FIELD

The present teachings generally relate to mass spectrometry, and more particularly to sampling probes and sampling interfaces for mass spectrometry systems and methods.

INTRODUCTION

Mass spectrometry (MS) is an analytical technique for determining the elemental composition of test substances with both qualitative and quantitative applications. MS can be useful for identifying unknown compounds, determining the isotopic composition of elements in a molecule, determining the structure of a particular compound by observing its fragmentation, and quantifying the amount of a particular compound in a sample. Given its sensitivity and selectivity, MS is particularly important in life science applications.

In the analysis of complex sample matrices (e.g., biological, environmental, and food samples), many current MS techniques require extensive pre-treatment steps to be performed on the sample prior to MS detection/analysis of the analyte of interest. Such pre-analytical steps can include sampling (i.e., sample collection) and sample preparation (separation from the matrix, concentration, fractionation and, if necessary, derivatization). It has been estimated, for example, that more than 80% of the overall analytical process can be spent on sample collection and preparation in order to enable the analyte's detection via MS or to remove potential sources of interference contained within the sample matrix, while nonetheless increasing potential sources of dilution and/or error at each sample preparation stage.

Ideally, sample preparation techniques for MS should be fast, reliable, reproducible, inexpensive, and in some aspects, amenable to automation. One recent example of an improved sample preparation technique is solid-phase microextraction (SPME), which essentially integrates sampling, sample preparation, and extraction into a single solvent-free step. Generally, SPME devices utilize a fiber or other surface (e.g., blades, micro-tips, pins, or mesh) coated with an extracting phase to which analytes within the sample can be preferentially adsorbed when the device is inserted into the sample. Because extraction can take place in situ by inserting a biocompatible device directly into tissue, blood, or other biological matrix for a short period of time, SPME does not require any sample collection. Alternatively, SPME devices can be used for ex vivo analysis using a small amount of a collected sample (i.e., a sample aliquot).

Though SPME is generally considered to be accurate and simple and can result in decreased sample preparation time and disposal costs, the mass-spectrometric based analysis of SPME-prepared samples may nonetheless require additional equipment and/or time-consuming steps in order to ionize the analyte from the SPME device directly or to desorb the analytes from the SPME device prior to ionization as required for mass spectrometry (MS). By way of example, various ionization methods have been developed that can desorb/ionize analytes from condensed-phase samples with minimal sample handling (e.g., desorption electrospray ionization (DESI) and direct analysis in real time (DART), which “wipe-off” analytes from the samples by exposing their surfaces to an ionizing medium such as a gas or an aerosol). However, such techniques can also require sophisticated and costly equipment.

Alternatively, additional desorption steps have been utilized to extract the analytes from the SPME device prior to ionization via ionization techniques other than DESI or DART. For example, because electrospray ionization (ESI) is one of the most common ionization methods and requires the analyte to be in solution, some users have utilized liquid desorption and subsequent purification/separation of the extracted/enriched analytes via high-performance liquid chromatography (HPLC) prior to MS analysis. However, liquid desorption prior to HPLC may require several minutes to transfer the analyte from the SPME coating to the liquid phase due to requirements imposed on the HPLC mobile phase (weak solvent strength). Moreover, as discussed above, these increased sample-preparation/separation steps can decrease throughput, introduce potential sources of error, increase dilution, and cannot be easily automated. Alternatively, some groups have proposed substantial modifications to the standard electrospray ion source. Typically in ESI, a liquid sample is continuously discharged into an ionization chamber from within an electrically conductive capillary, while an electric potential difference between the capillary and a counter electrode generates a strong electric field within the ionization chamber that electrically charges the liquid sample. This electric field causes the liquid discharged from the capillary to disperse into a plurality of charged micro-droplets drawn toward the counter electrode if the charge imposed on the liquid's surface is strong enough to overcome the surface tension of the liquid (i.e., the particles attempt to disperse the charge and return to a lower energy state). As solvent within the micro-droplets evaporates during desolvation in the ionization chamber, charged analyte ions can then enter a sampling orifice of the counter electrode for subsequent mass spectrometric analysis. PCT Pub. No. WO2015188282 entitled “A Probe For Extraction Of Molecules Of Interest From A Sample,” which is incorporated by reference herein in its entirety, for example, thus purports to provide for electrospray ionization from an SPME device by applying the ionizing electric potential to the conductive SPME device itself (to which a discrete amount of a desorption solution is applied) such that ions are generated directly from the edges of the wetted substrate.

In addition, mass spectrometry sampling interfaces for liquid samples containing analytes of interest are also highly desired in the field. U.S. Pat. No. 9,632,066 discloses an open port sampling interface that can be used for liquid droplets. There remains a need for improved and/or reduced-cost systems that enable fast-coupling of SPME and droplet dispenser devices to MS systems with minimal alterations to the front-end while maintaining sensitivity, simplicity, selectivity, speed and throughput.

SUMMARY

Devices, methods, and systems for delivering a sample to an ion source for the generation of ions and subsequent analysis by mass spectrometry are provided herein.

