Ion Sources for Inductively Coupled Plasma Mass Spectrometry

Abstract

An ICP source (100) for generating ions using an inductively coupled plasma is configured to be coupled to a mass spectrometer (200). A sample is introduced into the plasma under gravity in a downwardly directed vertical direction (G). In this way, the sample can reach the plasma regardless of the condition of the sample, for example regardless of the droplet or particle size. A transport efficiency of up to 100% can be achieved. A continuous flow including the sample can be supplied to the ICP source.

Description

Technical Field

[0001] The present invention relates to an inductively coupled plasma (ICP) ion source configured to be coupled to a mass spectrometer. The present invention also relates to an ionization system comprising the ICP source, an ICP-mass spectrometry system and a corresponding ICP mass spectrometry method. Background Art

[0002] Inductively coupled plasma mass spectrometry (ICP-MS) is an analytical technique used to detect and quantify trace elements and / or isotope ratios in a sample. This is achieved by dissociating and ionizing the sample components in an ICP source using an inductively coupled plasma, and then separating and detecting the ions using a mass spectrometer. ICP-MS systems first became commercially available in the early 1980s.

[0003] The ICP source typically includes a plasma torch to confine the plasma discharge by means of a directional gas flow and to carry the sample aerosol to the center of the plasma discharge for dissociation and ionization. The sample aerosol is typically delivered to the plasma discharge through the central injection tube of the torch. In almost all prior art ICP-MS systems, the torch axis is horizontally oriented, and thus the sample aerosol is delivered to the plasma discharge using a carrier gas that flows horizontally through the horizontal injection tube. The carrier gas flow must be carefully adjusted to optimize the sample delivery to the plasma discharge and to ensure that the sample reaches a position within the plasma from which the sample can be extracted into the mass spectrometer system with the highest ion yield.

[0004] Even at optimized carrier gas flow rates, the delivery efficiency in prior art ICP-MS systems may also be very low. This is especially true for aerosols containing relatively large objects such as large droplets, particles or cells. In this regard, it should be noted that prior art sample introduction systems for liquid samples and suspensions typically include a pneumatic nebulizer that produces a wide droplet size distribution, followed by a spray chamber that is typically used to remove larger droplets from the aerosol, such as droplets with a diameter of more than 10 μm (see, for example, J. Olesik and L. Bates, "Characterization of aerosols produced by pneumatic nebulizers for inductively coupled plasma sample introduction: effect of liquid and gas flow rates on volume based drop size distributions", Spectrochimica Acta Part B: Atomic Spectroscopy, 1995, 50, 285-303, DOI10.1016 / 0584-8547(94)00151-K). With this system, the efficiency with which the sample is delivered into the ICP is typically in the range of 3% to 30%, depending on the nebulizer used. Specific nebulizers operating at very low liquid flow rates (<50 μL / min) can achieve higher efficiencies, but they clog easily, making them useful only for dilute solutions and suspensions with particles or cells in the low μm range.

[0005] Various attempts have been made to improve the introduction of samples into ICP-MS systems. For example, sample introduction systems using monodisperse microdroplet generators are disclosed in the following documents: S. Gschwind et al., "Capabilities of inductively coupled plasma mass spectrometry for the detection of nanoparticles carried by monodisperse microdroplets", J. Anal. At. Spectrom., 2011, 26, 1166-1174, DOI: 0.1039 / C0JA00249F; S. Gschwind et al., "Mass quantification of nanoparticles by single droplet calibration using inductively coupled plasma mass spectrometry", Anal. Chem. 2013, 85, 5875-5883, DOI: 10.1021 / ac400608c; K. Shigeta et al., "Application of a micro-droplet generator for an ICP-sector field mass spectrometer–optimization and analytical characterization”, J. Anal. At. Spectrom. 2013, 28, 646-656, DOI: 10.1039 / c2ja30207a. Although these documents disclose that droplets can pass vertically through a so-called drop tube, the axis of the plasma torch is still oriented horizontally and the droplets are ultimately transferred to the plasma in a horizontal direction using a horizontal carrier gas flow.

[0006] P. Verboket et al., "A New Microfluidics-Based Droplet Dispenser for ICPMS", Analytical Chemistry 2014, 86, p. 6012, DOI: 10.1021 / ac501149a discloses a microfluidic dispenser for introducing microdroplets into ICP-MS. The chip is coupled with a cyclone adapter, a heated steel tube, a membrane desolvator, and an ICP-MS unit. Although the droplets fall vertically through the steel tube, the ICP-MS unit is horizontally oriented in the usual manner and the droplets are introduced into the ICP-MS unit in a horizontal direction.

[0007] WO 2008 / 080224 A1 discloses a flow cytometer coupled to an ICP-MS system. The plasma torch of the ICP source is oriented horizontally in the usual manner.

[0008] An exception to the usual horizontal orientation of the plasma torch in an ICP-MS system is reported in II Stewart and JW Oresik, "Time resolved measurements with Single Droplet Introduction to Investigate Space-Charge Effects in Plasma Mass Spectrometry", J. Am. Soc. Mass Spectrom. 1999, 10, 159-174. The authors proposed a vertically upward pointing orientation of the plasma torch. The ions from the plasma were analyzed using a vertically upward oriented mass spectrometer, the interface of which was coupled to the plasma torch. It is reported that this arrangement achieves better signal stability and reproducibility in terms of droplet signals compared to prior art systems. However, the vertically upward pointing setting requires very careful adjustment of the operating conditions in order to properly deliver the droplets into the plasma.

[0009] In the context of inductively coupled plasma optical emission spectroscopy (ICP-OES), different orientations of plasma torches have been proposed. For example, in A. Murtazin, S. Groh and K. Niemax, "Measurement of element mass distributions in particle ensembles applying ICP-OES", J. Anal. At. Spectrom. 2010, 25, 1395-1401, DOI: 10.1039 / c004946h, an upward pointing plasma torch is disclosed. Plasma torches are only used for optical emission spectroscopy and are not compatible with mass spectrometers. US 4,766,287, US 2015 / 255262 A1 and US 2016 / 0270201 A1 also disclose upward pointing plasma torches focused on applications in optical emission spectroscopy.

[0010] M. Schild et al., "Replacing the Argon ICP: Nitrogen Microwave Inductively Coupled Atmospheric-Pressure Plasma (MICAP) for Mass Spectrometry", Anal. Chem. 2018, 90 (22), 13443-13450, DOI: 10.1021 / acs.analchem.8b03251 discloses a nitrogen continuous ICP source operating at microwave frequencies and coupled to a time-of-flight mass spectrometer. The plasma source is called a "microwave inductively coupled atmospheric pressure plasma (MICAP) source". It includes a ring-shaped dielectric resonator made of technical ceramics, which, when immersed in a microwave field, exhibits a body polarized current around the ring that oscillates with the microwave frequency. The dielectric resonator ring does not have a significant net potential, and the energy coupled to the plasma is purely inductive. The plasma torch of the MICAP source is horizontally oriented. US 2016 / 0025656 A1 discloses the MICAP source in more detail.

