operating mode, and that the discharge orifice remains open so that the conduit can deliver rinsing liquid into the capillary in a second operating mode to flush the sample out of the capillary through the discharge orifice.

[0010] The capillary of this electrospray device serves as the emitter, which, in a first operating mode, can eject a liquid sample via an outlet orifice to electrospray the sample. However, the capillary also includes a discharge orifice (separate from the outlet orifice), and a flushing cycle can be performed on the device to remove substantially all sample retained in the capillary via the discharge orifice after the device has been used for electrospraying a sample. This allows for the reuse of the same capillary while preventing one sample from being carried over and contaminating the next sample supplied to the capillary. The ability to reuse the same capillary, in addition to greater cost efficiency, also allows for greater reproducibility / consistency of the electrospray process.

[0011] Electrospray equipment may include a voltage source arranged to energize the sample.

[0012] A voltage source can be used to energize the sample in a first operating mode so that the sample delivered into the capillary is electro-sprayed through an outlet orifice, thereby forming charged droplets.

[0013] The device can be configured to energize a sample in any suitable manner using a voltage source. For example, a capillary may include a conductive material (e.g., a conductive coating) for energizing the sample, a conduit may include a conductive material (e.g., a conductive coating) for energizing the sample, and / or an electrode (e.g., a wire or plunger) may be inserted into the capillary to energize the sample.

[0014] The voltage source can supply a voltage greater than 100V, and preferably a voltage greater than 1kV, for electrospraying the sample.

[0015] The electro-spray device can be configured to supply flushing gas to the capillary via a conduit in a third operating mode, so as to force the flushing liquid out of the capillary through the discharge orifice.

[0016] The device can perform a flushing cycle by supplying flushing liquid to the capillary via a conduit in a second operating mode, and optionally subsequently supplying gas in a third operating mode. Using the same conduit to supply flushing liquid and gas, as well as the sample, means that the conduit (and the capillary) can also be flushed during the device's flushing cycle.

[0017] Electrospray capillary emitters are typically not flushed through their outlet orifice for reuse, as this may not reliably ensure sample removal from the capillary. In this regard, liquid within a typical capillary emitter does not readily drain from the outlet, especially for capillary emitters with small inner diameters intended for small sample volumes. For example, the capillary emitter may require centrifugation to reliably wet the tip before use, and emission from the tip may only be possible with the application of voltage. The relatively low flow rate out of the outlet will also mean that adequate flushing of the capillary via the outlet may take excessively long to perform.

[0018] However, the applicant has discovered that by providing a capillary with a discharge orifice larger than the outlet orifice and configuring the device for removing liquid via the discharge orifice, the capillary can be suitably reused as an electrospray emitter and a flushing cycle can be performed, optionally without the need to remove the capillary from the device.

[0019] The discharge orifice is larger than the outlet orifice because it has a larger cross-sectional area, which allows for a relatively greater flow velocity (at a given pressure) of the liquid passing through it compared to the outlet orifice. Preferably, the diameter or width of the discharge orifice is greater than that of the outlet orifice. Both the discharge and outlet orifices may have a circular cross-section; however, any suitable shape may be used for either or both of the outlet and discharge orifices.

[0020] The outlet orifice can have a diameter of less than 100µm.

[0021] Providing a small outlet orifice for the capillary allows the capillary to be used with small sample volumes (e.g., less than 10 µl), and thus for nano-ESI.

[0022] The diameter of the outlet orifice can be less than 50µm, such as less than 25µm, and preferably between 0.1µm and 20µm.

[0023] The discharge orifice may have a diameter greater than 25µm, greater than 50µm, or greater than 100µm.

[0024] During the rinsing cycle (in the second and / or third operating modes), a certain proportion of the liquid (rinsing liquid and / or sample) within the capillary can be discharged via the outlet orifice. However, a larger size of the outlet orifice can result in substantially all of the rinsing liquid being discharged via it. In this respect, the outlet orifice can resist or reduce flow through it to a greater extent than at the outlet orifice, thereby creating fluid pressure characteristics that discharge the liquid within the capillary through the outlet orifice. Rinsing gas can optionally be used to discharge the rinsing liquid through the outlet orifice. However, in embodiments, the rinsing liquid can flow out of the outlet orifice without the use of gas. For example, the capillary can be oriented such that gravity will cause the rinsing liquid to flow out of the outlet orifice in the second operating mode.

[0025] However, in the first operating mode, the catheter can supply the liquid sample to the outlet orifice, and the liquid sample will not leave the capillary at the discharge orifice. This can be achieved based on the positioning of the catheter within the capillary, the inner diameter of the capillary, the direction in which the catheter guides the liquid sample into the capillary, and / or the pressure at which the catheter supplies the liquid sample into the capillary.

[0026] The conduit of the electrospray device can be positioned inside the capillary to output the sample into the capillary near the outlet orifice.

[0027] The outlet of the conduit inside the capillary can face the outlet orifice.

[0028] Liquid samples can be output from the conduit to the capillary at the outlet of the conduit, and the distance between the outlet of the conduit and the outlet orifice of the capillary can be less than 15 mm, less than 10 mm, or less than 5 mm.

[0029] The liquid sample supplied to the capillary can be conveyed to the outlet orifice by electrostatic stress and / or by the surface tension between the capillary and the liquid sample. The capillary can be oriented, at least in the first operating mode, such that gravity will help to convey the liquid sample toward the outlet orifice; however, this is not necessary.

[0030] After the sample has been electrosprayed, the orientation of the capillary can be changed so that, in the second operating mode, gravity will assist in directing the flushing liquid toward the discharge orifice to remove the sample retained within the capillary. However, this is not necessary because the flushing liquid and / or gas can simply be supplied in sufficient volume to fill the length of the capillary between the outlet and discharge orifices, allowing the flushing liquid to drain from the discharge orifice (as more flushing liquid and / or gas is supplied into the capillary). Therefore, the device can be configured such that a relatively small volume of fluid supplied to the capillary does not cause liquid within the capillary to flow out of the discharge orifice (and liquid within the capillary can be ejected from the outlet orifice), but a relatively large volume of fluid supplied to the capillary can cause liquid within the capillary to flow out of the discharge orifice.

[0031] The conduit of the electrospray device can be inserted into the capillary through the discharge port and extends along the capillary from the discharge port toward the outlet port.

[0032] Alternatively, the catheter can be inserted into the discharge (and outlet) port through a separate orifice. However, in this case, the orifice through which the catheter enters the capillary can be sealed to prevent fluid outside the catheter from flowing through that orifice.

[0033] The catheter preferably does not extend the entire length of the capillary. However, the catheter may extend within the capillary such that the catheter outlet is close to the outlet orifice.

[0034] A capillary can have two opposite ends: an inlet end where the discharge orifice is located and an outlet end where the outlet orifice is located. A capillary can be substantially straight or it can be curved.

[0035] The capillary may include a tip portion where the inner diameter of the capillary decreases in the direction toward the outlet orifice, and the conduit may extend into the tip portion of the capillary.

[0036] The inner diameter of the capillary can remain substantially constant in the direction from the discharge orifice toward the outlet orifice until the tip is reached.

[0037] Capillaries can be glass capillaries, such as drawn glass capillaries. However, this is not mandatory, and capillaries can be made of other materials such as ceramics or metals. Capillaries can be made of materials advantageously chosen to resist permanent deformation in order to reduce the chance of the capillaries being damaged throughout their use.

[0038] Electrospray devices may include a capillary housing that houses the capillary.

[0039] The capillary housing can be configured to hold the catheter within the capillary. For example, the capillary housing may include a clamping portion that prevents the catheter from moving therein and can hold a portion of the catheter downstream of the clamping portion toward the capillary with sufficient length for insertion into the capillary (and into the desired location therein).

[0040] Electrospraying equipment may include a heater configured to heat the conduit and / or capillary. This allows the sample to be heated in the conduit and / or capillary before it is electrosprayed out of the capillary. The capillary housing may include the heater.

[0041] The conduit can be formed continuously (e.g., provided as a (preferably flexible) material tube), but can otherwise be formed from separate components fixed together. For example, the conduit may include a separable portion that is inserted into the capillary and removably attached to another portion of the conduit located within the capillary housing, thereby allowing the capillary and conduit to be removed together from the capillary housing without having to pull the separable portion of the conduit out of the capillary. Removing the capillary and conduit together allows the portion of the conduit inserted into the capillary to remain substantially in the same position within the capillary.

[0042] The capillary housing may include a housing body and a capillary retainer, wherein the capillary retainer has a capillary supported therein. The capillary retainer may be removably attached to the housing body and may be detached from the housing body without removing the capillary from the capillary retainer and optionally without removing the conduit from the housing body.

[0043] The capillary retainer may include a bore for delivering a conduit into the capillary. The bore may have a tapered inlet for guiding the conduit into the bore.

[0044] The capillary housing (e.g., a capillary retainer) may include a retractable sheath for protecting the capillary.

[0045] The retractable sheath can move between the extended position and the retracted position.

[0046] 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 retainer). Optionally, the retractable sheath has an annular cross-section for completely surrounding at least the outlet end of the capillary in the extended position.

[0047] In the retracted position, a portion of the capillary (at the outlet end) may extend beyond the retractable sheath (so that at least a portion of the capillary is not surrounded by the retractable sheath when in the retracted position).

[0048] The retractable sheath can be configured to move from an extended position to a retracted position when inserted into the housing of a mass spectrometer and / or ion mobility spectrometer. For example, the retractable sheath may include one or more engagement structures (e.g., protrusions) for changing the retractable sheath from an extended position to a retracted position when a capillary is inserted through an aperture of the housing of the mass spectrometer and / or ion mobility spectrometer.

[0049] The retractable sheath can be biased toward the extended position. For example, the capillary housing (e.g., a capillary retainer) may include a spring arranged to bias the retractable sheath toward the extended position.

[0050] The capillary housing may include a counter electrode. In use, a potential difference is maintained between the counter electrode and the sample inside the capillary to allow the sample to be emitted from the capillary outlet orifice.

[0051] A voltage source can be configured to provide a potential difference between the sample and the counter electrode. The potential difference can be greater than 100V, such as greater than 1kV. The potential difference can be between 50V and 5kV, such as between 100V and 3kV. A potential difference between the sample and the counter electrode can be provided by applying a potential of opposite polarity relative to the sample to the counter electrode, by grounding the counter electrode while the sample is energized, or by applying a lower amplitude potential of the same polarity relative to the sample to the counter electrode.

[0052] The counter electrode can be arranged to control the propagation of the spray of energized sample when emitted from the capillary (e.g., by influencing the travel and / or diffusion direction of the emitted sample droplets). For example, the counter electrode may include an orifice downstream of the capillary's outlet orifice (and outlet end), wherein the device is configured for energized sample emitted from the capillary's outlet orifice to pass through the orifice of the counter electrode. The orifice may be coaxial with the outlet orifice.

[0053] The capillary retainer may include a counter electrode, and the capillary retainer may be configured to be attachable to and detachable from the housing body of the capillary housing, while holding the counter electrode in a fixed position relative to the capillary.

[0054] The sheath component may include a counter electrode and / or the counter electrode may be provided in the form of a sheath component (as a sheath electrode). Providing the counter electrode in the sheath or as a sheath can protect the capillary (and the user from the effects of the capillary, as the capillary may be sharp and / or contain hazardous materials), while also enabling the counter electrode to function in maintaining the potential difference between the area around the exit end of the capillary and the charged sample inside the capillary.

[0055] The sheath member can circumferentially surround a portion of the (axial) length of the capillary, and the electrode can extend downstream from the capillary outlet orifice (and outlet end) (with a position axially beyond the outlet orifice).

[0056] Therefore, in an embodiment, the electrospray device includes a capillary retainer having a capillary supported therein, wherein the capillary retainer includes a sheath member (circumferentially) surrounding at least a portion of the (axial) length of the capillary, and the sheath member includes an electrode (counter electrode) extending downstream from the outlet orifice of the capillary, and wherein the electrospray device is arranged to provide a potential difference between the sample and the electrode within the capillary during use so that droplets of the sample are electrosprayed from the outlet orifice of the capillary.

[0057] The sheath member may have other optional features, such as one or more side holes, as described below with respect to the sheath member.

[0058] In addition to the retractable sheath, a sheath member may be provided (where the retractable sheath also at least partially surrounds the sheath member to provide protection thereto), or a sheath member may be provided without the retractable sheath. However, when both the sheath member and the retractable sheath are provided, when the retractable sheath is in the retracted position, the sheath member preferably retains a portion extending beyond the outlet end of the capillary (e.g., the position of the sheath member may be fixed, while the retractable sheath may move between the extended and retracted positions).

[0059] The electrospray device can be configured to supply pressurized gas into a capillary in a first operating mode so as to force the sample in the capillary toward the outlet orifice.

[0060] Pressurized gas can be supplied into the capillary via an outlet port (e.g., from the capillary housing) and can also be supplied externally to the conduit. For example, the conduit can be inserted through the outlet port while allowing pressurized gas to be supplied through outlet ports around the conduit.

[0061] Any suitable pressurized gas can be used, such as air or an inert gas, such as nitrogen. The pressurized gas may or may not have the same composition as the flushing gas, which can be supplied to the capillary via a conduit in the third operating mode.

[0062] The applicant has recognized that using gas to force the sample toward the outlet orifice in the manner described herein can remove or reduce any present air bubbles. 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 desires to remove any such air bubbles because they may otherwise adversely affect the spray characteristics when the sample is ejected from the outlet orifice.

[0063] However, the device can be configured to reduce the pressure of the pressurized gas in the capillary after forcing the sample toward the outlet orifice, so as to prevent the gas from otherwise resisting the removal of the sample and / or flushing liquid from the discharge orifice in the second and / or third operating modes.

[0064] During electrospraying, the pressure of the pressurized gas can be maintained to continue forcing the sample toward the outlet orifice for emission from it, or the pressure of the pressurized gas can be reduced before electrospraying (after removing any bubbles).

[0065] The device can be configured to control the pressure of pressurized gas inside the capillary by controlling the pressure inside the chamber of the capillary housing, through which the pressurized gas is supplied to the capillary.

[0066] The device may include any suitable components for controlling and / or measuring the gas pressure within the capillary and / or capillary housing. For example, the device may include one or more valves (such as pneumatic valves), pressure gauges, and / or volumetric flow controllers.

[0067] The device can be configured to supply pressurized gas from a chamber of a capillary housing into a capillary, and the capillary housing may include a valve having a closed configuration for preventing pressurized gas from flowing out of the chamber via the valve, and an open configuration for allowing pressurized gas to flow out of the chamber via the valve.