In certain embodiments, a system for sampling a composition of a substance that can be analyzed in a mass spectrometer is provided, comprising: (a) a liquid reservoir containing a solvent; (b) a gas reservoir containing a nebulizer gas; (c) a conduit that is in fluid communication with the liquid reservoir, the conduit comprising a first portion, a second portion and a junction portion, the first portion and second portion being joined at the junction portion, and defining an angle therebetween at the junction, and the junction portion contains an aperture through a wall of the junction portion to open an interior of the conduit to atmosphere to receive and pass sample from the atmosphere into the interior of the conduit; and (d) a nebulizer conduit that is co-axial and partially surrounds the second portion and completely surrounds a discharge end of the second portion, the nebulizer conduit being fluidly connected to the gas reservoir and that allows the nebulizer gas to flow from the gas reservoir over an external surface of the second portion and the discharge end of the second portion to draw solvent through the second portion by creating a suction force.

In some embodiments the conduit comprises a continuous tube of a same material and the first portion, second portion, and junction portion may comprise portions of a common section. In some embodiments, the first portion, second porting and junction portion may comprise separate segments that are mechanically connected or fused together. In some embodiments, the aperture may comprise a hole drilled or cut through one side of the conduit to provide the opening through the wall of the conduit to the interior of the conduit.

In certain embodiments, the angle between the first and second portions is at least 20 degrees and in certain embodiments, the angle is about 120 degrees and in some embodiments the angle is about 180 degrees.

In certain embodiments, the system further comprises an electrode disposed at the end of the second portion and wherein an electric field is created between the end of the second portion and a counter electrode.

In certain embodiments, one side of the junction portion is defined by the angle between the first and second portions and the other side of the junction portion contains the aperture.

In certain embodiments, the system further comprises a mass analyzer and wherein an entrance to the mass analyzer is the counter electrode. In some embodiments, the system may also comprise a differential mobility spectrometer and the discharge end of the conduit may discharge the solvent and sample passed through the aperture and captured in the solvent flow into the differential mobility spectrometer.

In certain embodiments, the system further comprising a droplet dispenser configured to dispense a droplet of the substance into the aperture. In some cases, the droplet dispenser may comprise an acoustic droplet dispenser. In some aspects, the droplet dispenser may comprise a pneumatic droplet dispenser. In some aspects, the droplet dispenser may comprise a capillary delivering a metered flow of sample.

In certain embodiments, the system further comprises a substrate and wherein the substance is a solid that is applied to the substrate. In other embodiments, the system comprises a substrate and wherein the substance is a liquid that is applied to the substrate.

In certain embodiments, the aperture is disposed at any position on the joint portion. In some embodiments, the conduit may be positioned to orient the aperture facing down such that sample may be delivered to the aperture in an upward trajectory against the force of gravity. In some embodiments, the conduit may be positioned to orient the aperture facing up such that sample may be delivered to the conduit in a downward trajectory falling with the force of gravity. In some embodiments, the conduit may be adjustable to allow for re-positioning the aperture relative to a sample delivery trajectory.

In certain embodiments, a method for analyzing a composition of a substance is described which comprises: (a) providing a liquid reservoir containing a solvent; (b) providing a gas reservoir containing a nebulizer gas; (c) providing a conduit that is in fluid communication with the liquid reservoir, the conduit comprising a first portion, a second portion and a junction portion, the first portion and second portion being joined at the junction portion, and defining an angle therebetween at the junction, and the junction portion contains an aperture that is open to the atmosphere and; (d) providing a nebulizer conduit that is co-axial and partially surrounds the second portion and completely surrounds an end of the second portion, the nebulizer conduit being fluidly connected to the gas reservoir and that allows the nebulizer gas to flow from the gas reservoir over an external surface of the second portion and the end of the second portion; (e) flowing the solvent through the conduit from the liquid reservoir through the first portion, the junction and to the end of the second portion; (f) flowing the nebulizer gas through the nebulizer conduit so as to cause aspiration of solvent exiting the end of the second portion; (g) contacting the substance to the flowing solvent at the aperture.

In certain embodiments, the method further comprises providing an electrode disposed at the end of the second portion and wherein an electric field is created between the electrode and a counter electrode and wherein the electric field is sufficient to cause ionization of the substance.

In certain embodiments, one side of the junction portion is defined by the angle between the first and second portions and the other side of the junction portion contains the aperture

In certain embodiments, wherein the angle is at least 20 degrees or is 20 degrees. In other embodiments, the angle is 180 degrees.

In certain embodiments, the method further comprises providing a mass analyzer and performing a mass analysis on the substance and wherein an entrance to the mass analyzer is the counter electrode.

In certain embodiments, the method further comprises providing a differential mobility spectrometer and performing a differential mobility separation on the substance.

In certain embodiments, the method further comprises providing a droplet dispenser and having the droplet dispenser dispense a droplet of the substance into the aperture. In some embodiments, the droplet dispenser is an acoustic droplet dispenser. In some embodiments, the droplet of the substance is immiscible with the solvent

In certain embodiments, the method further comprises providing a solid surface and applying the substance to the solid surface and then contacting the solid surface with the substance to the solvent in the aperture. In some embodiments, the substance is a solid and in other embodiments, the substance is a liquid.

In certain embodiments, the aperture is disposed at any position of the joint portion.

In certain embodiments, a conduit in fluid communication with a liquid reservoir that provides a continuous liquid pathway from the liquid reservoir to a discharge end of the conduit, the conduit comprising: a first supply portion supplying solvent from the liquid reservoir to an aperture portion positioned between the liquid reservoir and the discharge end; and a second discharge portion receiving the supplied solvent at the aperture portion and delivering the supplied solvent to the discharge end of the conduit, the aperture portion comprising an opening through a portion of a wall of the conduit that exposes liquid flowing through the conduit to atmosphere.