[0011] WO 97 / 13141 discloses a microwave plasma monitoring system in which a plasma flame is generated by microwaves in a waveguide and the optical emission from the flame is studied by a spectrometer. In one embodiment, the plasma flame is oriented vertically in a downward direction. Different types of samples such as droplets or particles are introduced using a suction pump that regulates the gas flow. The plasma source is not an ICP source, and the system is designed only for optical spectroscopy and is not compatible with a mass spectrometer.

[0012] US 2014 / 0287162 discloses a downwardly directed microwave plasma source for material processing, for example for applying a surface coating or for powder production. US 2005 / 0211018 A1, US 2014 / 0217630 A1, US 2013 / 0270261 A1 and US 2013 / 0118304 A1 also disclose downwardly directed plasma sources for material processing. These arrangements are designed for industrial applications in material processing and are clearly not suitable for elemental analysis of samples. These arrangements are more suitable for coupling to a mass spectrometer.

[0013] US 2015 / 255262 A1 discloses an upwardly directed plasma source. Droplets are supplied to the plasma torch by a single droplet microdispenser (SDMD) with an upwardly directed vertical orientation. The document mentions that the SDMD can also be oriented horizontally or downwardly. Summary of the invention

[0014] In a first aspect, it is an object of the present invention to provide an ICP source configured to be coupled to a mass spectrometer, the ICP source enabling an improved introduction of a sample into a plasma discharge.

[0015] This is achieved through an ICP source.

[0016] The present invention provides an ICP source for generating ions from a sample using an inductively coupled plasma. The ICP source is configured to be coupled to a mass spectrometer. According to the present invention, the ICP source is configured to allow the introduction of the sample into the plasma in a vertical direction pointing downward.

[0017] Therefore, the introduction of the sample into the plasma starts from the top. The sample is introduced into the plasma in the direction of the gravity vector. Therefore, the sample introduction is not very sensitive to the carrier gas flow rate. It is even conceivable to introduce the sample without using any carrier gas flow at all, and the sample trajectory before the sample enters the plasma is completely determined by gravity. Thereby a large amount of carrier gas can be saved, which has certain significance, especially when the carrier gas is an expensive inert gas such as argon or argon-helium mixture. The size of the droplets or objects (e.g., cells) that can reach the plasma is basically limited only by the size of the sample introduction system. Since the collision of the droplets or objects with the wall of the sample introduction system can be avoided, the proposed arrangement can achieve a transport efficiency of up to 100%. Any type and sample under any conditions, such as aerosols or single droplets or objects such as solid particles or cells, can be studied. A high degree of flexibility in sample size, aerosol humidity and sample quantity can be obtained. For example, eukaryotic cells with a diameter of typically about 10 μm to 150 μm can reach the plasma regardless of their size or mass. The droplets will reach the plasma regardless of how much solvent has evaporated during the transport in the carrier gas. The throughput of samples through the ICP source can be significantly increased compared to prior art devices.

[0018] Extraction of ions from the plasma can also be performed in a downwardly directed vertical direction. To this end, the ICP source can have an extraction opening that opens toward the bottom and is located below the region where the plasma is formed in the ICP source. After extraction, the ions can be transferred to a mass spectrometer with an arbitrary orientation using known ion optical elements such as electrostatic mirrors and / or bending magnets.

[0019] Typically, an ICP source comprises a plasma torch, i.e., an arrangement of (typically at least three concentric) tubes for feeding gas to a plasma discharge region. One of these tubes is typically used to feed a sample to the plasma. This tube is typically referred to as an injection tube. The injection tube is typically arranged in the center of the plasma torch and is surrounded by the other tubes. In the present invention, the longitudinal axis of the injection tube (if present) is vertically oriented, and the injection tube has an upper end configured to receive a sample and a lower end configured to introduce the sample into the plasma. Then, an extraction opening for extracting ions from the plasma can advantageously be located below the lower end of the injection tube.

[0020] Since the plasma torch is arranged above the plasma discharge region in the present invention, components such as connectors for feeding gas to the plasma torch can be arranged above the plasma discharge. In order to protect these components from the convective heat generated by maintaining the plasma discharge, the ICP source may include a metal cooling plate at least partially surrounding the plasma torch, and thereby shielding these components from the heat generated by the plasma discharge. The cooling plate preferably extends in a horizontal plane. When the cooling plate is installed, it may have a cutout configured to receive the plasma torch.

[0021] The ICP source may include a cooling system that actively cools the metal cooling plate with a forced flow of a fluid (e.g., a cooling gas such as air or a cooling liquid such as water) through the metal cooling plate and / or through an additional component connected to the metal cooling plate (e.g., by connecting the cooling plate to one or more metal panels of a torch box surrounding the plasma torch). To this end, the cooling plate and / or the component to which the cooling plate is connected may be provided with one or more holes extending in the plane of the cooling plate or the additional component, the one or more holes being used to allow the flow of a cooling fluid (e.g., air or water) to pass through these holes.

[0022] The ICP source typically includes an electromagnetic coupling element for feeding energy to the plasma to maintain the plasma discharge by inductive coupling. The electromagnetic coupling element can be coupled to an induction coil of an RF generator, in particular via an electrical conductor. Such an induction coil is typically operated in a frequency range between 10 MHz and 100 MHz, for example at 27 MHz or 40 MHz. In other embodiments, the ICP source can employ a toroidal dielectric resonator immersed in a microwave field that can be generated, for example, by a magnetron. The microwave field can be in a frequency range of, for example, 1 GHz to 10 GHz, with a typical frequency of 2.45 GHz. Examples are the so-called MICAP sources disclosed in M. Schild et al., “Replacing the Argon ICP: Nitrogen Microwave Inductively Coupled Atmospheric-Pressure Plasma (MICAP) for Mass Spectrometry”, Anal. Chem. 2018, 90(22), 13443-13450, DOI: 10.1021 / acs.analchem.8b03251 and US 2016 / 0025656 A1, see the “Prior Art” section above.

[0023] Regardless of the type of electromagnetic coupling element, the coupling element defines a longitudinal axis which advantageously extends vertically. The coupling element may surround a lower end portion of the plasma torch. If a metallic cooling plate is present, the coupling element may be arranged below the cooling plate.