[0068] The device can be configured to switch the valve from a closed configuration (e.g., automatically) to an open configuration, such that the valve is in a closed configuration in a first operating mode and in an open configuration in a second (and / or third) operating mode.

[0069] The device can be configured to control the pressure inside the capillary housing such that after pressurized gas is supplied into the capillary to force the liquid sample toward the outlet orifice, the pressure inside the capillary housing can be released (e.g., by opening a valve) before the sample and flushing liquid flow out of the discharge orifice (so that the pressurized gas can flow back into the capillary and does not resist the liquid flowing out of the capillary).

[0070] Therefore, the device can be configured to control the pressure of the pressurized gas to be relatively high in a first operating mode to force the sample in the capillary toward the outlet orifice; and relatively low in a second (and / or third) operating mode to allow the sample (and / or flushing liquid) to be flushed out of the discharge orifice in the second (and / or third) operating mode.

[0071] The capillary housing may include a gas inlet conduit for supplying pressurized gas into the capillary via the capillary housing in a first operating mode.

[0072] The capillary housing may include a discharge element (or discharge conduit) for receiving liquid output from the capillary via a discharge orifice.

[0073] The valve can be configured to control whether fluid can enter the discharge port from the chamber of the capillary housing.

[0074] For example, the discharge device may include a conduit that includes a valve for controlling the pressure of the pressurized gas, such that the valve of the discharge device can be used to maintain or release the pressure within the capillary housing. For example, in a first operating mode, the valve may be closed to prevent fluid from being supplied outside the capillary housing via the discharge device (to maintain the pressure of the pressurized gas in the first operating mode), and during a second and / or third operating mode, the valve may be opened to allow fluid (e.g., gas, sample, and / or flushing liquid) to be received by the discharge device.

[0075] The discharge element of the capillary housing may include a removable container, such as a bottle, for collecting the liquid output from the capillary. The discharge element may also otherwise completely deliver the liquid (and / or gas) out of the device (to another location).

[0076] The gas inlet conduit may include a valve for controlling the flow of gas therethrough. The valve of the gas inlet conduit may be open in a first operating mode to supply pressurized gas and may optionally be closed (at least initially) in a second and / or third operating mode to stop the flow of pressurized gas. Closing the valve of the gas inlet conduit in the second and / or third operating modes can help reduce the pressure in the chamber of the capillary housing to remove the sample and / or flushing liquid from the capillary. However, the valve of the gas inlet conduit may otherwise remain open (and the pressure is released, for example, by opening the valve of the discharge element), allowing pressurized gas to continue to be supplied to the capillary housing to help flush the sample and / or flushing liquid out of the discharge element. Optionally, the valve of the gas inlet conduit may initially be closed in the second and / or third operating modes and then opened after the sample and / or flushing liquid has been supplied from the capillary into the capillary housing, allowing the pressurized gas supplied via the gas inlet conduit to then help flush any sample or flushing liquid remaining in the capillary housing into the discharge element.

[0077] After at least some portion of the sample has been supplied from the conduit into the capillary (and optionally after the sample has been completely supplied from the conduit into the capillary), pressurized gas can be supplied into the capillary (e.g., by opening a valve in the gas inlet conduit).

[0078] Pressurized gas can be supplied before the sample is energized (e.g., by opening a valve in the gas inlet conduit) to remove any air bubbles present before the sample is electrosprayed out of the capillary.

[0079] The device can be appropriately configured (e.g., automated) for relevant steps to be performed in the appropriate sequence. For example, the device can be configured to automatically operate valves, supply samples, and / or energize samples at appropriate times to achieve the functionality described herein.

[0080] The voltage source can be part of the capillary housing, or the voltage source can supply voltage to the sample through the capillary housing.

[0081] The capillary housing may include an electrode configured to supply a voltage to the sample within the capillary to energize the sample.

[0082] The device can be configured to supply voltage to the sample directly via electrodes, or via capillary tubes and / or conduits.

[0083] Electrospray equipment may include a supply housing for receiving a supply device that supplies fluid into a conduit for delivery to a capillary.

[0084] The supply housing can be configured to receive any suitable supply device, such as a syringe, pump, injection pump, autosampler, or liquid chromatograph.

[0085] The supply device can be configured to prepare samples supplied to a capillary via a conduit (e.g., without disconnecting from the supply housing). For example, the supply device can be configured to convert a sample into a liquid for supply to the capillary, mix components to form a sample, and / or receive a composition containing the sample and extract the sample therefrom for supply to the capillary. In this respect, for electrospray devices using disposable electrospray capillaries that need to be replaced between different samples, sample preparation can typically be performed “offline” and separately from the electrospray device. However, for the electrospray device according to the invention, the applicant has recognized that since the capillary can be rinsed between uses, continuous use of the sample is not prevented by the need to replace the capillary, and therefore performing sample preparation “online” with the electrospray device also allows for more continuous / efficient (e.g., automated) use of the electrospray device, while extending spray time and / or reducing downtime.

[0086] For example, biological samples stored in buffer solutions incompatible with mass spectrometry need to have the buffer replaced / removed before electrospray ionization for mass analysis. For instance, multiprotein components (e.g., viral capsids) stored in phosphate or tris(hydroxymethyl)aminomethane buffer solutions may require the buffer to be replaced with ammonium acetate. This can be achieved, for example, by size exclusion chromatography (SEC).

[0087] Therefore, the supply device may include size exclusion chromatography (SEC) apparatus or other sample extraction or collection apparatus.

[0088] Electrospray equipment may include a supply device. The supply housing may include a connector for delivering a sample from the supply device into a catheter. The connector may include one or more injector ports (e.g., injector valves), wherein different injector ports may be able to receive fluid from different corresponding supply devices for delivery into the catheter (at the appropriate time).

[0089] The supply housing and capillary housing can be separated by a flexible connecting portion through which the catheter extends from the supply housing to the capillary housing, and which allows for desired positioning of the capillary housing and the supply housing relative to each other. The flexible connecting portion may include, for example, a sheath made of a material such as plastic, surrounding the catheter and providing additional protection. The flexible connecting portion may otherwise consist of (only) a portion of the catheter.

[0090] Electrospraying equipment may include a supply device, and the supply device may include a fluid controller configured to control the supply device to supply fluid from a different source into a conduit for delivery to a capillary.

[0091] The electrospray device may include the different sources. These sources may include a source of the sample, a source of the rinsing liquid, and optionally a source of the rinsing gas used to force the rinsing liquid out of the capillary.

[0092] The fluid controller can be manually operated to select which source to supply to the conduit, or it can be programmable to automatically supply different sources to the conduit at different corresponding times.

[0093] Other operations of the device can be automated as needed; for example, the device may include a consumable replacement robot for changing capillaries (when needed).

[0094] Electrospraying devices may include optical devices, such as imaging devices, like cameras. The optical devices may be configured to observe the position of the conduit and / or capillary within the device. The optical devices may be configured to observe the presence of any air bubbles within the capillary (e.g., at the capillary outlet end). The device may include multiple optical devices, such as those to allow imaging of the capillary 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 device may include a first optical device configured to observe the presence of any air bubbles within the capillary (e.g., at the capillary outlet end), and a second optical device configured to observe the presence of any air bubbles within the capillary.

[0095] According to a second aspect of the invention, a mass spectrometer and / or ion mobility spectrometer is provided, which includes an electrospray device as described herein for generating ions via electrospray ionization.

[0096] Mass spectrometers and / or ion mobility spectrometers include one or more ion analyzers, such as mass analyzers and / or ion mobility analyzers, which can analyze ions generated using electrospray devices.

[0097] Liquid samples may include analytes that can be ionized to generate analyte ions for analysis by mass spectrometry and / or ion mobility spectrometry.

[0098] According to a third aspect of the present invention, a method for preparing an electrospray liquid sample is provided, the method comprising:

[0099] An electrospraying device is provided, comprising a capillary and a conduit, wherein the capillary includes an outlet orifice and an outlet orifice, and wherein the conduit extends into and extends within the capillary.

[0100] The liquid sample is supplied from the conduit into the capillary and then to the outlet orifice of the capillary.

[0101] To electrify the liquid sample so that charged droplets of the liquid sample are electrosprayed from the outlet orifice of the capillary; and

[0102] The rinsing liquid is supplied to the capillary via a conduit, where the rinsing liquid flows within the capillary and out of the drain orifice so that the liquid sample can be removed from the capillary via the drain orifice.

[0103] The electrospray device described above can be used to perform this method. Therefore, the method may include providing an electrospray device having any of the optional features disclosed herein.

[0104] Liquid samples may include analytes that are ionized to form analyte ions generated or released from charged droplets, for example, for analysis via mass spectrometry.

[0105] The method may include supplying flushing gas to a capillary via a conduit so as to force flushing fluid out of the capillary through a discharge orifice.

[0106] The rinsing liquid ensures the removal of the liquid sample retained in the capillary after electrospraying. However, gas can be used to remove substantially all the rinsing liquid from the capillary. A suitable electrospray device for use with this method can be configured to supply both the rinsing liquid and the rinsing gas, regardless of whether the implementation of the method can be performed without the use of rinsing gas.

[0107] Any suitable rinsing liquid can be used for a particular liquid sample. The rinsing liquid used in the aspects of the invention described above is preferably miscible with the liquid sample therein, diluting the liquid sample. For example, the rinsing liquid may contain or consist of a solvent that dissolves the liquid sample therein and / or the liquid sample may also contain the solvent.

[0108] The rinsing liquid can at least dissolve the components of the liquid sample.

[0109] Supplying flushing liquid to the capillary via a conduit allows the liquid sample and / or flushing liquid to flow out of the discharge orifice before the flushing gas is supplied.

[0110] When the flushing liquid is supplied into the capillary, it can form a mixture or solution with the liquid sample. Supplying a sufficient volume of flushing liquid itself allows the flushing liquid and / or liquid sample to flow from the outlet orifice to the outlet orifice and out of the capillary via the outlet orifice. For example, the method may include supplying a larger volume of flushing liquid than the liquid sample (to adequately dilute the liquid sample and / or allow it to drain from the outlet orifice). Thus, the liquid sample can be supplied into the capillary, causing the flushing liquid to flow within the capillary and out of the outlet orifice, thereby removing the liquid sample from the capillary via the outlet orifice. However, the flushing liquid and / or liquid sample may not otherwise flow out of the outlet orifice until flushing gas is supplied to cause this to occur.

[0111] Before supplying any rinsing liquid, the volume of liquid sample supplied to the capillary can be less than 20 µl.

[0112] The volume of liquid sample supplied to the capillary can be between 1 nL and 20 µL, such as between 100 nL and 15 µL or between 500 nL and 10 µL.

[0113] Supplying a liquid sample from a conduit into a capillary and to the capillary's outlet orifice may include supplying pressurized gas into the capillary to force the liquid sample toward the outlet orifice.

[0114] Pressurized gas can be supplied into the capillary via an outlet orifice, and can also be supplied outside the conduit. For example, the conduit can extend into the capillary through an outlet orifice, and pressurized gas can be supplied into the capillary through an outlet or outside the conduit (e.g., around).

[0115] As described in this article, pressurized gas can force a liquid sample toward the outlet orifice to remove any air bubbles present.

[0116] The method may include supplying pressurized gas from a chamber of a capillary housing to the capillary.

[0117] The method may include opening a valve in the capillary housing to reduce the pressure of the pressurized gas in the capillary before the flushing liquid removes the liquid sample from the capillary via a discharge orifice.

[0118] In this respect, after pressurized gas is supplied into the capillary to force the liquid sample toward the outlet orifice, the pressure inside the capillary housing can be reduced before the flushing liquid flows out of the discharge orifice, so that the pressurized gas can flow back into the chamber from the capillary without resisting the flushing liquid from flowing out of the capillary.

[0119] The pressure of the pressurized gas can be reduced by any other suitable means other than the valve in the capillary housing.

[0120] The pressure of the pressurized gas can be reduced before or after the liquid sample is energized so that charged droplets of the liquid sample can be electrosprayed from the outlet orifice of the capillary.

[0121] The valve in the capillary housing can control the flow of fluid into the discharge element of the capillary housing, for example, so that when the valve is open, the sample, rinsing liquid and gas can be received by the discharge element.

[0122] The method may include supplying pressurized gas into the capillary housing via a gas inlet conduit (for supplying to the capillary). After supplying pressurized gas into the capillary to force the liquid sample toward the outlet orifice, the supply of pressurized 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 pressurized gas into the capillary housing via the gas inlet conduit may be continued in other ways (or may be resumed later, e.g., by opening a valve in the gas inlet conduit) to flush the liquid sample and rinsing liquid out of the capillary housing.

[0123] Liquid samples may contain protein components and / or adduct molecules (e.g., non-volatile salts).

[0124] Energizing a liquid sample can include supplying a voltage greater than 100V to the liquid sample. For example, a voltage between 200V and 2kV can be supplied.

[0125] Applying electricity to a liquid sample causes a liquid interface to form at the outlet orifice between the liquid sample and a fluid (e.g., air) or void (vacuum) outside the capillary. The liquid interface can extend beyond the capillary and take the form of, for example, a curved meniscus or a Taylor cone. A portion of the liquid interface can overlap with the outer surface of the capillary. Charged droplets can be emitted from the liquid interface.

[0126] The method may include a sample in a heated conduit and / or a capillary.

[0127] The method may include supplying the next liquid sample from the conduit to the capillary after the flushing liquid has been supplied.

[0128] When using flushing gas to remove flushing liquid, the next liquid sample can be supplied after the flushing gas is supplied. The entire process can be repeated for the next liquid sample, and so on, as needed. For example, the process can be repeated such that it is performed for at least three, four, five, or more than five liquid samples supplied to the same capillary at different times.

[0129] The process can be automated, allowing for the supply of one or more liquid samples, flushing liquids, and / or flushing gases at programmable times.

[0130] The next liquid sample can be supplied without removing the capillary from the capillary housing, which includes the capillary.

[0131] This method may include centrifuging the capillary before inserting it into the electrospray device. The centrifugation step is not necessary in all embodiments. However, in embodiments where the liquid sample supplied from the conduit when the capillary is inserted completely “dry” may not otherwise be delivered to the outlet orifice, this may allow the outlet end of the capillary (where the outlet orifice is located) to be wetted before the conduit supplies the sample into the capillary, but centrifugation to wet the outlet end can allow the liquid sample supplied by the conduit to be delivered to the outlet orifice. However, once the capillary is inserted into the device after wetting, it may retain some of the liquid at its outlet end via surface tension, making a subsequent centrifugation step unnecessary. This may also be the case even if contamination of subsequent samples is substantially avoided due to the small volume of liquid that may remain after a rinsing cycle and / or the use of rinsing liquid to dilute any remaining portion of the previous liquid sample.

[0132] This method allows the position of the capillary and the voltage applied to the liquid sample to be optimized and kept constant as one or more consecutive liquid samples are supplied into the capillary.

[0133] During rinsing, the voltage supply to the liquid in the capillary can be stopped or maintained. Maintaining the voltage allows a portion of the rinsing liquid to be discharged through the outlet orifice (and emitted as droplets) to further rinse the capillary of the liquid sample.

[0134] The use of pressurized gas in an electrospray device to remove air bubbles by forcing the sample toward the outlet orifice of a capillary in a manner disclosed herein is considered novel and inventive, regardless of whether the sample is flushed out of the capillary.

[0135] Therefore, according to a fourth aspect of the present invention, an electrospraying device is provided, the electrospraying device comprising:

[0136] A capillary tube having an outlet orifice for dispensing an electrosprayed sample from it; and

[0137] A conduit that extends into a capillary in such a manner that it enables the delivery of the sample into the capillary.

[0138] The device is configured to supply pressurized gas into a capillary to force the sample within the capillary toward the outlet orifice.

[0139] According to a fifth aspect of the present invention, a method for preparing an electrospray liquid sample is provided, the method comprising:

[0140] An electrospray device is provided, comprising a capillary and a conduit, wherein the capillary includes an outlet orifice, and wherein the conduit extends into and extends within the capillary.

[0141] The liquid sample is supplied from the conduit to the capillary;

[0142] Pressurized gas is supplied to the capillary to force the sample inside the capillary toward the outlet orifice; and

[0143] The liquid sample is energized so that charged droplets of the liquid sample are electrosprayed from the outlet orifice of the capillary.

[0144] The fourth and fifth aspects of the invention may include any of the features or steps described herein with respect to the first through third aspects and associated embodiments.

[0145] For example, the outlet orifice may have a diameter of less than 100 µm. Optionally, the diameter of the outlet orifice is less than 50 µm, such as less than 25 µm, and preferably between 0.1 µm and 20 µm.

[0146] The capillary may include an inlet orifice, which optionally has any of the features or functionalities described herein with respect to an outlet orifice.

[0147] For example, a conduit can be inserted into a capillary through an inlet orifice, and the device can be arranged to supply pressurized gas into the capillary via the inlet orifice and outside the conduit.

[0148] Electrospray equipment may include a voltage source arranged to energize the sample.

[0149] A voltage source can be used to energize the sample so that the sample delivered into the capillary is electrosprayed through the outlet orifice (and thereby forms charged droplets).

[0150] The device can be configured to energize a sample in any suitable manner using a voltage source. For example, a capillary may include a conductive material (e.g., a conductive coating) for energizing the sample, a conduit may include a conductive material (e.g., a conductive coating) for energizing the sample, and / or an electrode (e.g., a wire or plunger) may be inserted into the capillary to energize the sample.

[0151] A voltage source may be arranged for, and the method may include, supplying a voltage greater than 100V, and preferably greater than 1kV, for electrospraying the sample.

[0152] The device can be configured to control the pressure of the pressurized gas within the capillary.

[0153] During electrospraying, the pressure of the pressurized gas can be maintained to continue forcing the sample toward the outlet orifice for emission from it, or the pressure of the pressurized gas can be reduced before electrospraying (after removing any bubbles).

[0154] Therefore, the method may include, and the device may be configured to, reduce the pressure of a pressurized gas in a capillary between the following steps: supplying pressurized gas into the capillary to force the sample within the capillary toward an outlet orifice; and energizing the liquid sample to electrospray charged droplets of the liquid sample from the outlet orifice of the capillary.

[0155] The device may include any suitable components for controlling and / or measuring the gas pressure within the capillary and / or capillary housing, through which pressurized gas is supplied to the capillary. For example, the device may include one or more valves (such as pneumatic valves), pressure gauges, and / or volumetric flow controllers. For instance, a valve may be opened (e.g., within the capillary housing) to reduce the pressure of the pressurized gas in the capillary.

[0156] The device may include a capillary retainer (e.g., as a component of a capillary housing) having a capillary supported therein.

[0157] Capillary retainers may include retractable sheaths for protecting the capillary.

[0158] The capillary retainer may include a sheath member that includes (pair) electrodes.

[0159] The retractable sheath and the sheath component may each have any of the features described herein for the retractable sheath and the sheath component respectively.

[0160] In any of the foregoing aspects of the invention, the capillary retainer may be configured to include an electrospray emitter assembly comprising a capillary and a sheath member. The capillary retainer may also include 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.

[0161] The electrospray emitter assembly can therefore constitute a consumable (replaceable) part of the electrospray device. For example, it can make the electrospray emitter assembly easily replaceable in case of blockage or damage, and / or make it possible to provide different electrospray emitter assemblies for different samples and / or different electrospray emitter assemblies can be configured with different characteristics / parameters (e.g., different outlet orifice diameters).

[0162] The electrospray device described herein, featuring a capillary retainer including connector elements and a removable electrospray emitter assembly, is considered novel and inventive in itself.

[0163] According to a sixth aspect of the present invention, an electrospraying device is provided, the electrospraying device comprising:

[0164] A capillary holder for holding a capillary tube from which a sample is emitted, the capillary holder comprising:

[0165] A sheath member for surrounding at least a portion of a capillary, wherein the sheath member has one or more holes therein to allow observation of the capillary; and

[0166] A connector element for connecting a sheath component to position a capillary within an electrospray device.

[0167] The sheath component protects the capillary and provides protection to the user from capillary interference, and is attached to the connector element to position the capillary within the electrospray device. In use, the sample can then be fed into the capillary and electrosprayed from it.

[0168] A capillary retainer may include a capillary. In particular, a capillary retainer may include an emitter assembly that includes a capillary and a sheath member.

[0169] The sheath member may have a connector end for connecting to the connector element and a distal end opposite to the connector end.

[0170] The connector end and the distal end may be separated in the axial direction, and the sheath member may include one or more holes to allow observation of the capillary (such as the capillary outlet orifice) from the radial direction (perpendicular to the axial direction). For example, one or more holes may be located radially outside the capillary outlet orifice and at the same axial position as the capillary outlet orifice.

[0171] In this respect, the sheath member may extend between the connector end and the distal end to have a longitudinal axis extending between the connector end and the distal end, wherein the axial direction and the radial direction are defined relative to the longitudinal axis.

[0172] The sheath component can be removably attached to the connector element.

[0173] The capillary may have an outlet orifice for emitting a sample from it, and the sheath member may at least partially surround the capillary and extend beyond the outlet orifice of the capillary (i.e., downstream, for example in the axial direction).

[0174] Capillary tubes can have a length that extends in the axial direction.

[0175] Connector elements may include bores for conveying samples into capillaries when the connector element is attached to a sheath member.

[0176] As described herein, the conduit can be inserted into and into the capillary through a bore in the connector element to deliver liquid samples and / or gases into the capillary. The transmitter assembly and / or connector element may include the conduit, but preferably, if desired, the capillary retainer can be used independently of the conduit.

[0177] The sheath component may include electrodes for providing a potential difference between the electrodes and the sample within the capillary, for example, for providing a potential difference between the sample within the capillary and a location (axially) beyond the outlet orifice of the capillary.

[0178] Electrospray devices can be arranged to provide a potential difference between the sample inside the capillary and the electrodes of the sheath component during use, so that droplets of the sample are electrosprayed from the outlet orifice of the capillary.

[0179] Therefore, the electrodes of the sheath component can serve as the counter electrode within the electrospray device.

[0180] Voltage can be supplied to the electrodes of the sheath component via the connector element.

[0181] The electrode is preferably electrically isolated from the outlet end of the capillary, for example, so that different potentials can be applied to the electrode and the capillary.

[0182] The device can be configured to hold the electrode in a fixed position relative to the outlet orifice of the capillary.

[0183] Electrospray devices may include a support element (e.g., as part of a sheath assembly) for securing the capillary within a sheath member. The securing element may be radially positioned between the capillary and the sheath member. The support element secures the sheath member to the capillary.

[0184] The support element may be or may include a collar.

[0185] The capillary retainer can be configured to insert the support element into the bore of the connector element while the support element holds the sheath member in position relative to the capillary.

[0186] The support element can be arranged to form a seal with the circumferential wall of the connector element surrounding the bore, for example, preventing fluid from flowing out of the bore except through an inlet capillary. For example, the connector element and / or support element may include sealing elements, such as O-rings, for forming a fluid-impermeable connection between the transmitter assembly and the connector element.

[0187] The sheath member can (circumferentially) surround the axial length of the capillary between the support element and the outlet end of the capillary (i.e., the sheath member can extend along the entire axial length of the capillary downstream of the support element).

[0188] The sheath member may also surround the inlet orifice of the capillary. The inlet orifice of the capillary may be located at the upstream end of the capillary opposite the outlet end where the outlet orifice is located. This may, for example, provide protection to the upstream end of the capillary when the transmitter assembly is disconnected from the rest of the device. 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.

[0189] The electrodes can extend the entire length of the sheath component.

[0190] The capillary can be located entirely within and between the ends of the electrode.

[0191] The sheath component can consist entirely of electrodes, thus providing the sheath component as a sheath electrode. However, this is not necessary, and the electrodes can form only some parts of the sheath component.

[0192] Support elements can be attached (e.g., secured by adhesive) to capillary and / or sheath components.

[0193] However, the support element can secure the sheath member to the capillary in any other suitable manner (so that the sheath member has a fixed position and orientation relative to the capillary).

[0194] The capillary may have any of the features described herein for capillaries used in electrospray devices. For example, the capillary may comprise a conductive material, such as a metal, or may comprise an electrically insulating material, such as glass. The capillary may be made of a material advantageously selected to resist permanent deformation in order to reduce the chance of the capillary being damaged throughout its use.

[0195] The support element can electrically isolate the capillary from the electrode (so that different potentials can be applied to the electrode and the capillary).

[0196] The diameter of the outlet orifice can be less than 100µm, for example less than 50µm, such as less than 25µm, and preferably between 0.1µm and 20µm.

[0197] The outer diameter of the transmitter assembly can be less than 20 mm, for example, less than 15 mm or less than 12 mm. This allows the transmitter assembly (with a sheathing member) to be inserted into a standard-sized sample tube (e.g., a sample tube with a volumetric capacity of 0.1 ml to 20 ml) for initial wetting of the capillary outlet end before centrifugation prior to use. However, this is not necessary, and the transmitter assembly can be inserted directly into the centrifuge (e.g., without a sample tube).

[0198] The electrospray device may include a cap into which a sheath member can be inserted and removed. The sheath member can be attached to a connector element without removing it from the cap, and the cap can be removed once the emitter assembly is attached to the connector element. The cap may include a closure that is closable when the cap is removed from the sheath member, which substantially seals the cap to prevent any accidental accumulation of material in the cap when the sheath member is not inserted. The cap may be a sample tube with a volumetric capacity of 0.1 ml to 20 ml, and the emitter assembly can be inserted into a centrifuge with the sheath member inside the sample tube.

[0199] The sheath component may include an attachment portion at the connector end for removably attaching the sheath component to the connector element.

[0200] The sheath component may include an observation portion at the distal end, wherein one or more holes are located in the observation portion.

[0201] The sheath component can completely circumferentially enclose the capillary between the attachment portion and the observation portion.

[0202] The attachment portion can be a single, integral (monolithic) part (rather than an assembly of separately manufactured parts). The attachment portion can also be integral with other parts of the transmitter assembly. For example, the sheath member can include a single, integral part that includes the attachment portion. The single, integral part can extend (axially) beyond the outlet orifice of the capillary. The single, integral part can be attached to or include the electrodes of the sheath member.

[0203] The sheath component can be a single, integral (whole) part.

[0204] The applicant has recognized that providing (at least) the attachment portion of the sheath component as a single integral part, in whole or in part, can provide a suitable attachment of the sheath component to the electrospray device, while simplifying the manufacturing of the component and / or the electrical connection path to the electrode.

[0205] The sheath member can be configured to be attached to the connector element by rotating the sheath member relative to the connector element.

[0206] The capillary retainer can be configured to allow the sheath component to be rotated to a predetermined position relative to the connector element.

[0207] The predetermined position may correspond to a rotation of the sheath member relative to the connector element about its longitudinal axis of less than a full turn (360 degrees). For example, the predetermined position may correspond to a quarter turn (90 degrees) or a half turn (180 degrees).

[0208] The capillary retainer can be configured to provide a releasable snap-fit ​​or interference fit between the connector element and the sheath component at a predetermined position.

[0209] The applicant has discovered that a releasable snap-fit ​​or interference fit can provide a tool-free connection that allows for intuitive operation by the user, provide a reproducible connection position for the transmitter assembly, and allow for quick connection and disconnection.

[0210] The sheath component can be configured to provide an audible sound (e.g., a "click") at a predetermined location.

[0211] The sheath member or connector element may include a flexible arm. The flexible arm may be configured to provide a releasable snap-fit ​​engagement between the connector element and the sheath member, such as by rotating the sheath member relative to the connector element.

[0212] The flexible arm may include a connected end attached to the support structure and a free end opposite the connected end, wherein the flexible arm is configured to allow the free end to be displaced relative to the connected end (e.g., in the axial direction).

[0213] The free end of the flexible arm can be configured to move between a first (stationary) position and a second (displaced) position, allowing the sheath member to connect to the connector element. During connection, the flexible arm can move from the first position to the second position and then back from the second position to the first position. Once connected, the flexible arm can be in the first position or in a third (connected) position.

[0214] The free end of the flexible arm can be biased (e.g., by material elasticity) to return to the first position.

[0215] One of the connector elements and the sheath component may include a flexible arm, and the other of the connector elements and the sheath component may include an engagement structure.

[0216] The engagement structure can be configured to form a releasable snap-fit ​​connection with the flexible arm.

[0217] The device can be configured to displace the free end of the flexible arm (e.g., to a second and / or third position) during the attachment of the sheath member to the connector element (e.g., when the sheath member is rotated relative to the connector element).

[0218] The flexible arm may include a protrusion (e.g., at a free end), and the device may be configured such that the protrusion abuts a surface of the engagement structure when the connector element is attached to the sheath member. For example, the device may be configured such that the engagement structure is located between the support structure and the protrusion when the sheath member is attached to the connector element.