[0024] The ICP source may also comprise an RF generator for feeding energy to the electromagnetic coupling element.The term "RF generator" should be broadly understood to include any AC generator operating in a frequency range of at least 10 MHz to 10 GHz.

[0025] If the electromagnetic coupling element is an induction coil, it is advantageous to connect the induction coil to the RF generator via at least one metal strip extending in the horizontal direction, preferably two parallel metal strips. This makes it possible to place the induction coil at a horizontal distance from the RF generator to gain space. The metal strips can be made of any highly conductive material, in particular copper, silver or gold, to minimize ohmic losses between the RF generator and the induction coil.

[0026] The ICP source can be combined with an aerosolization device to form an ionization system for obtaining ions from a large number of samples. Advantageously, the ICP source is coupled to the aerosolization device in such a way that the aerosolized sample is transferred from the aerosolization device to the ICP source in a vertical direction pointing downwards. In this way, the above-mentioned advantages of the vertical design of the currently proposed ICP source are also retained during the transfer of the aerosolized sample to the ICP source.

[0027] According to the type of sample, the aerosolization device can be constructed in different ways. In some embodiments, the aerosolization device can include a droplet generator for aerosolizing the sample by generating droplets. A vertically oriented drop tube can be coupled to the droplet generator. The drop tube allows the droplets to be transported downward under gravity. During their passage through the drop tube, the size of the droplets can be reduced or the droplets can be completely dried by solvent evaporation. For this reason, the drop tube can have a sample inlet, a gas inlet and an outlet, and the drop tube can be configured to receive droplets from the droplet generator at its sample inlet and receive an airflow at its gas inlet, so that the droplets can be reduced in size by the evaporation of the solvent entering the airflow while moving downward under gravity. The outlet of the drop tube can be directly or indirectly connected to the inlet of the ICP source in such a way that the aerosolized sample is transferred to the ICP source from the drop tube along a downwardly directed vertical direction without the need for horizontal sample transport by a carrier gas flow as required in the prior art.

[0028] In other embodiments, the aerosolization device may include a nebulizer for aerosolizing the sample and a spray chamber coupled to the nebulizer, the spray chamber having a downwardly directed outlet, the outlet of the spray chamber being connected to the inlet of the ICP source in such a manner that the aerosolized sample is transferred from the spray chamber to the ICP source in a downwardly directed vertical direction.

[0029] In other embodiments, the aerosolization device may include a laser ablation cell having an outlet pointing downward, the outlet of the laser ablation cell being connected to an inlet of the ICP source in such a way that the aerosolized sample passes from the laser ablation cell to the ICP source in a downwardly pointing vertical direction. Various configurations of the laser ablation cell are contemplated.

[0030] Other types of aerosolization equipment may also be used.

[0031] In other embodiments, no separate aerosolization device is employed. Instead, the injection tube of the plasma torch may form a direct injection nebulizer for breaking up the bulk sample liquid into droplets immediately within the plasma torch, ie, before the sample enters the plasma.

[0032] The ICP source of the present invention can be used in conjunction with a flow cytometer. Typically, in a flow cytometer, a sample is injected into a sheath fluid stream. The fluid is broken up into droplets by a vibrating nozzle, each droplet ideally containing a cell or particle. The flow cytometer then analyzes the optical properties of the cells or particles shortly before or after the droplets are released from the nozzle. The ICP source can be coupled to the flow cytometer in such a way that the sample is transferred from the flow cytometer to the ICP source in a vertical direction pointing downward. In this way, maximum transfer efficiency from the flow cytometer to the ICP source can be ensured. All cell / particle sizes will fall into the ICP source and can be analyzed by ICP-MS. This prevents cell or particle analysis from being biased in size or mass. The flow cytometry results for each individual cell or particle can be correlated with the mass spectrometry results for the very same cell or particle, thereby maximizing the information that can be obtained from a single cell or particle. To this end, the ICP-MS system may include a correlator configured to receive flow cytometric information from the flow cytometer and mass spectrometry information from the mass spectrometer and to correlate the flow cytometric information with the mass spectrometry information to obtain combined flow cytometric and mass spectrometry information for individual cells or particles.

[0033] Alternatively, the flow cytometer can be coupled to a cell sorter. In this case, objects (particularly cells or nanoparticles) that have passed through the cell sorter are transferred from the cell sorter to the ICP source in a vertical direction pointing downward. In particular, the cell sorter can be an electrostatic cell sorter, in which an electric charge is provided to the droplets according to the results of the flow cytometric analysis. The charged droplets then fall through an electrostatic deflection system that disperses the droplets into different containers according to the charge of the droplets. Instead of collecting droplets of a specific charge state, these droplets can be directly transferred to the ICP source by allowing the droplets to fall vertically into the inlet of the ICP source.

[0034] The flow cytometer or cell sorter may be coupled directly to the ICP source. Optionally, a drop tube as described above may be provided between the flow cytometer or cell sorter and the ICP source to reduce the size of the droplets before they enter the plasma.

[0035] Compared to prior art devices, the ICP source of the present invention is capable of transferring samples to the sample introduction system of the ICP source in the form of a continuous fluid flow. In particular, the sample introduction system of the ICP source of the present invention can be coupled to any type of continuous flow liquid sample supply system that provides a continuous sample flow, for example, a pump or a continuous flow sample pretreatment device. In the case of a pump, the pump can be a peristaltic pump. In the case of a sample pretreatment system, the pretreatment system can be a device for separating chemical species in a sample, such as a chromatography device or an electrophoresis device, or a device for separating biological cell aggregates, such as a cell sorter coupled to a flow cytometer. Compared to prior art devices, the ICP source of the present invention enables samples to be transferred from a continuous liquid sample supply system to the ICP source in the form of a continuous fluid flow without the need for an intermediate offline storage device.

[0036] Generally speaking, an ionization system is provided, the ionization system comprising:

[0037] Continuous flow sample supply system;

[0038] a sample introduction system; and

[0039] As described above, the ICP source

[0040] wherein the sample introduction system is coupled to the continuous flow sample supply system in such a way that a continuous sample flow comprising the sample is transferred from the continuous flow sample supply system to the sample introduction system, and

[0041] Therein, the sample introduction system is configured to introduce the sample into the ICP source in a vertical direction pointing downward.

[0042] The continuous flow sample supply system may include a continuous flow sample pretreatment device having an inlet configured to receive a continuous inflow flow including a sample and having an outlet configured to provide a continuous outflow flow including the sample, at least a portion of the continuous outflow flow forming a continuous sample flow, and the continuous flow sample pretreatment device is configured to subject the continuous inflow flow to at least one operation for analyzing and / or modifying its components.