[0219] The protrusion may have a curved or inclined portion (e.g., a chamfer or bevel) to allow the flexible arm to be displaced by the engagement structure for example, to remove the sheath member from the connector element when the sheath member is rotated relative to the connector element in a direction opposite to the direction in which the sheath member is rotated to attach the sheath member to the connector element.

[0220] The engagement structure may include a curved or inclined surface that contacts a protrusion when the sheath member rotates relative to the connector element. This allows the flexible arm to gradually shift in a controlled manner based on the curvature or gradient of the ramp.

[0221] Connector elements may include circumferential walls surrounding the bore.

[0222] The sheath member may include 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 each other. The collar portion may be provided as a support structure to which a flexible arm is connected.

[0223] The engagement structure can be disposed on the circumferential wall of the connector element surrounding the bore, for example, the engagement structure can protrude radially outward from the circumferential wall of the connector element.

[0224] The collar portion may include a circumferential slot for receiving the engaging member therein.

[0225] The slot may have a first portion and a second portion, the first portion allowing the engaging structure to slide axially relative to the sheath member within the slot, and the second portion allowing the sheath member to rotate relative to the engaging structure while retaining the engaging structure within the slot. During connection, the engaging structure may travel within the first portion and then within the second portion.

[0226] The slot can be partially defined by a flexible arm.

[0227] The sheathing component may include a circumferential wall for surrounding at least a portion of the axial length of the capillary.

[0228] When the sheath member and the connector element are connected, the axial ends of the circumferential wall of the sheath member and the circumferential wall of the connector element can be adjacent to each other.

[0229] The circumferential wall of the sheath member may include one or more holes, for example, such that the circumferential wall encloses the periphery of one or more holes. The holes may otherwise be opened rather than enclosed at the distal end of the sheath member, for example, in an arrangement where the sheath member includes a pointed end as described below.

[0230] The sheath component may include an outlet orifice for a sample emitted from the capillary to pass through. When the capillary is located within the sheath component, the outlet orifice may extend axially beyond the outlet opening of the capillary (downstream therefrom).

[0231] The outlet orifice may be adjacent to or not adjacent to one or more orifices used for observing the capillary.

[0232] The electrode may include an outlet orifice.

[0233] The electrode may extend along at least a portion of the circumferential wall of the sheath member.

[0234] The electrode may include one or more (side) apertures for observing the capillary. For example, the electrode may include a mesh or cage structure that surrounds a portion of the (axial) length of the capillary (and includes the side apertures).

[0235] One or more (side) holes allow observation of the capillary's position within the sheath component during assembly, making it easier to set / verify the capillary's location.

[0236] One or more holes allow for optical (e.g., with a camera) observation of the sample at the capillary outlet end, which can allow for verification / evaluation of aspects of the electrospray process, such as wetting of the capillary outlet end, the absence of any bubbles, and the formation of a Taylor cone. Side holes in the counter electrode can also be used to control / set the shape of the electric field at the capillary outlet end, thereby setting an appropriate electric field for the desired propagation of the droplet spray emitted from the capillary.

[0237] Therefore, the device may include one or more cameras for observing capillaries through one or more holes in the sheath electrode.

[0238] The sheath member may include a pointed end (at the distal end). The pointed end may extend axially (downstream) from the circumferential wall of the sheath member.

[0239] The tip can extend beyond the capillary's outlet orifice (down to its downstream position).

[0240] One or more holes can be multiple holes, and the tips can circumferentially separate the holes from each other (the holes can be gaps that are open at the distal end and circumferentially located between the corresponding pairs of tips).

[0241] Therefore, the tips can be spaced apart in the circumferential direction around the longitudinal axis of the sheath member (and / or capillary) to define holes (gap) therebetween.

[0242] The orifice (gap) can be located at the same axial position as the outlet orifice of the capillary.

[0243] The tip can extend from an upstream (axial) position to a downstream (axial) position of the capillary outlet orifice. For example, the sheath member may include a wall circumferentially surrounding at least a portion of the axial length of the capillary upstream of the outlet orifice, and the tip can extend from the circumferential wall to a position downstream of the capillary outlet orifice.

[0244] The tips can have any suitable size and shape. Tips can be the same size (and shape) as each other, or tips of different sizes / shapes can be provided. The tips can be circumferentially spaced apart around the longitudinal axis of the capillary. The gaps between the tips can be the same size (and shape) as each other.

[0245] The electrode may extend along one or more of the tips. For example, the electrode may extend along multiple tips (and optionally each of the tips), in which case portions of the electrode disposed on different tips may merge upstream of the tips (e.g., as discussed above, the sheath member may consist entirely of the electrode).

[0246] Multiple electrodes may otherwise exist, with different electrodes positioned on different tips within the tip, and each electrode may correspond to the electrodes described herein for the sheath member. In use, the electrodes on the different tips may each have an equal potential applied thereto (but this is not required). The sheath member may be made of a conductive material such as a metal, may include a conductive coating (e.g., paint) applied to an electrically insulating material such as a plastic material, or may include an electrically insulating material filled with conductive powder (e.g., carbon powder, metal powder) dispersed therein. For example, the sheath member may include (electrically insulating) plastic materials such as polypropylene, polyetheretherketone (PEEK), or polyimide. The conductive material located / dispersed within the sheath member may form electrodes.

[0247] One or more holes used for observing capillaries may not contain any solid material, or an optically transparent and / or electrically insulating solid material may be located in one or more holes.

[0248] The sheath component or electrospray emitter assembly can be attached to the connector element while maintaining the position of the electrodes (and optionally the entire sheath component) relative to the capillary.

[0249] When the electrospray emitter assembly is attached to the connector element, the sheath member can extend outward from the connector element beyond the outlet end of the capillary (the sheath member can circumferentially surround the entire axial length of the capillary extension beyond the connector element).

[0250] The electrospray emitter assembly may include 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 inclined spring between the connector element and the sheath member), using a press fit, snap fit, bayonet connection, or threaded connection. The connector element may be attachable to or integrated with a device for supplying samples into a capillary (e.g., a housing body as described herein).

[0251] As discussed above, connector elements may include bores for delivering samples and / or conduits into capillaries. The bores in the connector elements may have tapered inlets for guiding conduits into the capillaries.

[0252] The downstream end of the connector element and the upstream end of the emitter assembly can form a fluid-impermeable connection with each other. For example, the connector element and / or the electrospray emitter assembly may include one or more sealing elements, such as "O-rings," to provide a fluid-impermeable connection between the emitter assembly and the connector element.

[0253] It is believed that the electrospray emitter assembly, including the sheath component and capillary, can be novel and inventive, independent of the connector element.

[0254] Therefore, according to a seventh aspect of the invention, an electrospray emitter assembly is provided, the electrospray emitter assembly including a capillary and a sheath member surrounding at least a portion of the length of the capillary.

[0255] The sheath components and / or capillaries may have any of the optional features of the electrospray device described herein.

[0256] In one embodiment, the capillary has an outlet orifice at its outlet end for emitting a sample from it, the sheath member includes an electrode extending downstream from the outlet orifice of the capillary, and the electrospray emitter assembly is arranged to provide a potential difference between the sample within the capillary and the electrode of the sheath member during use, so that droplets of the sample are electrosprayed from the outlet orifice of the capillary.

[0257] As described above, the sheath component can provide protection to the capillary and to the user from the influence of the capillary, and can also function as an electrode, i.e., provide a potential difference between the energized sample inside the capillary and the region outside the capillary outlet end.

[0258] This component can hold the counter electrode in a fixed position relative to the capillary.

[0259] According to an eighth aspect of the present invention, a method for preparing an electrospray liquid sample is provided, the method comprising:

[0260] An electrospraying device is provided, the electrospraying device including a capillary and a sheath member, the capillary having an outlet orifice at an outlet end of the capillary, the sheath member (circumferentially) surrounding at least a portion of the (axial) length of the capillary, wherein the sheath member includes an electrode extending downstream from the outlet orifice of the capillary (having a position axially beyond the outlet orifice).

[0261] Supplying the liquid sample into the capillary; and

[0262] A potential difference is provided between the liquid sample inside the capillary and the electrodes of the sheath component to electrospray charged droplets of the liquid sample from the outlet orifice of the capillary.

[0263] Providing an electrospray device may include providing electrospray according to any of the aspects or embodiments described above. For example, providing an electrospray device may include providing an electrospray emitter assembly comprising a capillary and a sheath member, and attaching the electrospray emitter assembly to the housing of the electrospray device (e.g., via a capillary retainer) while maintaining the sheath member in a fixed position relative to the capillary.

[0264] The electrospray emitter assembly and the capillary retainer may have any of the corresponding optional features described herein. For example, the capillary retainer may include a connector element for attaching the electrospray emitter assembly to the capillary housing.

[0265] Supplying a liquid sample into a capillary can include supplying the liquid sample into the capillary through a bore in a capillary holder.

[0266] Liquid samples can be supplied to the outlet end of the capillary via a conduit inserted into the capillary through the inlet orifice.

[0267] The catheter can be inserted through the bore in the capillary retainer.

[0268] Providing a potential difference between a liquid sample and an electrode within a capillary can include energizing the liquid sample by applying a voltage to the liquid sample via a conduit.

[0269] Any other suitable device that provides a potential difference can be used in other ways, and it is not necessary to apply voltage to the liquid sample via a conduit. For example, voltage can be applied to the liquid sample via a capillary or electrodes within a capillary.

[0270] The potential difference can be greater than 100V, such as greater than 1kV. The potential difference can be between 50V and 5kV, such as between 100V and 3kV. A potential difference can be provided between the sample and the electrode by applying a potential of opposite polarity to the electrode relative to the sample, by grounding the electrode while energizing the sample, or by applying a lower amplitude potential of the same polarity to the electrode relative to the sample.

[0271] The method may include supplying rinsing liquid into a capillary via a conduit, wherein the rinsing liquid flows within the capillary and exits through an inlet orifice to remove a liquid sample from the capillary via the inlet orifice.

[0272] Any of the other optional steps or features described herein related to flushing liquid samples and / or flushing liquids out of the capillary may be provided.

[0273] The method may include supplying pressurized gas into a capillary to force the sample within the capillary toward an outlet orifice.

[0274] Any of the other optional steps or features described herein related to using pressurized gas to force the sample toward the outlet orifice may be provided.

[0275] The method may include centrifuging the electrospray emitter assembly (including the sheath member and the capillary) to wet the outlet end of the capillary before attaching the electrospray emitter assembly to the capillary retainer. A liquid sample can then be subsequently supplied into the capillary via a conduit.

[0276] The sheath component can consist entirely of electrodes, thus providing the sheath component as a sheath electrode. However, this is not necessary, and the electrodes can form only some parts of the sheath component.

[0277] According to a ninth aspect of the present invention, a method for providing an electrospray device is provided, the method comprising:

[0278] A sheath member is provided surrounding at least a portion of a capillary, wherein the sheath member has one or more holes located therein to allow observation of the capillary; and

[0279] Connect the sheath component to the connector element to position the capillary for electro-spraying the sample.

[0280] The method may include any of the steps or features used in the above-described electrospray device or method.

[0281] For example, the sheath component can be connected to the connector element while keeping the capillary in a fixed position relative to the sheath component.

[0282] Connector elements may include bores for conveying samples into capillaries when the connector element is attached to a sheath member.

[0283] The support element can hold the capillary inside the sheath component, and when the sheath component and the connector component are connected to each other, the support element can be inserted into the bore of the connector component.

[0284] The sheath component may include electrodes for applying a potential to cause the sample to be electrosprayed from the capillary.

[0285] The sheath component can be attached to the connector element by rotating the sheath component relative to the connector element.

[0286] The sheath component can be rotated relative to the connector element to a predetermined position, and at the predetermined position, a releasable snap-fit ​​or interference fit can be provided between the connector element and the sheath component.

[0287] The sheath component can be a single, integral part.

[0288] The sheath component may include a tip, one or more holes may be multiple holes, and the tip may circumferentially separate the multiple holes from each other.

[0289] According to a tenth aspect of the present invention, a method for electrospraying a liquid sample from a transmitter is provided, the method comprising:

[0290] A transmitter is provided, which contains flushing liquid and has an orifice;

[0291] The liquid sample is transferred to the transmitter through the orifice, wherein the flushing liquid and the liquid sample are immiscible, so that the liquid sample is located inside the transmitter, between the flushing liquid and the orifice;

[0292] Charged droplets of a liquid sample are generated by energizing the liquid sample to eject it through an orifice; and

[0293] The flushing liquid removes the liquid sample from the emitter through the orifice.

[0294] Using a flushing liquid that is immiscible with the liquid sample, as disclosed herein, allows the flushing liquid to be used to remove the liquid sample from the emitter, thereby avoiding the “dead volume” of the liquid sample that might otherwise be unintentionally retained within the emitter. The immiscible flushing liquid can be, for example, oil. However, in such a method, any liquid that is appropriately immiscible with a particular liquid sample can be used as the flushing liquid.

[0295] The ability to remove or at least substantially reduce any dead volume of a liquid sample allows this method to be applied to small liquid samples. For example, the volume of a liquid sample transferred to the transmitter can be less than 5 µL, less than 1 µL, or less than 500 nL.

[0296] The diameter of the orifice can be less than 100µm, less than 50µm, less than 25µm, and preferably between 0.1µm and 20µm.

[0297] The emitter may include a capillary with an orifice, such as a glass capillary. When in the emitter, the liquid sample and rinsing liquid can be completely contained within the capillary.

[0298] Providing a transmitter in which a flushing liquid is contained may include transferring the flushing liquid to the transmitter via an orifice before transferring a liquid sample to the transmitter via an orifice.

[0299] The rinsing liquid and / or liquid sample can be transferred to the emitter from any suitable supply source of the rinsing liquid and liquid sample, respectively. For example, when the emitter is transferred to the supply source of the rinsing liquid / liquid sample, the emitter can be immersed in it.

[0300] The flushing fluid can be used to remove the liquid sample from the emitter in any suitable manner. For example, the emitter may include a displacement device (e.g., a plunger) for displacing the flushing fluid (located between the displacement device and the liquid sample), thereby removing the liquid sample from the emitter through an orifice.

[0301] The displacement device can be used to transfer liquid samples and / or flushing liquids into the emitter.

[0302] The transmitter may include a displacement device for changing the amount of fluid volume that can be held within the transmitter, and the method may include:

[0303] By moving the displacement device to increase the volume of fluid that can be retained within the emitter, thereby drawing the liquid sample into the emitter through the orifice, the liquid sample is transferred into the emitter via the orifice; and

[0304] By moving the displacement device to reduce the volume of fluid that can be retained in the emitter, the flushing liquid is used to remove the liquid sample from the emitter through the orifice.