[0043] In this context, analysis may be performed by any known means such as fluorescence detection, absorption measurement, spectral analysis, etc. Likewise, modification of the composition of the incoming sample stream may be performed by any known means such as filtering, retention by absorption, modification by application of electromagnetic fields, etc. Importantly, no intermediate off-line storage is required between sample pretreatment and introduction into the ICP source.

[0044] In particular, the continuous flow sample pretreatment device may include a separation device, in particular a chromatography device, an electrophoresis device or a cell sorter, which is configured to separate chemical species or particulate matter, in particular cells, in a continuous inflow flow and elute the chemical species or particulate matter after separation in a continuous outflow flow.

[0045] Each of the influent stream, the effluent stream and the sample stream may be a carrier fluid stream carrying the sample in dispersed or dissolved form. The fluid may be a liquid or a gas.

[0046] The outflow stream from the separation device may have a flow rate much greater than the maximum flow rate that can be accepted by the sample introduction system. To cope with this, the ionization system may include a flow splitting device configured to continuously split the continuous outflow stream into a continuous sample stream and a residual stream.

[0047] The ionization system may also include a correlator configured to receive sample separation information from the separation device and mass spectrometry information from a mass spectrometer coupled to the ICP source, and to correlate the sample separation information with the mass spectrometry information to obtain combined separation and mass spectrometry information, such as LC / MS information.

[0048] The present invention also provides an ICP-MS system, comprising an ICP source of the present invention and a mass spectrometer coupled to the ICP source for receiving ions from the ICP source. The mass spectrometer can have any orientation in space, and one or more ion optical elements can optionally be present to deflect ions into the mass spectrometer after extraction from the ICP source.

[0049] In another aspect, the present invention provides a mass spectrometry method comprising:

[0050] The plasma is maintained using an ICP source;

[0051] introducing the sample into the plasma to generate ions from the sample; and

[0052] A mass spectrometer coupled to an ICP source is used to analyze the mass-to-charge spectrum of ions that have been extracted from the plasma.

[0053] Therein, the sample is introduced into the plasma in a vertical direction pointing downward.

[0054] In a preferred embodiment, ions are also extracted from the plasma in a downwardly directed vertical direction in order to deliver the ions to a mass spectrometer.

[0055] The method may further include:

[0056] aerosolizing the sample using an aerosolization device; and

[0057] The aerosolized sample is passed from the aerosolization device in a downwardly directed vertical direction to the ICP source.

[0058] In particular, the method may include aerosolizing a sample using a droplet generator, passing the aerosolized sample in a downwardly directed vertical direction through a vertically oriented drop tube, and introducing the aerosolized sample into an inlet of an ICP source in the downwardly directed vertical direction.

[0059] In other embodiments, the method can include aerosolizing the sample using a nebulizer, passing the aerosolized sample through a spray chamber having a downwardly directed outlet, and introducing the aerosolized sample into an inlet of the ICP source in a downwardly directed vertical direction.

[0060] In yet another embodiment, the method may include aerosolizing the sample using a laser ablation cell having a downwardly directed outlet, and passing the aerosolized sample from the outlet of the laser ablation cell into the plasma in a downwardly directed vertical direction.

[0061] In yet another embodiment, the method may include:

[0062] analyzing at least one characteristic of the sample using a flow cytometer; and

[0063] The sample is passed from the flow cytometer in a downward-pointing vertical orientation into the ICP source.

[0064] The method may also include receiving flow cytometric information from the flow cytometer and mass spectrometry information from the mass spectrometer, and correlating the flow cytometric information with the mass spectrometry information to obtain combined flow cytometric and mass spectrometry information for the plurality of individual cells or particles.

[0065] In yet another embodiment, the method may include:

[0066] sorting the sample droplets according to at least one property, particularly an optical property, using a cell sorter; and

[0067] The sample droplet is transferred from the cell sorter in a downwardly directed vertical direction into the ICP source.

[0068] In yet another embodiment, the method may include:

[0069] continuously supplying a continuous sample flow including the sample from the continuous flow sample supply system to the sample introduction system,

[0070] The sample is introduced into the plasma by a sample introduction system along a vertical direction pointing downward.

[0071] As described above, the continuous flow sample supply system may include a continuous flow sample pretreatment device having an inlet and an outlet. Then, the method may include:

[0072] receiving a continuous influent stream including a sample at an inlet;

[0073] subjecting the continuous influent stream to at least one operation for analyzing and / or modifying its composition in a continuous flow sample pretreatment device;

[0074] providing a continuous outflow including the sample at an outlet; and

[0075] At least a portion of the continuous effluent stream is formed into a continuous sample stream.

[0076] As described above, the continuous flow sample pretreatment device may include a separation device, in particular a chromatographic device, an electrophoretic device or a cell sorter. Then, the method may include: using the separation device to separate chemical species or particulate matter, in particular cells, in the continuous inflow, and eluting the chemical species or particulate matter after separation in the continuous outflow.

[0077] The method may include continuously splitting the continuous effluent stream into a continuous sample stream and a residual stream. BRIEF DESCRIPTION OF THE DRAWINGS

[0078] The preferred embodiments of the present invention are described below with reference to the accompanying drawings, which are for the purpose of illustrating the current preferred embodiments of the present invention and not for the purpose of limiting the present invention.

[0079] Figure 1 shows a schematic sketch of an ICP-MS system according to an embodiment of the present invention;

[0080] Figure 2 Shows Figure 1 A magnified view of a portion of an ICP-MS system and a highly schematic sketch of a flow cytometry-based cell sorter;

[0081] Figure 3 Shows Figure 1 A top view of the cooling plate of the ICP source in FIG.

[0082] Figure 4 A plasma torch configured to be injected directly into an atomizer is shown;

[0083] Figure 5 A plasma torch coupled to a drop tube is shown;

[0084] Figure 6 A plasma torch coupled to a total consumption sample introduction system is shown;

[0085] Figure 7shows a plasma torch coupled to a laser ablation unit according to a first embodiment;

[0086] Figure 8 shows a plasma torch coupled to a laser ablation unit according to a second embodiment;

[0087] Fig. 9 shows a suitable coupling to Figure 1 TOF mass spectrometer with ICP source;

[0088] Fig.10 A MICAP source according to an embodiment of the present invention is shown;

[0089] Fig.11 Shown is the inclusion 133 Time-resolved ICP-MS peak trajectory of monodisperse droplets of Cs;

[0090] Fig.12 Shown is the inclusion 232 Time-resolved ICP-MS peak trace of monodisperse droplets of Th;

[0091] Fig.13 The ion signal pair shown contains 133 Calibration curve of the dependence of the analyte mass of the droplet on Cs;

[0092] Fig.14 The ion signal pair shown contains 232 Calibration curve of the dependence of Th on the analyte mass of the droplet;

[0093] Fig.15 Shown is a time-resolved ICP-MS peak trace for a Cd-enriched Chinese hamster ovary (CHO) cell suspension in phosphate-buffered saline;

[0094] Fig.16 shows the time resolved ICP-MS peak trace for a Pb-enriched Chinese Hamster Ovary (CHO) cell suspension in water; and

[0095] Fig.17 Shows Figure 1 An enlarged view of a portion of an ICP-MS system and a highly schematic sketch of the sample pretreatment system, the flow splitting device, and the sample introduction system. DETAILED DESCRIPTION

[0096] Figure 1 An ICP-MS system according to an exemplary embodiment of the invention is shown in a highly schematic manner.The ICP-MS system comprises an ICP source 100 for generating an argon plasma and a mass spectrometer 200 coupled to the outlet end of the ICP source.

[0097] In this example, the ICP source 100 includes an RF generator 110 mounted on a lift 150 so that it can be adjusted relative to the mass spectrometer 200 at a height h. The RF generator 110 feeds an alternating current, typically in the frequency range of 10 MHz to 100 MHz, such as 27 MHz or 40 MHz, to a resonant circuit including a capacitor 112 and an induction coil 115. One end of the capacitor 112 and the induction coil 115 is electrically connected via a vertical metal strip 113 and via a horizontal metal strip 114 supported by a PTFE support 116, the metal strip being preferably made of a highly conductive metal such as copper, silver or gold. Similarly, the other end of the induction coil 115 is electrically connected to the RF generator via another horizontal metal strip 114 and another vertical metal strip 113. By using the horizontal metal strip 114, the induction coil 115 can be placed in a position at a sufficiently large lateral distance from the RF generator 110 so that the mass spectrometer 200 can be arranged below the induction coil 115 without interfering with the RF generator 110. The standard length of the horizontal metal strip 114 is 10 cm to 50 cm, in particular, about 20 cm.

[0098] The ICP source 100 also includes a torch box 120. The torch box 120 includes a housing made of a conductive metal so as to provide electromagnetic shielding to the interior thereof. Figure 2 The plasma torch 130, described in more detail, is arranged in a torch box 120 together with an induction coil 115, a horizontal metal strip 114, and a vertical metal strip 113. The induction coil 115 surrounds the lower portion of the plasma torch 130. A horizontal cooling plate 140 is arranged above the induction coil 115. The cooling plate 140 is supported in the torch box 120 by two vertical, fluid-cooled (e.g., cooled by water or by a mixture of a coolant such as ethylene glycol and water) metal panels 141. The cooling plate 140 protects the components in the torch box 120 arranged above the induction coil 115 from the convective heat generated during operation of the ICP source. A ventilation grid 121 enables gases and heat to escape from the torch box 120.

[0099] At its outlet end 122, the torch box 120 is open toward the bottom and forms an extraction opening for connecting the ICP source 100 to the mass spectrometer 200. The mass spectrometer includes the following Figure 2 The vacuum interface 210 is shown in more detail, followed by the ion optical unit 215, the entrance baffle 220, the quadrupole mass analyzer 230, the exit baffle 240, and the detector 250. A mechanical pump 261 evacuates the area of ​​the vacuum interface 210. A turbomolecular pump 262 evacuates the area of ​​the ion optical unit 215, the mass analyzer 230, and the detector 250. The arrangement of a mass spectrometer of this type is well known in the art; however, extraction of ions from the ion source usually occurs horizontally, and Figure 1 The ion extraction axis in the setup is oriented vertically downwards.

[0100] Figure 2 The plasma torch 130 and the interface 210 to the mass spectrometer 200 are shown in more detail. The plasma torch 130 is constructed in a manner known in the art. It includes three concentric tubes 131, 132, 133. The gas flow (usually argon gas flow) used to form the plasma passes between the outer tube 133 and the intermediate tube 132 at a flow rate of usually 12L / min to 17L / min. The second gas flow passes between the intermediate tube 132 and the central tube 131 at a flow rate of 1L / min, and is used to maintain the plasma and adjust the position of the base of the plasma relative to the ends of these tubes. The central tube 131, which is generally referred to as the injection tube, is used to feed the sample to the plasma.

[0101] The plasma torch 130 is located in the center of the induction coil 115. When RF power is applied to the induction coil 115, a strong electromagnetic field is generated inside the induction coil 115. The high voltage spark is used to ionize a portion of the gas inside the induction coil 115, and the plasma can be sustained by accelerating electrons and ions through the RF electromagnetic field. The coupling between the coil and the plasma is inductive, that is, the energy transfer occurs mainly through the magnetic field generated by the oscillating current in the induction coil, and only to a lesser extent through the electric field gradient along the induction coil.

[0102] The sample is introduced into the plasma under the effect of gravity through a central tube (injection tube) 131. The plasma is hot enough to gradually evaporate the sample, dissociate the sample and ionize the elements contained in the sample.

[0103] The interface 210 to the mass spectrometer 200 is formed between a first baffle 211 comprising a small opening in a so-called sampling cone 212 and a second baffle 213 comprising a small opening in a so-called skimmer cone 214. A mechanical pump is connected to evacuate the space between the first baffle 211 and the second baffle 213. Ions having passed both the sampling cone 212 and the skimmer cone 214 enter a space under high vacuum and are focused by an ion optical unit 215 into a mass analyzer.

[0104] Figure 2It is further schematically shown how the ICP-MS system of the present invention can be coupled to an electrostatic cell sorter 320, which in turn is coupled to a flow cytometer 310. This combination of a flow cytometer and a cell sorter in cooperation is known in the art as a fluorescence activated cell sorter. In the flow cytometer 310, a cell suspension 311 is fed to a nozzle 312. Droplets containing a plurality of individual cells are produced by the nozzle 312. Each droplet is interrogated by one or more laser beams produced by one or more lasers 313. The light along the direction of illumination and the fluorescence emitted by the droplets are detected by an optical detection system 314 and analyzed by an analyzer 315. Depending on the results of the analysis, the analyzer 315 applies a positive or negative charge to the nozzle tip or a charging electrode so as to apply a charge of a predefined sign to the droplets before the droplets are discharged from the nozzle. In the cell sorter 320, the droplets are deflected by a deflection plate 321 to which a DC voltage is applied according to their charge state. Depending on their charge state, the droplets end up in a collection container 322 or in a sample inlet 323. From the sample inlet 323, the droplets are passed directly down into the injection tube 131 of the plasma torch 130 where they fall vertically under the effect of gravity.

[0105] The cell sorter 320 may also be omitted and the droplets exiting the flow cytometer 310 may be introduced directly into the plasma by placing the inlet of the ICP source directly below the output nozzle of the flow cytometer. No additional nebulization system is required and 100% delivery efficiency may be obtained.