[0305] Transferring flushing fluid to the emitter via the orifice may include moving the displacement device to increase the volume of fluid that can be retained in the emitter before transferring the liquid sample to the emitter, thereby drawing the flushing fluid into the emitter through the orifice.

[0306] After removing the liquid sample from the emitter via the orifice using a flushing liquid, the method can be repeated any number of times for subsequent liquid samples. Therefore, the method could include transferring the next liquid sample into the emitter via the orifice, repeating the process to generate charged droplets of the next liquid sample, and removing them from the emitter using a flushing liquid, etc.

[0307] Different liquid sample volumes separated by the flushing liquid can also be maintained within the emitter by alternating between transferring the flushing liquid into the emitter and transferring the liquid sample into the emitter any number of times, such that a certain volume of liquid sample is located within the emitter between a certain volume of flushing liquid and the orifice, and one or more other volumes of liquid sample (the same sample or different samples) are each located within the emitter between their respective volumes of flushing liquid. Then, once any volume of flushing liquid and other volumes of liquid sample maintained within the emitter between their respective volumes of liquid sample and the orifice have been removed from the orifice, different volumes of liquid sample can be sequentially emitted by emitting the respective volumes of liquid sample.

[0308] The liquid sample can be energized in any suitable manner. For example, voltage can be supplied from the transmitter to the liquid sample via rinsing the liquid, via a displacement device, via a conductive coating on the transmitter, and / or via electrodes (e.g., wires) within the transmitter.

[0309] In one embodiment, the method includes energizing the liquid sample by supplying voltage to the liquid sample via a rinsing liquid and / or via a displacement device.

[0310] According to an eleventh aspect of the present invention, a method for mass spectrometry and / or ion mobility spectrometry is provided, the method comprising providing ions from charged droplets generated using a method for producing an electrospray liquid sample as described herein, and performing mass and / or ion mobility analysis on said ions or ions derived from said ions.

[0311] Ions generated from charged droplets can be fed into the inlet of a mass spectrometer and / or ion mobility spectrometer and analyzed in any suitable manner. Ions generated from charged droplets can include analyte ions generated from analytes within the sample. Attached Figure Description

[0312] The various embodiments will now be described by way of example only, with reference to the accompanying drawings, wherein:

[0313] Figure 1A An electro-spraying device according to an embodiment of the present invention is shown;

[0314] Figure 1B An electro-spraying device according to another embodiment of the present invention is shown;

[0315] Figure 1C It shows Figure 1B Enlarged view of certain components of the electro-spraying device;

[0316] Figure 1D An electrospraying device according to another embodiment of the invention is shown, the device having a retractable sheath shown in an extended position;

[0317] Figure 1E It shows Figure 1D The electro-spraying equipment, wherein the retractable sheath is in the retracted position;

[0318] Figure 1F An electrospraying device according to another embodiment of the invention is shown, the device having a sheathed electrode surrounding a capillary;

[0319] Figure 1G It shows Figure 1F A cross-sectional view of an electro-spraying device;

[0320] Figure 1H The sample was shown from Figure 1F and Figure 1G Electro-spraying at the outlet end of the capillary of the electro-spraying device;

[0321] Figure 1I An electrospraying device according to another embodiment of the invention is shown, wherein the device has a fork-shaped sheath member;

[0322] Figure 1J This illustrates the situation when the sheath component is attached to the connector element. Figure 1I Electrospraying equipment;

[0323] Figure 1K It shows Figure 1I and Figure 1J Electrospray equipment, in which sample tubes are covered with sheath components;

[0324] Figure 1L This illustrates the situation when the sheath component is attached to the connector element. Figure 1K Electrospraying equipment;

[0325] Figure 1M This illustrates when the sheath component is attached to the connector element and the connector element is attached to the housing body. Figure 1I and Figure 1J A cross-sectional view of an electro-spraying device;

[0326] Figure 1N It shows Figure 1M The rear view of the electro-spraying equipment, and indicating Figure 1M The cutting plane;

[0327] Figure 10 It shows Figure 1M and Figure 1N Offset cross-sectional view of the electro-spraying device;

[0328] Figure 1P It shows Figure 10 The rear view of the electro-spraying equipment, and indicating Figure 10 The cutting plane;

[0329] Figure 2 A method for electrospraying samples according to an embodiment of the present invention is shown;

[0330] Figure 3 A to Figure 3 C shows a graph of data demonstrating the reusability of the capillary in the electrospray device according to an embodiment of the present invention;

[0331] Figure 4 An electrospray device according to another embodiment of the present invention is shown. Detailed Implementation

[0332] Figure 1A An electrospray device 100 according to an embodiment of the present invention is shown. The device 100 includes a capillary 102 housed within a capillary housing 104. The capillary 102 is configured to act as an emitter that, in use, when a sample is supplied to the outlet orifice 108 of the capillary 102 and the sample is energized, the emitter will emit charged droplets 106 of the sample via the electrospray process.

[0333] The outlet orifice 108 is located at the outlet end of the capillary 102, and its dimensions can be designed to allow the capillary 102 to be used in nanoelectrospray ionization (nanoESI) processes. For example, the diameter of the outlet orifice 108 at the downstream end can be less than 100µm, less than 50µm, or less than 25µm, and is preferably between 0.1µm and 20µm.

[0334] In use, the sample meniscus can be formed such that a capillary 102 extends from the outlet orifice 108 (e.g., in the form of a Taylor cone), and the electrostatic stress within the sample generated by the energization of the sample can cause charged droplets 106 to be emitted from the meniscus. A series of smaller droplets can then be generated from the charged droplets, for example, through sample evaporation, as the electrostatic force within the charged droplets 106 increases with their size, causing the droplets to decrease in size and break into smaller droplets. In electrospray ionization, this process can result in the acquisition of gaseous ions emitted from the droplets for use, for example, by entering the inlet 110 of a mass spectrometer for analysis.

[0335] Capillary 102 may be a drawn glass capillary including a conductive (e.g., metallic) coating, and the capillary housing may be configured to supply a voltage received from voltage source 111 to the conductive surface of capillary 102 to energize the sample at its tip. However, this is not required, and in other embodiments, capillary 102 itself may be made of a conductive material so that no coating is needed, or capillary 102 may not have a conductive surface, and other means for energizing the sample may be provided, such as by providing electrodes (e.g., wires, rods, or needles) located within, upstream of, or downstream of capillary 102.

[0336] Any suitable voltage can be used for electrospraying a specific sample. However, it is preferable to supply a voltage greater than 100V to the sample for electrospraying. For example, the voltage can be between 100V and 10kV, and preferably between 200V and 2kV.

[0337] Device 100 includes a conduit 112 configured to fill the capillary 102 at its outlet end with a sample to be emitted from outlet 108. The conduit 112 enters the capillary 102 through a discharge orifice 114 at its inlet end (the end opposite the outlet end) and extends within the capillary 102 from the inlet end toward the outlet end. The outlet of the conduit 112 may be arranged within and near the outlet end of the capillary 102 such that a sample can be supplied from the conduit to the outlet end of the capillary 102 without wetting the entire length of the capillary 102. For example, the outlet 116 of the conduit 112 (from which a sample can be supplied into the capillary 102) may be located at at least 60%, 70%, 80%, or 90% of the distance from the inlet end toward the outlet end of the capillary 102. In this respect, the conduit 112 preferably does not extend the entire length of the capillary 102 to enter the outlet orifice 108. However, the conduit 112 extends within the capillary such that the outlet 116 of the conduit is close to the outlet orifice 108 of the capillary 102.

[0338] Positioning the outlet 116 of the conduit 112 near the outlet orifice 108 of the capillary 102 allows for a more efficient and reliable supply of small sample volumes to the outlet end of the capillary 102 for electrospraying via the outlet orifice 108. For example, the device 100 can be operated with sample volumes less than 10 µL.

[0339] The inlet end of capillary 102 opens at a discharge orifice 114 for receiving a conduit therein, and the size of the discharge orifice 114 is larger than that of the outlet orifice 108 (e.g., having a larger area or diameter). Capillary 102 may be substantially straight, having a discharge orifice 114 and an outlet orifice 108 at two opposite ends, and the inner diameter of capillary 102 may be substantially constant in the direction from the inlet end toward the outlet end until reaching the tip portion of capillary 118, at which point the inner diameter may decrease toward the outlet orifice 108, and the conduit 112 extends into the tip portion 118 of the capillary.

[0340] In use, the surface energy / tension between the inner wall of capillary 102 and the sample supplied into capillary 102 can cause the sample to flow toward the outlet orifice 108 of capillary 102. Other forces may also be employed if desired. For example, pressure (e.g., with a pump) may be provided to deliver the sample toward the outlet orifice 108 and / or, at least during sample supply to capillary 102, capillary 102 may be oriented such that gravity will contribute to the supply of the sample to the outlet orifice 108 of capillary 102. However, it is not necessary for some external force or pressure to wet the tip of capillary 102 for the sample.

[0341] Continue to refer to Figure 1A The device 100 includes a supply housing 120 and an injection pump 122 that supplies a sample to be electrosprayed into a conduit 112 housed within a portion of the supply housing 120. The supply housing 120 includes a sample connector 124 adapted and configured to deliver a sample from the injection pump 122 into the conduit 112. The sample connector 124... Figure 1A The sample connector 124 is shown as a separate component connected to the catheter 112, but may otherwise be integrated with the catheter 112. The sample connector 124 may be made of a thermoplastic such as PEEK. The catheter 112 extends from the supply housing 120 to the capillary housing 104 and into the capillary 102 for supplying a sample 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 catheter 112 extends, and this flexible connection portion allows for desired positioning of the capillary housing 104 and the supply housing 120 in use. The flexible connection portion 126 may include, for example, a sheath made of a material such as plastic or other electrically insulating material, surrounding the catheter 112 and providing additional protection for the catheter 112. The flexible connection portion 126 may otherwise consist (entirely) only of a portion of the catheter 112. The flexible connection portion 126 can electrically isolate the supply housing 120 from the voltage applied downstream from the supply housing 120. This ensures that the voltage applied to the sample is not transmitted to the user or some other upstream fluid components.

[0342] The device 100 is configured to allow the capillary 102 to be reused with different samples electrosprayed at different times. Between different samples, the device 100 can flush the capillary 102 to remove the previous sample retained in the capillary 102. The device 100 can flush the capillary 102 by supplying flushing liquid to the capillary 102 via conduit 112 and then optionally supplying flushing gas to the capillary 102 via conduit 112 to remove the flushing liquid.

[0343] The same syringe pump 122 can optionally be used to supply sample, flushing liquid, and gas. For example, to supply flushing liquid to conduit 112, syringe pump 122 can be withdrawn from sample housing 120, refilled with flushing liquid, and reinserted into sample housing 12 for supplying flushing liquid to conduit 112 via sample connector 124. This process can then be repeated to supply flushing gas from syringe pump 122 to conduit 112 for delivery to capillary 102.

[0344] However, any suitable supply device can be used instead of the syringe pump 122. Optionally, a supply device capable of sequentially supplying different fluids into the conduit 112 without being withdrawn from the sample housing 120 can be used to supply at least two (and optionally all three) of the sample, flushing liquid, and gas. Different syringe pumps or other supply devices can be used in other ways to supply the sample, flushing liquid, and gas into the conduit separately.

[0345] The capillary housing 104 includes a discharge port 128 for receiving flushing liquid from the capillary discharge port 102, and the device 100 is configured such that, for example, when flushing gas is supplied to the capillary 114 via conduit 112, flushing liquid flows into the discharge port 128 through the discharge orifice 114 of the capillary 102. The capillary 102 can then be resupplied with another sample via conduit 112 for electrospraying. A bottle or other storage device (not shown) can be connected to the discharge port 128 to collect the fluid that has been flushed out of the capillary 102.

[0346] The flushing gas supplied to capillary 102 can cause a portion of the flushing liquid to flow out of the capillary outlet orifice 108. This can also occur, or otherwise, due to the voltage maintained on capillary 102 during flushing, as discussed below. However, flushing liquid outflow from outlet orifice 108 is not necessary, and due to the larger size of discharge orifice 114 compared to capillary outlet orifice 108, the fluid pressure characteristics can cause the flushing gas supplied to capillary 102 to force substantially all of the flushing liquid out of capillary 102's discharge orifice 114.

[0347] While rinsing capillary 102, the voltage supplied by the device 100 for electrospraying can be stopped. However, in an embodiment, voltage can be supplied while the capillary contains rinsing liquid, which can cause a portion of the rinsing liquid to be electrosprayed through the outlet orifice 108 of capillary 102. This allows for maintaining the same voltage throughout use if desired and ensures that any sample retained in the outlet end of capillary 102 is removed.

[0348] Any suitable rinsing liquid can be used, and a specific rinsing liquid can be selected for a specific sample. The rinsing liquid is preferably miscible with the previously used (sprayed) sample and can be a solvent for the sample. For example, the rinsing liquid may include or consist of a solvent, and the sample may also include that solvent, for example, where the sample (but not the rinsing liquid) contains an analyte dissolved in the solvent. Any suitable rinsing gas can be used, such as air or an inert gas, such as nitrogen.

[0349] Using device 100 to flush and refill capillary 102 via a catheter in the manner disclosed herein allows capillary 102 and capillary housing 104 to remain in place while being flushed and refilled with (another) sample. This avoids the need to remove capillary 102 from capillary housing 104 for refilling (or discarding) after use with the first sample.

[0350] However, capillary 102 is preferably removable from capillary housing 104. This allows capillary 102 to be replaced when appropriate (e.g., if capillary 102 is damaged).

[0351] Furthermore, in certain embodiments, the outlet end of capillary 102 may be wetted with fluid by other means, such as via centrifugation, before it is inserted into capillary housing 104. This may be performed, for example, before capillary 102 is first used in device 100. Once the outlet end is wetted, the outlet orifice 108 may retain a small amount of fluid (e.g., sample and / or flushing liquid) throughout its use, including during rinsing, which will allow for more reliable delivery of the next sample to the capillary outlet orifice 108 when supplied via conduit 112. Due to the small size of any fluid retained at the outlet orifice 108 of capillary 102 after rinsing, this can be achieved without significantly affecting the composition of the sample emitted via the outlet orifice 108 of capillary 102.

[0352] Figure 1B An electrospraying device 130 according to another embodiment of the present invention is shown. The electrospraying device 130 includes a capillary housing 134 having a... Figure 1A The capillary housing 104 of the electrospray device 100 has a different structure. However, Figure 1A Other components and functions of the electro-spray device 100 can be combined with Figure 1B The electrospray device 130 is used together (such as sample housing 120 and capillary 102), and in Figure 1B In the following description, the same reference numerals are used for the same parts.