[0106] Regardless of whether the droplets are sorted or not, for each individual droplet, the results obtained from the flow cytometer 310 can be correlated with the results from the mass spectrometer 200. By combining flow cytometry with mass spectrometry in the presently proposed configuration, the number of cellular parameters that can be quantified simultaneously is increased compared to flow cytometry alone or mass spectrometry alone. To this end, the analyzer 315 can be configured to perform a correlation between the flow cytometry results and the mass spectrometry results, or a separate correlator can be provided.

[0107] Figure 3 The cooling plate 140 and the vertical metal face plate 141 are shown in more detail. The cooling plate 140 has a cutout 142 for accommodating the plasma torch when the cooling plate is installed. The vertical face plate is provided with a plurality of channels or holes 143 extending in a plane within each of the face plates for passing a cooling fluid such as cold air or water through the holes in order to actively cool the cooling plate.

[0108] Figure 4A variation is shown in which the plasma torch 130' is configured as a so-called direct injection high-efficiency nebulizer (DIHEN), which enables the sample to be introduced directly into the plasma without the need for a separate aerosolization device. The high-efficiency nebulizer 134 replaces the injection tube in the plasma torch 130'. Thus, the sample can be introduced directly into the plasma without prior aerosolization. Thus, a 100% delivery efficiency is obtained. This direct injection nebulizer is known per se (A. Montaser, "Inductively Coupled Plasma Mass Spectrometry", Wiley-VCH: Washington, DC, 1998). However, it is usually operated in a horizontal configuration, while in the present invention, the direct injection nebulizer is operated in a vertical configuration.

[0109] Figures 5 to 8 shows the coupling to Figure 1 Four examples of aerosolization devices of plasma torches 130 of ICP sources are shown. The figures are schematic and the relative sizes of the components shown in the figures are not drawn to scale.

[0110] exist Figure 5 In FIG. 4 , a droplet delivery and cryogenic desolvation system 410 is shown. A droplet distributor 411 is connected to a flow adapter 412 located on top of a so-called drop tube 413. The drop tube 413 is a 40 cm long stainless steel tube with an inner diameter of 4 mm. A mixture of argon and helium is used to desolvate the droplets in the drop tube 413. The desolvation of the droplets results in a reduction in local cooling of the plasma. For more details, refer to S. Gschwind et al., "Capabilities of inductively coupled plasma mass spectrometry for the detection of nanoparticles carriedby monodisperse microdroplets", J. Anal. At. Spectrom., 2011, 26, 1166-1174, DOI: 0.1039 / C0JA00249F. In the prior art, the aerosolized sample leaving the drop tube 413 is transported horizontally to the ICP source using a carrier gas flow, whereas in this example, the aerosolized sample is introduced directly into the injection tube 131 of the plasma torch in a downward direction without an additional carrier gas flow. In this way, all sample droplets or particles leaving the drop tube 413 will reach the plasma, regardless of their size and regardless of the gas flow rate.

[0111] exist Figure 6In the embodiment of the present invention, aerosolization is performed by a so-called total consumption sample introduction system 420. A low flow nebulizer 421, which is usually operated at a liquid flow rate of less than 10 μL / min, is coupled to a small volume spray chamber 422, which forces the droplets generated by the nebulizer 421 to flow downward along its central axis and prevents the droplets from adhering to the walls of the spray chamber 422. The spray chamber 422 is open at its bottom to form an outlet. The outlet is directly coupled to the injection tube 131 of the plasma torch 130.

[0112] exist Figure 7 In the embodiment of the present invention, a laser 431 is used in a laser ablation unit 430 to aerosolize a solid sample 432. The laser 431 irradiates an intense pulsed laser beam onto the back side of the sample 432 facing away from the ICP source. The induced shock wave causes the ejection of the sample material, which falls into the injection tube 131 of the plasma torch 130 ("back side ablation").

[0113] Figure 8 Aerosolization using a laser ablation unit 440 according to US 9,922,811 B2 is shown. A laser 441 irradiates laser light onto the surface of a solid sample 442, causing the sample material to be ablated. The ablated material enters a flow channel 443, from which it is passed directly downward into the injection tube 131 of the plasma torch 130. For more details on the laser ablation unit 440 and its mode of operation, reference is made to US 9,922,811 B2. In the prior art, the flow channel 443 is horizontally oriented and the laser beam impinges vertically onto the sample surface, whereas in this example, the flow channel 443 is vertically oriented and the laser beam is horizontally oriented.

[0114] The ICP source proposed so far can be used in any type and configuration of mass spectrometer. For example, Fig. 9 Shows that it can be Figure 1 and Figure 2 The TOF mass spectrometer 200' is used in conjunction with the ICP source shown in FIG. Figure 1 and Figure 2 The ions extracted from the ICP source can be constructed in the same manner. Through interface 210, the ions extracted from the ICP source can enter the TOF mass analyzer 280 through notch filter 260 and extractor 270. Any other type and mass spectrometer of configuration can be adopted. For example, a quadrupole mass spectrometer, a sector field mass spectrometer or an ion trap mass spectrometer can be used to replace. If necessary, an electrostatic mirror and / or a bending magnet can be used to deflect the ions into the mass spectrometer.

[0115] Fig.10A microwave inductively coupled atmospheric pressure plasma (MICAP) source 500 configured for vertical sample introduction is shown. The MICAP source includes an RF generator (microwave generator) 510 in the form of a magnetron. A fan 511 provides cooling for the magnetron 510. An antenna 512 couples the microwave field into the interior of a torch box 520. A ring-shaped dielectric resonator 515 is immersed in the microwave field. The resonator exhibits a body polarized current around the ring that oscillates with the microwave frequency. A plasma torch 530 is arranged above the resonator 515. The plasma torch 530 is arranged in a manner that is combined with Figure 2 The plasma torch 130 described is constructed in the same manner. Nitrogen is introduced into the central region of the resonator 515. The nitrogen plasma is maintained by inductive coupling by the electromagnetic field at the center of the resonator 515. For details, refer to US2016 / 0025656 A1 and M. Schild et al. "Replacing the Argon ICP: Nitrogen Microwave Inductively Coupled Atmospheric-Pressure Plasma (MICAP) for Mass Spectrometry", Anal. Chem. 2018, 90 (22), 13443-13450, DOI: 10.1021 / acs. analchem. 8b03251. In the prior art, the plasma torch of the MICAP source is horizontally oriented, while in this example, the plasma torch 530 is vertically oriented, allowing the sample to be introduced through the central tube 531 in the direction of the gravity vector.

[0116] Figures 11 to 16 Shows the use of Figure 1 Experimental results obtained with the setup shown.