[0353] The capillary housing 134 includes a housing body 136 and a capillary retainer 138 removably attached to the housing body 136. The capillary retainer 138 holds the capillary 102 therein and can be removed from the housing body 136 without removing the capillary 102 from the capillary retainer 138. The capillary retainer 138 may include a removable cap or sheath (not shown) for sealing (and thus protecting) the outlet end of the capillary when not in use. The capillary retainer 138 includes a tapered inlet 140 for guiding the conduit 112 into a discharge orifice 114 of the capillary 102. Gases and liquids can flow through the tapered inlet 140 outside the conduit 112 and flow into and out of the capillary 102 via the discharge orifice 114.

[0354] The capillary housing 134 includes a chamber 142 therein and a gas inlet conduit 144 having a valve 146 (e.g., a pneumatic valve) for controlling the supply of pressurized gas from the gas inlet conduit 144 to the chamber 142. The capillary housing also includes a discharge conduit 148 having a valve 150 (e.g., a pneumatic valve) for controlling the flow of fluid out of the chamber 142 via the discharge conduit 148.

[0355] The bottom wall 151 of chamber 142 is angled to remove liquid from chamber 142 into discharge conduit 148 (and capillary 102 is also angled downward when fixed in capillary housing 134 to help the sample flow to outlet orifice 108).

[0356] The capillary housing 134 also includes a conduit retainer 152 for securing the conduit 112 within the capillary housing 134, such that the conduit 112 is in a fixed position within the capillary 102 (when the capillary 102 and the capillary retainer 138 are attached to the housing body 136). The conduit retainer 152, the gas inlet conduit 144, and the outlet conduit 148 can all be removably attached to the housing body 134 (but this is not required). When the conduit retainer 152 is removed from the housing body 136, the conduit retainer 152 can hold the conduit 112 in place.

[0357] The conduit 112 includes an electrically insulating conduit portion 112a that extends into the conduit retainer 152 and engages with a conductive conduit portion 112b of the conduit 112 at a connector 154 within the capillary housing 134. The electrically insulating conduit portion 112a may include, for example, a flexible tube (e.g., made of a plastic material such as thermoplastic PEEK), and the conductive conduit portion 112b may include a (rigid) metal (e.g., stainless steel) tube for insertion into the capillary 102. A conductive tube 155 surrounds the connector 154 between the electrically insulating conduit portion 112a and the conductive conduit portion 112b, and extends downstream from the connector 154. The conductive tube 155 does not extend upstream out of the conduit retainer 152 to prevent external components from being energized and to reduce the likelihood of electric shock to the user. Downstream of the connector 154, the conductive tube 155 has a tab 156 that extends inward and makes electrical contact with the conductive conduit portion 112b within the capillary housing 134. Upstream of connector 154, collar 158 is in electrical contact with conductive tube 155, and in use, voltage can be applied to collar and delivered to sample to energize sample via conductive tube 155 and conductive conduit portion 112b.

[0358] Figure 1C The diagram shows an enlarged view of the cross-section of the conductive tube 155, as well as the cross-sections of the conductive conduit portion 112b and the electrically insulating conduit portion 112a, which also best shows the structure of the tab 156 that contacts the conductive conduit portion 112b.

[0359] like Figure 1C As shown, the conductive tube 155 includes a fluid vent 160 such that if the connector 154 fails, fluid flowing into the conductive tube 155 from the connector 154 can leak into the chamber 142 via the fluid vent (160), rather than potentially leaking out of the capillary housing 134 via the conduit retainer 152, which could potentially pose a danger to the user.

[0360] Combination Figure 1B and Figure 1C The described devices for energizing the sample are not essential, and alternative electrodes / devices may be provided. However, when the conduit 112 is used to energize the sample, the conductive conduit portion 112b of the conduit 112 preferably does not extend beyond the capillary housing 134 so as not to pose an electrical hazard to the user.

[0361] In use, the sample is supplied to the capillary 102 through the conductive conduit portion 112b. Pressurized gas can be supplied to 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 discharge conduit 148 can remain closed, such that the pressure of the pressurized gas within the chamber 142 increases with the amount of gas supplied to the chamber 142. The pressurized gas is supplied from the chamber 142 into the capillary 102 via the discharge orifice 114, forcing the sample toward the outlet orifice 108. Forcing the sample toward the outlet orifice 108 in this way reduces any air bubbles present in the portion of the capillary 102 intended to be occupied by the sample. After the sample has been forced toward the outlet orifice 108 by the pressurized gas, the valve 150 of the discharge conduit 148 can be opened (and the valve 146 of the gas inlet conduit 144 optionally closed) to allow the pressurized gas to be released therethrough, thereby reducing the pressure of the pressurized gas within the capillary 102. This can be done before or after the sample is electrosprayed from the outlet orifice 108. For electrospraying the sample, the sample is energized by applying voltage to the conductive conduit portion 112b (via the collar 158 and the conductive tube 155). Energizing the sample causes charged droplets of the sample to be ejected from the outlet orifice 108. To flush the sample out of the capillary 102, flushing liquid is supplied to the capillary 102 via conduit 112 to flush the sample out of the capillary 102 through the discharge orifice 114. Optionally, flushing gas is subsequently supplied to the capillary 102 via conduit 112 to force the flushing liquid out of the capillary 102 through the discharge orifice 114. Before flushing the sample out of the capillary 102, the valve 150 of the discharge conduit 148 is opened to reduce the pressure of the pressurized gas, preventing this from otherwise resisting the flow of liquid out of the capillary 102. During rinsing, valve 150 of discharge conduit 148 remains open to allow the sample and rinsing fluid to be removed from chamber 142 via discharge conduit 148. Valve 146 of gas inlet conduit 144 may remain open (or reopen if closed earlier) to allow gas to (continue to) flow from gas inlet conduit 144 into chamber 142 to help flush the fluid out of chamber 142 and into discharge conduit 148. When the next sample is about to be or has already been supplied to capillary 102 (after the previous sample has been rinsed into the discharge port), valve 150 of discharge conduit 148 may close, allowing pressurized gas supplied to chamber 142 to be re-supplied to capillary 102 at an appropriate pressure to force the next sample toward outlet orifice 108.

[0362] Although the gas inlet conduit 144 is described as having a valve 146, this is not necessary, and the pressure inside the chamber 142 can be controlled while the gas is continued to be supplied to the chamber 142 by opening or closing the valve 150 of the outlet conduit 148, and / or the flow of gas into the chamber 142 can be stopped or started in other ways by some other upstream components that supply pressurized gas.

[0363] although Figure 1A The capillary housing 104 is not described as having Figure 1B Some parts of the capillary housing 134, but Figure 1B Any one of the components of the capillary housing 134 can be provided Figure 1A The capillary housing 104 includes, for example, a capillary retainer 138, a conduit retainer 152, a gas inlet conduit 144, and / or an outlet conduit 148.

[0364] Optionally, the gas inlet conduit 144 and / or the outlet conduit 148 may be connected to (or integrated with) the conduit retainer 152, rather than being separately attached to the housing body 136.

[0365] The following is for reference. Figure 2 The sample was further described from the capillary 102.

[0366] Figure 1D and Figure 1E An electrospray device 160 according to another embodiment of the present invention is shown. The electrospray device 160 is shown as being inserted into the orifice 162 of a mass spectrometer and / or ion mobility spectrometer 163. The electrospray device 160 includes a capillary housing 164 having a... Figure 1B The capillary housing 104 of the electrospray device 130 has a different structure. However, Figure 1A and Figure 1B Other components and functions of the electro-spraying equipment can be combined with Figure 1D and Figure 1E The electrospray device 160 is used together (such as sample housing 120 and capillary 102), and in Figure 1D and Figure 1E In the following description, the same reference numerals are used for the same parts.

[0367] The capillary housing 164 includes a housing body 166 and a capillary retainer 168. The capillary retainer 168 and... Figure 1B The capillary retainer 138 differs in that it includes a sheath assembly 170, however, Figure 1D and Figure 1E The capillary retainer 168 can be used with Figure 1B Used together with the housing body 136.

[0368] Continue to refer to Figure 1D and Figure 1E The capillary retainer 168 supports the capillary 102, which is surrounded by the sheath assembly 170. The capillary housing 164 is optionally configured to... Figure 1B The conduit 112 is fixed therein in the same manner as the capillary housing 134.

[0369] The sheath assembly 170 includes a support body 172 surrounding a portion of the capillary 102 and a retractable sheath 174 surrounding the support body 172 and movable relative to the support body 172. The retractable sheath 174 can be in an extended position ( Figure 1D (shown in the image) and the retraction position ( Figure 1E (shown in the diagram) The capillary tube 102 moves between the extended and retractable sheaths. In the extended position, the retractable sheath 174 surrounds the outlet end of the capillary tube 102 to protect the capillary tube when not in use. In the retracted position, the capillary tube extends through an orifice 176 in the retractable sheath 174, such that the outlet end of the capillary tube 102 extends outward beyond the retractable sheath 174. The capillary tube retainer 168 includes a sealing element 177 to prevent leakage of liquid flushed from the capillary tube through the sheath assembly 170.

[0370] The retractable sheath 174 is biased toward an extended position by a first (longitudinal) spring 178, which coaxially surrounds the capillary 102 within the retractable sheath 174. A second (annular) spring 180 is located between the support body 172 and the retractable sheath 174, wherein the axis of the second spring 180 is bent about the support body 172. In the extended position, the second spring 180 contracts within a first annular recess 182a in the support body 172, contacting the flat wall of the first annular recess 182a to prevent further extension of the retractable sheath 174. As the retractable sheath 174 retracts away from the outlet end of the capillary by sliding along the support body 172, the second spring 180 is forced to expand as it travels along the inclined wall of the first annular recess 182. The support body 172 includes a second annular recess 182b to limit the extent to which the retractable sheath can slide along the support body 172 away from the outlet end of the capillary 102. The retractable sheath 174 includes a protruding edge 184 that extends radially outward to engage the surface of the mass spectrometer and / or ion mobility spectrometer 163 when the capillary 102 is inserted through the orifice 162 of the mass spectrometer and / or ion mobility spectrometer 163, such that the protruding edge 184 contacts the surface of the spectrometer 163 and retracts the sheath 174 (and causes the first spring 180 to contract) as the capillary is further inserted into the spectrometer 163. Alternative arrangements may be provided for biasing the retractable sheath 174 toward the extended position and limiting the extent to which the retractable sheath can slide relative to the capillary 102. Alternative means for retracting the sheath 174 may also be provided.

[0371] The capillary retainer 168 includes a bore 186 for delivering the conduit 112 into the capillary 102. The bore 186 has a tapered inlet for guiding the conduit 112 into the bore 186. The capillary retainer 168 is removable from the housing body 166 without removing the capillary 102 from the capillary retainer 168 and without removing the conduit 112 from the housing body 166. The capillary retainer 168 and the housing body 166 include corresponding threads for connecting one to the other; however, any other suitable attachment means may be alternatively provided.

[0372] Figure 1F , Figure 1G and Figure 1H An electrospray device 190 according to another embodiment of the present invention is shown. Figure 1G A cross-sectional view of device 190 is shown, and Figure 1H An enlarged view is shown of the sample being electro-sprayed from the outlet orifice 108 of the capillary 102 of the device 190.

[0373] The electrospray device 190 includes a capillary retainer 191, which is connected to... Figure 1B The capillary retainer 138 and Figure 1D and Figure 1E The capillary retainer 168 differs in that it includes an electrospray emitter assembly 192 with a sheathed electrode 193. However, Figures 1A to 1E Other components and functions of the electro-spraying equipment can be combined with Figures 1F to 1H It can be used with an electro-spray device 190. For example, the capillary 102 fixed within the capillary holder 191 can be used with... Figures 1A to 1E The capillary described in either of these is consistent and can provide the same Figure 1A Consistent sample housing 120, and in Figures 1F to 1H In the following description, the same reference numerals are used for the same parts.

[0374] The electrospray emitter assembly 192 includes a sheath member in the form of a sheath electrode 193 (but in other embodiments, the electrode may only form part of the sheath member), a capillary 102 (e.g., a glass capillary), and a collar 194 fixed to the capillary 102 and the sheath electrode 193 such that the collar 194 supports the sheath electrode in a coaxial arrangement with the capillary, and that the sheath electrode 193 surrounds the capillary 102 along its axial length.

[0375] The capillary retainer 191 also includes a connector element 195 to which the electrospray emitter assembly 192 is attached. The connector element 195 is attached to the electrospray emitter assembly 192 using a beveled spring 195a between the connector element 195 and the sheath electrode 193, and an O-ring 195b between the collar 194 and the connector element 195 forms a fluid-impermeable seal. However, any alternative or additional attachment or sealing device, such as a threaded fit, snap-fit ​​fit, or press-fit mechanism, may be provided.

[0376] The electrospray emitter assembly 192 can be attached to (and removed from) the connector element 195 while holding the sheath electrode 193 in a fixed position relative to the capillary 102. Thus, the electrospray emitter assembly 192 can be provided as an easily assembled consumable without the need for subsequent alignment of the sheath electrode 193 relative to the capillary 102.

[0377] Connector element 195 can operate with different electrospray emitter assemblies, such as electrospray emitter assemblies having capillaries with different sizes (e.g., different outlet orifice diameters) or different electrode arrangements. Connector element 195 can optionally operate with sheath assemblies having retractable sheaths (such as those described above). Figure 1D and Figure 1E The described sheath assembly (170) is compatible.

[0378] Capillary retainer 191 can be attached to the housing body 166 of the capillary housing, which has a similar structure to... Figure 1B Capillary housing 134 or Figure 1D and Figure 1E The features of the capillary shell 164 are consistent with those of the capillary shell.

[0379] The electrospray emitter assembly 190 also includes a conduit 112 that extends through a bore 195c in the connector element 195 to a capillary 102 and is inserted into the capillary 102 via a discharge orifice 114. (As stated above regarding...) Figure 1A and Figure 1B As described, the conduit can supply a sample to the outlet orifice 108 of the capillary, and the discharge orifice 114 can be used to supply pressurized gas to force the sample within the capillary 102 toward the outlet orifice 108 and / or allow the sample to be flushed out of the capillary (in which case, the pressurized gas and / or sample flushed out of the capillary also pass through the bore 195c in the connector element 195). The bore 195c has a tapered inlet for guiding the conduit 112 into the capillary 102.