[0117] Fig.11 and Fig.12 Shown is the inclusion 133 Cs( Fig.11 )and 232 Th( Fig.12 ) of monodisperse droplets. Using a droplet generator, the peak traces were obtained from a sample containing 20 ppb 133 Cs and 232 Droplets with a diameter of 66 μm were generated in each of the two Th solutions. All the dispensed droplets reached the plasma and were successfully detected by ICP-MS. It is noted that 133 Cs has an ionization energy of 3.89 eV, while 232 Th has an ionization energy of 6.31 eV. These results demonstrate that the ICP-MS system of the present invention can easily achieve a 100% delivery efficiency.

[0118] Fig.13 and Fig.14 The ion signal pair shown contains 133 Cs( Fig.11 )and 232 Th( Fig.12 ) of the droplets. These results are obtained by 133 Cs and 232 Th was obtained by studying monodisperse droplets of different analyte concentrations as follows: 2 ppb (leftmost data point), 5 ppb, 10 ppb and 20 ppb (rightmost data point). Both figures show a linear relationship between analyte mass and ion signal, indicating complete desolvation, evaporation, dissociation and ionization of the droplets using the vertical plasma configuration of the present invention.

[0119] Fig.15 Shown are time-resolved ICP-MS peak traces for a Cd-enriched Chinese hamster ovary (CHO) cell suspension in phosphate-buffered saline. Fig.16 Time-resolved ICP-MS peak traces for a suspension of Pb-enriched Chinese Hamster Ovary (CHO) cells in water are shown. These traces demonstrate that cells can be successfully introduced into the plasma using the vertical configuration of the present invention. Since the expected delivery efficiency is 100%, it is believed that the "missing" peaks are due to the droplets not containing cells. On the other hand, other droplets containing multiple cells cannot be excluded.

[0120] Fig.17 Schematically illustrates the coupling of an ICP-MS system according to an embodiment of the present invention to a continuous sample supply system including a sample pretreatment device 610. The sample pretreatment device 610 may be a separation device, for example, a chromatographic device such as an HPLC device or a GC device or an electrophoresis device such as a CE device. In other embodiments, the sample pretreatment device may be any other device that subjects an influent fluid flow including a sample to some kind of analysis or treatment.

[0121] The sample pretreatment device 610 has an inlet 611 and an outlet 612. It receives a continuous inflow fluid flow F at its inlet 611. in At its outlet 612, it provides a continuous outflow of fluid flow F out If the sample pretreatment device 610 is a separation device, the outflow fluid flow F out A composition that varies over time may be included and the separation device may be configured to determine information about the composition, as is known in the art.

[0122] The flow splitting device 620 is coupled to the output end of the sample pretreatment device 610. The flow splitting device 620 divides the continuously flowing fluid flow F outSplit into sample stream F sample and the residual fluid flow F res . Sample flow F sample The flow rate can be much smaller than the residual fluid flow F res The two fluid streams may be of the same composition except for the different flow rates.

[0123] Sample Flow F sample Enter the sample introduction system, which in this example is configured as above combined with Figure 5 The droplet delivery and desolvation system discussed herein. However, any other sample introduction system capable of introducing a small continuous stream of a liquid sample into the plasma of an ICP source may be employed. In particular, the sample introduction system may be a total consumption system, such as Figure 6 As shown, or it may include a DIHEN atomizer, such as Figure 4 The sample introduction system can be integrated with the ICP source to form a single unit.

[0124] The flow splitter 620 is provided because the flow rate at the outlet of some sample pretreatment devices, especially separation devices such as HPLC devices, is usually much greater than the flow rate required by the sample introduction system (for example, using a droplet generation device between 0.1 μl / min and 10 μl / min at a rate of 1000 Hz). For some other sample pretreatment devices, such as some CE devices, the flow splitter 620 may not be needed and may be omitted.

[0125] The sample introduction system is arranged above the ICP source in such a way that the sample is introduced into the ICP source in a vertical direction G pointing downwards, ie in the direction of gravity.

[0126] The correlator 630 receives separation information about the various fractions exiting the sample pretreatment device 610. It also receives mass information about the mass distribution in the fractions from a mass spectrometer coupled to the ICP source. It correlates the separation information with mass information well known in the art, for example in the form of LC / MS, GC / MS or CE / MS information.

[0127] Without departing from the scope of the invention, many modifications may be made. In particular, other types of ICP sources other than the two types discussed above may be employed. The sample may be split into droplets or particles in other ways than those discussed above. Any type and orientation of mass spectrometer may be employed.

[0128] Reference numerals list

[0129] 100 ICP source

[0130] 110 RF generator

[0131] 112 Plate capacitors

[0132] 113 vertical metal bars

[0133] 114 Horizontal Metal Strips

[0134] 115 Induction Coil

[0135] 116 PTFE support

[0136] 120 Torch Box

[0137] 121 Ventilation Grid

[0138] 122 Exit

[0139] 130, 130' Plasma Torch

[0140] 131 Central tube (injection tube)

[0141] 132 Intermediate pipe

[0142] 133 External tube

[0143] 134 Atomizer

[0144] 140 Cooling Plate

[0145] 141 Vertical Panel

[0146] 142 Incision

[0147] 143 holes

[0148] 150 Lift

[0149] 200 Quadrupole Mass Spectrometer

[0150] 200' TOF Mass Spectrometer

[0151] 210 Interface

[0152] 211 First baffle

[0153] 212 Sampling Cone

[0154] 213 Second baffle

[0155] 214 Skimmer Cone

[0156] 215 Ion Optics Unit

[0157] 220 Inlet baffle

[0158] 230 Quadrupole Mass Analyzer

[0159] 240 Exit baffle

[0160] 250 Detector

[0161] 260 Notch Filter

[0162] 270 Extractor

[0163] 280 TOF Mass Analyzer

[0164] 261 Mechanical Pump

[0165] 262 Turbomolecular pump

[0166] 310 Flow Cytometer

[0167] 311 Suspension

[0168] 312 Nozzle

[0169] 313 Laser

[0170] 314 Detection System

[0171] 315 Analyzer

[0172] 320 Cell Sorter

[0173] 321 Deflector

[0174] 322 Collection Container

[0175] 323 Sample inlet

[0176] 410 Droplet Delivery and Desolvation System

[0177] 411 Droplet Dispenser

[0178] 412 Flow Adapter

[0179] 413 Drop tube

[0180] 420 Total Consumption Sample Introduction System

[0181] 421 Atomizer

[0182] 422 Spray Chamber

[0183] 430 Laser Ablation Unit

[0184] 431 Laser

[0185] 432 samples

[0186] 440 Laser Ablation Unit

[0187] 441 Laser

[0188] 442 samples

[0189] 443 Flow Channel

[0190] 500 MICAP sources

[0191] 510 RF generator (magnetron)