[0380] The sheath electrode 193 protects the capillary 102 from accidental collision with another object during device assembly and can also protect the user from accidental punctures by the capillary 102. However, the sheath electrode 193 also acts as a counter electrode, which can provide a potential difference between the energized sample 196 inside the capillary 102 and the region outside the outlet end of the capillary 102, so that the charged droplet 106 is emitted from the outlet orifice 108 of the capillary 102.

[0381] The sheath electrode 193 extends axially outward beyond the capillary outlet orifice 108 (and downstream thereof), and includes an outlet orifice 197 (as shown in the image). Figure 1H As shown, the device 190 is configured to allow charged droplets 106 emitted from the outlet orifice 108 of the capillary 102 to pass through the outlet orifice.

[0382] The sheath electrode 193 also includes a plurality of side holes 198 surrounding the outlet orifice 108 of the capillary 102 (and having the same axial position as the outlet orifice). The side holes 198 allow observation of the outlet end of the capillary 102 to monitor the electrospray process during use (e.g., to verify the removal of any air bubbles present at the outlet end of the capillary 102). The outlet orifice 197 and the side holes 198 also define the shape of the electric field in a region outside the outlet end of the capillary 102 for controlling the emission and propagation of charged droplets electrosprayed from the capillary 102.

[0383] Figure 1I and Figure 1J A capillary retainer 201 according to another embodiment of the invention is shown. The capillary retainer 201 includes an electrospray emitter assembly 202, which includes a sheath member in the form of a forked sheath electrode 203. Figures 1A to 1E Other components and functions of the electro-spraying equipment can be combined with Figure 1I and Figure 1J The capillary retainer 201 is used in conjunction with it. For example, a capillary (not shown) fixed within the capillary retainer 201 can be used with... Figures 1A to 1H The capillary 102 described in either of the above is consistent and can provide the same Figure 1A A consistent sample housing 120, and a capillary holder 201 can be formed as part of the capillary housing, such as Figure 1B The capillary shell 134, or Figure 1D and Figure 1E The capillary housing 164, such as by attaching to the capillary housing 164, is related to the capillary housing 164. Figure 1B The described shell body 166.

[0384] A collar 204 is fixed inside the sheath electrode 203. The collar 204 supports a capillary tube coaxially arranged with the sheath electrode 203, such that the collar 204 is radially positioned between the capillary tube and the sheath electrode 203. The collar 204 can... Figures 1F to 1H The description of the ring 194 is consistent with that in the text.

[0385] The capillary retainer 201 also includes a connector element 205 to which the electrospray emitter assembly 202 is removably attached. Figure 1I An electrospray emitter assembly 202 disconnected from connector element 205 is shown, while Figure 1J The connector element 205 and the electrospray emitter assembly 202 connected to each other are shown.

[0386] The electrospray emitter assembly 202 can be attached to (and removed from) the connector element 205 while holding the sheath electrode 203 in a fixed position relative to the capillary fixed therein. Thus, the electrospray emitter assembly 202 can be provided as an easily assembled consumable without the need for subsequent alignment of the sheath electrode 203 relative to the capillary.

[0387] Connector element 205 can operate with different electrospray emitter assemblies, such as electrospray emitter assemblies with capillaries of different sizes (e.g., different outlet orifice diameters) or different electrode arrangements.

[0388] A sheath electrode 203 extends in the axial direction 207 between connector end 203a and distal end 203b. Between connector end 203a and distal end 203b, the sheath electrode 203 includes a circumferential wall 209 for surrounding a portion of the axial length of the capillary when the capillary is held within the collar 204. The sheath electrode 203 also includes four tips 211 (although other numbers of tips may be provided) extending axially downstream from the circumferential wall 209. The tips 211 are spaced apart in the circumferential direction 212 to define a gap 213 therebetween. When the capillary is located within the sheath electrode 203 (and collar 204), the tips 211 can extend axially downstream from the capillary outlet orifice, allowing the capillary outlet orifice to be observed radially via the gap 213, and allowing the sheath electrode 203 to provide a potential difference (by applying a potential to the tips) between the sample within the capillary and a location downstream of the capillary outlet orifice. 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.

[0389] 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 includes a collar portion 215 and a flexible arm 217 connected to the collar portion 215. The collar portion 215 is arranged to mate over a circumferential wall 219 of the connector element 205, which surrounds a bore 221 for supplying a sample into the capillary. During the attachment of the sheath electrode 203 to the connector element 205, a collar 204 is inserted into the bore 221, and the collar 204 includes a sealing element 204a for forming a fluid-impermeable seal with the circumferential wall 219 to prevent sample leakage from the capillary holder 201 when the sample is supplied into the capillary.

[0390] When the collar 204 is inserted into the bore 219, the collar portion 215 surrounds the circumferential wall 219 of the connector element 205 and slides (axially) into the circumferential slot 225 within the sheath electrode 203 through the engagement structure 223 protruding from the circumferential wall 219 of the connector element 205. The sheath electrode 203 then rotates relative to the connector element 205, causing the flexible arm 217 to displace away from the distal end 203b of the sheath electrode 203 by contacting the protrusion 217a at the free end of the flexible arm 217 through the engagement structure 223. As the protrusion 217a passes the end of the engagement structure 223, the flexible arm returns toward the distal end 203b of the sheath electrode 203, thus forming a snap-fit ​​connection, wherein the engagement structure 223 is held between the protrusion 217a and the collar portion 215. This secures the sheath electrode 203 and the capillary (within the collar 204) in a predetermined position relative to the connector element 205.

[0391] In order to disconnect the sheath electrode 203 from the connector element 205, the sheath electrode 203 can be rotated in the opposite direction to the direction used to connect the two parts, which causes the flexible arm 217 to be displaced and the engagement structure 223 to be released so that it can be removed from the circumferential slot 225.

[0392] although Figure 1I and Figure 1J A sheathed electrode 203 with two tips and a flexible arm 217 is shown, but this combination is not required and other connection devices can be provided for the fork-shaped sheathed electrode, and a snap-fit ​​connection can be used to connect a sheathed electrode that does not include the tips.

[0393] Figure 1K and Figure 1L It shows Figure 1I and Figure 1J The capillary retainer 201, wherein a cover 227 surrounds the distal end 203b of the sheath electrode 203. Figure 1K The sheath electrode 203, disconnected from connector element 205, is shown, while Figure 1L A sheath electrode 203 connected to connector element 205 is shown. The same reference numerals are used for the same parts.

[0394] The cap 227 may be in the form of a standard sample tube and extend to the collar portion 215 of the sheath electrode 203. By providing a cap 227 in the form of a standard sample tube, the capillary and sheath electrode 203 can be conveniently inserted together into the centrifuge (to wet the end of the capillary) by surrounding the sheath member 203 with the cap 227 and inserting the cap 227 into the centrifuge. The sheath member 203 can be connected to the connector element 205 while surrounded by the cap 227, and the cap 227 can be removed once the sheath member 203 and the connector element 205 are connected to each other. The cap 227 includes a sealing cap 229, and the sealing cap 229 can be closed to seal the cap 227 and reduce the risk of contamination when the cap has been removed from the sheath member 203.

[0395] Figure 1M An electrospray device 230, including a capillary housing 231, is shown in cross-section. The capillary housing 231 includes... Figure 1I and Figure 1J The capillary retainer 201 and the housing body 232. The housing body 232 includes a capillary retainer 201 and a housing body 232. Figure 1B The shell body 136 has some of the same features as the main body, and Figure 1M In the following description, the same reference numerals are used for the same parts.

[0396] The capillary retainer 201 includes a transmitter assembly 202 and a connector element 205. The capillary retainer 201 is removably attached to the housing body 232 via fasteners 233 that secure the connector element 205 to the housing body 232. The transmitter assembly 202 holds the capillary 102 therein and is removably attached to the connector element 205 via a collar portion 215 surrounding the circumferential wall 219 of the connector element 205 and engaging the engagement structure 223 of the connector element 205. The transmitter assembly 202 can be removed from the connector element 205 without removing the capillary 102 from the transmitter assembly 202. As described above, the capillary retainer 202 includes a forked sheath electrode 203, and the sheath electrode includes a gap 213 between tips 211 for viewing the capillary 102. The transmitter assembly also includes a collar 204 that fixes the position of the capillary 102 relative to the sheath electrode 203. A collar 204 is inserted into the bore 221 of the connector element 205, and a sealing element 204a forms a fluid-impermeable seal with the circumferential wall 219 to prevent fluid leakage from the capillary retainer 201. The bore 221 has a tapered inlet for guiding the conduit 112 into the capillary 102. Gases and liquids can flow through the bore 221 outside the conduit 112 and into and out of the capillary 102.

[0397] The housing body 232 includes a chamber 234 therein and a discharge conduit 148. The discharge conduit 148 may have a valve 150 for controlling the flow of fluid out of the chamber 234 via the discharge conduit 148. The capillary housing 232 also includes a conduit retainer 152 for securing the conduit 112 within the capillary housing 232, and the conduit retainer 152 and the conduit 112 are described above regarding... Figure 1B and Figure 1C The description is as follows. The insulating portion 112a of the conduit 112 has a connection at its upstream end for attaching to the sample housing (as described above). Figure 1A The connector 235 of the sample housing 120 described.

[0398] The conduit holder 152 can energize the sample within the capillary 102 by supplying voltage to the first electrical terminal 236, and the first electrical terminal 236 supplies voltage to the sample via the conduit 112, for example, as described above regarding... Figure 1B and Figure 1C In the same manner as described. The capillary housing 231 also includes a second electrical terminal 237 for supplying voltage to the sheath electrode 203 via the connector element 205. Thus, by supplying different voltages to the first electrical terminal 236 and the second electrical terminal 237, a potential difference can be maintained between the sample in the capillary 102 and the sheath electrode 203, allowing the sheath electrode 203 to act as a counter electrode 203 to electrospray the sample out of the capillary 102.

[0399] Figure 1N It shows Figure 1M The rear view of the device, and the same reference numerals are used for the same parts. Figure 1N It shows Figure 1M The cutting plane of the sectional view is 238. (e.g.) Figure 1N As shown (but in Figure 1M (Not visible in the middle), capillary shell 231 includes the above-mentioned... Figure 1B The gas inlet conduit 144 is described, and the gas inlet conduit 144 can supply pressurized gas into chamber 234. The pressurized gas can then be supplied from chamber 234 into capillary 102 to force the sample toward the outlet of capillary 102.

[0400] Figure 10 It shows Figure 1M and Figure 1N A cross-sectional view of the device, which better illustrates the path for supplying pressurized gas into chamber 234 via gas inlet conduit 144.

[0401] Figure 1P It shows Figure 1M , Figure 1N and Figure 10 The rear view of the device, and shows Figure 10 The cutting plane of the cross-sectional view.

[0402] Figure 2 A flowchart of a method 240 for electrospraying samples according to an embodiment of the present invention is shown. This method can be used... Figures 1A to 1P The device 100 shown in either of these will be used to perform the operation, and will refer to the above regarding Figure 1A and Figure 1B The same parts are described.

[0403] When capillary 102 contains a sample for electrospraying (step 241), a voltage is supplied to the sample to emit it via the outlet orifice 108 of capillary 102 (step 242). After the sample has been emitted via the outlet orifice 108 of capillary 102, capillary 102 can then be flushed (step 243). To flush capillary 102, flushing liquid is supplied to capillary 102 via conduit 112 before flushing gas is supplied to capillary 102 via conduit 112 (step 243b) to remove flushing liquid from capillary 102 (step 243a). The flushing liquid can flush out the sample remaining in capillary 102 after the electrospraying step via the outlet orifice 114 of capillary 102. The flushing gas supplied to capillary 102 via conduit 112 can then discharge the flushing liquid through the outlet orifice 114 of capillary 102, so that capillary 102 is substantially emptied of any liquid and ready to receive the next sample. After the rinsing liquid is removed from the capillary 102 using rinsing gas, the next sample to be electrosprayed can be supplied to the capillary 102 via conduit 112 (step 244), and this process can be repeated until all desired samples have been electrosprayed. While the sample, rinsing liquid, and gas are all supplied to the capillary via the (same) conduit 112, the rinsing liquid can also remove residual sample from the conduit 112 via the capillary 102, and the rinsing gas can also drain the rinsing liquid residing in the conduit 112 into the capillary 102 and then out of the discharge orifice 114 of the capillary 102, thereby avoiding or reducing contamination of the next sample within the conduit 112 (and any other part of the electrospray devices 100, 130, upstream of the capillary 102).

[0404] Figure 3 A to Figure 3 C shows a graph of the data, demonstrating that flushing the capillary in the manner disclosed herein can substantially remove all sample previously supplied to the capillary. Analysis using the above-described... Figure 1A A graph showing the data obtained by the electrospray device 100 through the electrospray ionization of ions.

[0405] Figure 3 A shows the mass spectrum obtained by analyzing ions from a bovine serum albumin (BSA) solution. For a 10 µl sample of 10 µM BSA dissolved in 150 mM ammonium acetate, the mass spectrum was acquired within 1 minute.

[0406] Figure 3 B illustrates a mass spectrum obtained by analyzing ions generated by an electrospray device 100 having the same capillary 102 and conduit 112 but following a flushing cycle to remove BSA solution from the capillary 102. The mass spectrum was acquired within 1 minute after a flushing cycle using 250 µL of 150 mM ammonium acetate as the flushing liquid, followed by 250 µL of air.

[0407] Figure 3 A and Figure 3 The mass spectrum of B is shown as relative ion intensities based on different corresponding absolute intensities, which represent the 100% relative intensity values ​​of the two curves. Figure 3 Mass spectrometry in A and Figure 3 A comparison of the absolute ion signals from the mass spectrometer in B indicates that the proportion of ions from the sample measured after the rinsing cycle was approximately 0.08% compared to before the rinsing cycle. Correspondingly, the number of ions from the sample detected after rinsing was more than 1000 times lower than before rinsing. This suggests that virtually all of the sample was removed from the capillary 102 of the electrospray device 100 after the rinsing cycle.

[0408] Figure 3 C shows a graph of the relative intensity versus time, measured by analyzing the ions obtained during the sample injection and rinse cycles in the electrospray apparatus. The y-axis shows the combined relative intensity of the ions within the m / z range of 3700–5200. Time periods 301a and 301b each occurred during the injection of the same BSA sample into the electrospray apparatus. Time periods 302a and 302b each occurred during the rinse cycle. It can be seen that the amount of ion signal intensity of the second injected sample (during time period 301b) is similar to that of the first injected sample (during time period 301a), demonstrating that reasonably reproducible signals can be obtained before and after the rinse cycle.

[0409] Figure 4 A to Figure 4 B illustrates an electrospray device 400 according to another embodiment of the present invention.

[0410] Figure 4A illustrates an apparatus 400 when receiving a liquid sample 401. The apparatus 400 includes a transmitter 404 comprising a capillary 402. A flushing liquid 406, immiscible with the sample 401, is held within the capillary 402 between a displacement device 408 and an orifice 410 of a conduit through which the sample 401 can be transferred from a sample container 412 (e.g., a vial or plate containing a liquid sample, such as part of a tissue or single cell) into the capillary 402. The displacement device 408 may be, for example, a syringe plunger. The flushing liquid 406 may be, for example, oil. The displacement device 408 may be in the form of a plunger, and the flushing liquid 406 can be transferred into the capillary 402 by moving the displacement device 408 in a first direction 414 while the orifice 410 is immersed in the outer volume of the flushing liquid before transferring the sample 401 into the capillary 402. Moving the displacement device 408 in the first direction 114 increases the volume of fluid that can be held within the capillary 402, thereby drawing the rinsing liquid 406 into the capillary 402 through the orifice 410. After the rinsing liquid 406 has been transferred into the capillary 402, the sample 401 can then be transferred into the capillary 402 in the same manner as the rinsing liquid 406 by further moving the displacement device 414 in the first direction 114 while immersing the orifice 410 in a volume of sample 401 stored in the sample container 412, thereby increasing the volume of fluid that can be held within the capillary 402 and thereby drawing the sample 401 into the capillary 402.

[0411] Figure 4 B illustrates an apparatus 400 for generating droplets 416 by electrospraying a sample 401, which has been transferred via an orifice 410 into a capillary 402. As the sample 401 is transferred into the capillary 402, the sample 401 is positioned within the capillary 402 between the orifice 410 and the rinsing liquid 406, and the rinsing liquid 406 is positioned within the capillary 402 between the displacement device 408 and the sample 401.

[0412] To electrospray droplets from sample 401, a voltage supplied from voltage source 411 is applied to energize sample 401. Voltage source 411 may be included within emitter 404 or may be a separate component connected to emitter 404. Any suitable voltage for electrospraying a particular sample may be used. However, it is preferable to supply a voltage greater than 100V to electrospray the sample. For example, the voltage may be between 100V and 10kV, and preferably between 200V and 2kV. The device is configured to use voltage to energize sample 401 in any suitable manner. For example, rinsing liquid 406 and / or displacement device 408 may be energized to energize sample 401 by transferring charge to sample 401, or sample 401 may be energized without energizing rinsing liquid 406 (or at least without requiring energizing rinsing liquid 406 to energize sample 401). Capillary 402 may include a conductive surface configured to deliver voltage to sample 402. The conductive surface can be a coating, in which case the capillary 402 can comprise a non-conductive material, such as a drawn glass capillary or a ceramic capillary. However, the conductive surface can be provided by other means by fabricating the capillary 402 from a conductive material (e.g., a metal).

[0413] The energization of sample 401 may be sufficient to cause the sample to be ejected from capillary 402 through orifice 410 and form droplets 416. However, displacement device 408 may be operated to reduce the volume of fluid that can be retained within capillary 402, thereby displacing the liquid sample 401 within capillary 402 toward orifice 410 and thus aiding in wetting orifice 410 and ejecting sample 401 therefrom. Displacement device 418 may be operated to reduce the volume of fluid that can be retained within capillary 402 by moving in a second direction 418 opposite to the first direction 414.

[0414] When performing ESI (or nano-ESI), droplets emitted by device 400 can generate or release ions that can be transferred to the inlet 420 of the mass spectrometer for analysis in any suitable manner.

[0415] The displacement device 418 can continue to operate during electrospraying and / or after electrospraying to reduce the volume of fluid that can remain within the capillary 402. This can cause the sample 401 retained in the capillary 402 to be discharged from the orifice 410 (via electrospraying or discarded) by operating the displacement device to displace the flushing liquid 406 toward the orifice 410 and thereby displace the remaining sample 401 toward and out of the orifice. Displacement can occur until (only) a portion of the flushing liquid 406 is discharged from the orifice 410. This avoids any “dead volume” of the liquid sample 401 remaining within the capillary 402 before another sample can be transferred into the capillary 402 (e.g., in the same manner as the previous sample).

[0416] Therefore, device 400 is reusable, wherein the same capillary 402 of transmitter 404 is operable for use with different samples. Furthermore, eliminating dead volume allows device 400 to be used with small volumes of liquid samples. For example, the volume transferred into capillary 402 can be less than 1 µL, or less than 500 nL.

[0417] Although the invention has been described with reference to preferred embodiments, those skilled in the art will understand that various changes in form and detail may be made without departing from the scope of the invention as defined in the appended claims.

Claims

1. An electrospray apparatus comprising: a capillary tube having an exit orifice for electrospraying a sample therefrom; and a conduit extending into the capillary tube in a manner enabling it to deliver the sample into the capillary tube; wherein the apparatus is configured to supply pressurised gas into the capillary tube so as to force the sample within the capillary tube towards the exit orifice.

2. An electrospray apparatus according to claim 1, wherein the exit orifice has a diameter of less than 100 pm.

3. An electrospray apparatus according to claim 1 or 2, wherein the capillary tube comprises an inlet orifice through which the conduit is inserted into the capillary tube, and the apparatus is arranged for supplying the pressurised gas into the capillary tube and outside the conduit via the inlet orifice.

4. An electrospray apparatus according to claim 1, 2 or 3, comprising a voltage source arranged to energise the sample so that the sample delivered into the capillary tube is electrosprayed via the exit orifice.

5. An electrospray apparatus according to any preceding claim, comprising a capillary tube holder having the capillary tube supported therein, wherein the capillary tube holder comprises a retractable sheath for protecting the capillary tube.

6. An electrospray apparatus according to any of claims 1 to 4, comprising a capillary tube holder having the capillary tube supported therein, wherein the capillary tube holder comprises a sheath member surrounding at least a portion of a length of the capillary tube, and the sheath member comprises an electrode extending downstream from the exit orifice of the capillary tube; and wherein the electrospray apparatus is arranged, in use, to provide a potential difference between the sample within the capillary tube and the electrode so that droplets of the sample are electrosprayed from the exit orifice of the capillary tube.

7. A method of electrospraying a liquid sample, the method comprising: providing an electrospray apparatus comprising a capillary tube and a conduit, wherein the capillary tube comprises an exit orifice, and wherein the conduit extends into the capillary tube and extends within the capillary tube; supplying a liquid sample from the conduit into the capillary tube; supplying pressurised gas into the capillary tube so as to force the sample within the capillary tube towards the exit orifice; and energising the liquid sample so that charged droplets of the liquid sample are electrosprayed from the exit orifice of the capillary tube.

8. A method of electrospraying a liquid sample according to claim 7, comprising lowering the pressure of the pressurised gas in the capillary tube between the steps of: supplying pressurised gas into the capillary tube so as to force the sample within the capillary tube towards the exit orifice; and energising the liquid sample so that charged droplets of the liquid sample are electrosprayed from the exit orifice of the capillary tube.

9. An electrospray apparatus comprising a capillary tube holder for holding a capillary tube for emitting a sample therefrom, the capillary tube holder comprising: a capillary tube holder body having an inlet orifice for receiving the capillary tube into the capillary tube holder body; and a capillary tube holder sheath member surrounding at least a portion of a length of the capillary tube when the capillary tube is received into the capillary tube holder body, wherein the capillary tube holder sheath member comprises an electrode extending downstream from the exit orifice of the capillary tube. a sheath member for surrounding at least a portion of the capillary tube, wherein the sheath member has one or more apertures therein to allow viewing of the capillary tube; and a connector element for connecting the sheath member so as to position the capillary tube within the electrospray device.

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

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

12. The electrospray device of claim 11, wherein the electrospray device comprises a support element for securing the capillary tube within the sheath member, and wherein the capillary tube holder is configured for inserting the support element into the bore of the connector element while the support element maintains the position of the sheath member relative to the capillary tube.

13. The electrospray device 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 tube.

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

15. The electrospray device of claim 14, wherein the capillary tube holder is configured for enabling rotation of the sheath member relative to the connector element to a predetermined position, and wherein the capillary tube holder is configured for providing a releasable snap or interference fit between the connector element and the sheath member at the predetermined position.

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

17. The electrospray device of any one of claims 9 to 16, wherein the sheath member comprises a prong, the one or more apertures are a plurality of apertures, and the prong separates the plurality of apertures from one another circumferentially.

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

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

20. The electrospray emitter assembly of claim 19, wherein: the capillary tube has an exit orifice at an exit end of the capillary tube for emitting a sample therefrom; the sheath member comprises an electrode extending downstream from the outlet orifice of the capillary; and the electrospray emitter assembly is arranged, in use, to provide a potential difference 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. An assembly according to claim 19 or 20, comprising a support element radially between the capillary and the sheath member, wherein the support element secures the sheath member to the capillary.

22. An assembly according to claim 21, wherein the sheath member surrounds a length of the capillary between the support element and the outlet end of the capillary.

23. An assembly according to claim 21 or 22, wherein the support element is bonded to the capillary and / or the sheath member.

24. An assembly according to any of claims 20 to 23, wherein the outlet orifice has a diameter of less than 100 pm.

25. An assembly according to any of claims 20 to 24, wherein the electrode comprises an exit aperture downstream of 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 the exit aperture.

26. An assembly according to any of claims 20 to 25, wherein the sheath member comprises a wall that circumferentially surrounds at least a portion of an axial length of the capillary, and the wall comprises one or more apertures at the same axial location as the outlet orifice of the capillary; or the sheath member comprises a tip extending to a position downstream of the outlet orifice of the capillary, wherein the tip is spaced apart in a circumferential direction around a longitudinal axis of the capillary so as to define a gap therebetween, and wherein the gap is at the same axial location as the outlet orifice of the capillary.

27. An assembly according to any of claims 20 to 26, wherein the electrode extends the entire length of the sheath member.

28. An assembly according to any of claims 20 to 27, wherein the capillary is entirely within and between ends of the electrode.

29. A method of electrospraying a liquid sample, the method comprising: providing an electrospray device comprising a capillary having an outlet orifice at an outlet end of the capillary, and a sheath member surrounding at least a portion of a length of the capillary, wherein the sheath member comprises an electrode extending 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. A method according to 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 electrodes of the sheath member comprises energizing 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 pressurized gas into the capillary so as to force the sample within the capillary towards the outlet orifice.

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

35. A method of providing an electrospray device, comprising: providing a sheath member surrounding at least a portion of a capillary, wherein the sheath member has one or more holes located therein to allow viewing of the capillary; and connecting the sheath member to a connector element so as 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 is held fixed relative to the sheath member.

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

38. The method of claim 37, wherein a support element fixes the capillary within the sheath member, and the support element is inserted into the bore of the connector element when the sheath member and connector element are connected to each other.

39. The method of any one of claims 35 to 38, wherein the sheath member comprises electrodes for applying a potential to cause the sample to be electrosprayed from the capillary.

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

41. The method of any one of claims 35 to 40, wherein the sheath member is rotated relative to the connector element to a predetermined position, 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 to 41, wherein the sheath member is a single unitary component.

43. An electrospray device, comprising: a capillary having an outlet orifice for electrospraying a sample therefrom and a larger drain orifice for flushing the sample out of the capillary; and a sheath member surrounding at least a portion of the capillary, wherein the sheath member has one or more holes located therein to allow viewing of the capillary; and a connector element to which the sheath member is connected so as to position the capillary for electrospraying a sample therefrom. a conduit extending into the capillary in such a way that it is able to deliver the sample to the outlet orifice in a first mode of operation and such that the drain orifice remains open to enable the conduit to deliver a flushing liquid into the capillary in a second mode of operation to flush the sample out of the capillary through the drain orifice.

44. The electrospray apparatus of claim 43, comprising a voltage source arranged to energise the 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 of less than 100 pm.

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

48. The electrospray apparatus of any of claims 43 to 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 of claims 43 to 48, wherein the apparatus is configured to supply pressurised 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 pressurised 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 containing the capillary, wherein the apparatus is configured for supplying the pressurised gas into the capillary from a chamber of the capillary housing, and the capillary housing comprises a valve having a closed configuration for preventing the pressurised gas from flowing out of the chamber via the valve, and the valve has an open configuration for allowing the pressurised gas to flow out of the chamber via the valve.

52. The electrospray apparatus of claim 51, wherein the electrospray apparatus is configured for switching the valve 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 enter the drain from the chamber of the capillary housing.

55. An electrospray apparatus according to any of claims 43 to 54, comprising a supply housing for receiving a supply device, the supply device being capable of supplying fluid into the conduit for delivery to the capillary.

56. An electrospray apparatus according to claim 55, wherein the apparatus comprises the supply device, and wherein the supply device comprises a fluid controller configured to control the supply device to supply fluid from different sources into the conduit for delivery to the capillary.

57. An electrospray apparatus according to any of claims 43 to 56, comprising a capillary holder having the capillary supported therein, wherein the capillary holder comprises a retractable sheath for protecting the capillary.

58. An electrospray apparatus according to any of claims 43 to 56, comprising a capillary holder having the capillary supported therein, wherein the capillary holder comprises a sheath member surrounding at least a portion of a length of the capillary, and the sheath member comprises an electrode extending downstream from the outlet orifice of the capillary; and wherein the electrospray apparatus is arranged for providing, in use, 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 spectrometer and / or ion mobility spectrometer comprising an electrospray apparatus for generating ions via electrospray ionisation according to any of claims 1 to 6, 9 to 18 and 43 to 58.

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 the capillary and within the capillary; supplying a liquid sample from the conduit into the capillary and to the outlet orifice of the capillary; energising 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. A method according to claim 60, comprising supplying a flushing gas into the capillary via the conduit so as to force the flushing liquid out of the capillary through the drain orifice.

62. A method according to claim 60 or 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 comprising 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 pressurized 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 through the drain orifice into the capillary, and the pressurized 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 pressurized gas into the capillary from a chamber of a capillary housing housing the capillary; and opening a valve in the capillary housing to reduce the pressure of the pressurized gas in the capillary prior to the flushing liquid removing the liquid sample from the capillary via the drain orifice.

66. A method of electro-spraying a liquid sample from an emitter, comprising: providing an emitter having a flushing liquid therein and having 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 energizing the liquid sample to emit the liquid sample via the orifice; and causing the flushing liquid to remove 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 amount of 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, thereby drawing the liquid sample into the emitter through the orifice; and causing the flushing liquid to remove 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 the charged droplets generated using the method of any one of claims 60 to 68, and performing mass and / or ion mobility analysis on the ions or ions derived from the ions.

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