[0192] 511 Fan

[0193] 512 Antenna

[0194] 515 Resonator

[0195] 520 Torch Box

[0196] 530 Plasma Torch

[0197] 531 Injection pipe

[0198] 610 Sample pretreatment equipment

[0199] 611 Entrance

[0200] 612 Exit

[0201] 620 Diversion Equipment

[0202] h Height

[0203] G Direction of gravity

[0204] F in Inflow fluid flow

[0205] F out Outflow fluid flow

[0206] F sample Sample flow

[0207] F res Residual fluid flow

Claims

1. An ionization system comprising: Flow cytometer (310) and / or cell sorter (320); as well as An ICP source (100; 500) for generating ions from a sample using an inductively coupled plasma, the ICP source (100; 500) being configured to be coupled to a mass spectrometer (200; 200'), wherein the ICP source (100; 500) is configured to allow the sample to be introduced into the plasma in a vertical direction (G) pointing downwards, Wherein, the ICP source (100; 500) is coupled to the flow cytometer (310) or the cell sorter (320) in such a way that the sample is transferred from the flow cytometer (310) or the cell sorter (320) to the ICP source (100; 500) along the downwardly directed vertical direction (G) without the need for an intermediate offline storage.

2. The ionization system according to claim 1, comprising a correlator (315), which is configured to: receive flow cytometric information from the flow cytometer (310) and mass spectrometry information from a mass spectrometer (200; 200') coupled to the ICP source (100; 500), and correlate the flow cytometric information with the mass spectrometry information to obtain combined flow cytometric and mass spectrometry information of multiple individual cells or particles.

3. An ionization system comprising: Continuous flow sample supply system (610, 620); a sample introduction system (410); as well as An ICP source (100; 500) for generating ions from a sample using an inductively coupled plasma, the ICP source (100; 500) being configured to be coupled to a mass spectrometer (200; 200'), wherein the ICP source (100; 500) is configured to allow the sample to be introduced into the plasma in a vertical direction (G) pointing downwards, The sample introduction system (410) is coupled to the continuous flow sample supply system (610, 620) in such a way that the continuous sample flow (F sample ) is transferred from the continuous flow sample supply system (610, 620) to the sample introduction system (410) without intermediate offline storage, and Therein, the sample introduction system (410) is configured to introduce the sample into the ICP source (100; 500) along the downwardly directed vertical direction (G) without intermediate offline storage.

4. The ionization system according to claim 3, in, The continuous flow sample supply system (610, 620) comprises a continuous flow sample pretreatment device (610), wherein the continuous flow sample pretreatment device (610) has a device configured to receive a continuous inflow flow (F in ) and having an inlet configured to provide a continuous outflow flow (F out ) outlet, the continuous outflow flow (F out ) forms at least a portion of the continuous sample flow (F sample ), the continuous flow sample pretreatment device (610) is configured to make the continuous inflow flow (F in ) is subjected to at least one operation for analysis and / or modification of its components.

5. The ionization system according to claim 4, wherein: The continuous flow sample pretreatment device (610) comprises a separation device, wherein the separation device is configured to separate the continuous inflow flow (F in ) and eluting the continuous effluent flow (F out ) in the chemical species or the particulate matter after separation.

6. The ionization system according to claim 5, wherein: The separation device is an electrophoresis device.

7. The ionization system according to claim 5, wherein: The separation device is a chromatographic device.

8. The ionization system according to claim 5, wherein: The separation device is a cell sorter.

9. The ionization system according to claim 4 or 5, wherein: The ionization system includes a correlator (630) configured to receive analytical information from the continuous flow sample pretreatment device (610) and mass spectrometry information from a mass spectrometer (200; 200') coupled to the ICP source (100; 500) and to correlate the analytical information with the mass spectrometry information.

10. The ionization system according to claim 4 or 5, wherein: The continuous flow sample supply system (610, 620) includes a method for transferring the continuous outflow flow (F out ) is continuously split into the continuous sample flow (F sample ) and residual flow (F res ) of the diversion device (620).

11. An ICP-MS system comprising: An ionization system according to any one of claims 1 to 10; as well as A mass spectrometer (200; 200') coupled to the ICP source (100; 500) for receiving ions from the ICP source (100; 500).

12. A mass spectrometry method comprising: Using ICP source (100; 500) maintaining plasma; The continuous sample flow (F sample ) is continuously supplied from a continuous flow sample supply system (610, 620) to a sample introduction system (410) without an intermediate offline storage, the continuous sample flow (F sample ) includes a sample; introducing the sample into the plasma using the sample introduction system (410) to generate ions from the sample, wherein the sample is introduced into the plasma by the sample introduction system (410) in a downwardly directed vertical direction (G) without intermediate offline storage; as well as A mass spectrometer (200; 200') coupled to the ICP source (100; 500) is used to analyze the mass-to-charge spectrum of ions that have been extracted from the plasma.

13. The method according to claim 12, wherein: The ions are extracted from the plasma along the downwardly directed vertical direction (G).

14. The method according to claim 12 or 13, comprising: Analyzing at least one characteristic of the sample using a flow cytometer (310), and / or sorting the sample droplets according to at least one characteristic using a cell sorter (320); as well as The sample is transferred from the flow cytometer (310) or cell sorter (320) along the downwardly directed vertical direction (G) to the ICP source (100; 500) without intermediate off-line storage.

15. The method according to claim 12 or 13, in, The continuous flow sample supply system (610, 620) comprises a continuous flow sample pretreatment device (610) having an inlet (611) and an outlet (612), and Wherein, the method comprises: A continuous inflow (F) comprising the sample is received at the inlet (611) in ); In the continuous flow sample pretreatment device (610), the continuous inflow flow (F in ) is subjected to at least one operation of analyzing and / or modifying its components; Providing a continuous outflow (F) comprising the sample at the outlet (612) out );as well as The continuous outflow flow (F out ) forms at least a portion of the continuous sample flow (F sample ).

16. The method according to claim 15, in, The continuous flow sample pretreatment device (610) comprises a separation device, and Wherein, the method comprises: Using the separation device to separate the continuous inflow flow (F in ) and eluting the continuous effluent flow (F out ) in the chemical species or the particulate matter after separation.

17. The method according to claim 16, wherein: The separation device is a chromatographic device.

18. The method according to claim 16, wherein: The separation device is an electrophoresis device.

19. The method according to claim 16, wherein: The separation device is a cell sorter.

20. The method of claim 16, further comprising: The continuous outflow (F out ) is continuously split into the continuous sample flow (F sample ) and residual flow (F res ).

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