Stable cell collection for elemental analysis

Abstract

The invention relates to stable cell collection for elemental analysis. Analysis of a sample injected into an inductively coupled plasma source may be improved by one or more of a stabilizing solution that may be mixed with the sample prior to injection and a heated injector. The stabilized solution can minimize osmotic pressure differences between the solution and the cells with relatively low amounts of dissolved solids (e.g., at or below about 0.2%). The stabilized solution may contain a salt (e.g., ammonium nitrate) present at a concentration of at least 5 mM. The injector may be heated before and / or during the injection. In some cases, heat from adjacent portions may be directed into the injector to improve heating of the injector. The injector heated to a sufficient temperature may minimize solute build-up and may extend the time available between cleaning. These improvements may be particularly useful in elemental analysis such as inductively coupled plasma mass spectrometry or inductively coupled plasma light emission spectroscopy.

Description

[0001] This application is a divisional application of Chinese Patent Application No. 201980039049.9, filed April 12, 2019, entitled “Stabilized Cell Acquisition for Elemental Analysis.”

[0002] Incorporation by Reference of Related Applications

[0003] This application claims the benefit of U.S. Provisional Application No. 62 / 657,332, filed April 13, 2018, and entitled “Stabilized Cell Acquisition for Elemental Analysis,” which is incorporated herein by reference in its entirety. TECHNICAL FIELD

[0004] The present disclosure relates generally to improving signal stability in elemental analysis, and more specifically to improvements in ionizing a sample in connection with elemental analysis. BACKGROUND

[0005] Inductively coupled plasma (ICP) is a type of plasma source used in various fields such as elemental analysis. A sample provided to the plasma generated by an ICP source can be ionized and atomized prior to analysis such as by mass spectrometry (MS) or optical emission spectroscopy (OES) (e.g., atomic emission spectroscopy or AES). ICP sources can also be used for other purposes. The sample typically comprises a substance dissolved in a solution, such as a suspension of the substance in a liquid or a solid substance carried in a gas stream.

[0006] In an ICP source (e.g., an ICP torch), a plasma is generated when a gas stream, such as argon, is ionized in a strong electromagnetic field. When optimal plasma temperature and energy density are generated, a sample introduced into the plasma through the torch can be vaporized, atomized, and ionized. Generally, the conditions that achieve optimal plasma temperature and energy density are reflected by the argon gas flow rate and the power intensity of the electromagnetic field.

[0007] An ICP source can include an induction coil and a set of tubes for supplying gas and sample to pass through a torch region covered by the induction coil. An ICP source typically includes an inner tube that acts as an injector to cover the sample, a middle tube for supplying gas to be heated and ionized, and an outer tube for providing a tangential flow to help maintain the shape of the plasma and protect the torch wall from melting.

[0008] In elemental analysis, a sample provided to an ICP source can be ionized and then transferred into an elemental analyzer. The process of storing a sample and then injecting it into an ICP source can sometimes damage the sample in a way that can reduce the stability or resolution of the determination. It can be desirable to provide techniques and materials for improving the stability and resolution of ICP-based elemental analysis. Further, conventional ICP-based elemental analyzers can become contaminated over time, such as buildup present on an injector. It can be desirable to provide an ICP-based elemental analyzer or ICP source that is able to resist contamination over time.

[0009] In multiplexed elemental analysis of element-labeled cells (e.g., mass cytometry), cells are suspended in water to avoid that metals or heavy elements will generate background noise during elemental analysis. The absence of solutes also reduces clogging on the ICP injector walls, which can block the fluidics. SUMMARY

[0010] The terms embodiments and like terms are intended to refer broadly to all of the subject matter of this disclosure and the claims below. Statements containing these terms should be understood not to limit the subject matter described herein or to limit the meaning or scope of the claims below. Embodiments of this disclosure encompassed herein are defined only by the claims below. The summary is provided to introduce a selection of concepts that are further described in the detailed description section below. This summary does not identify key or essential features of the claimed subject matter and shall not be used to interpret the scope or essential features of the claimed subject matter. The subject matter should be understood from the entire description of the disclosure, with appropriate sections of the description, including any drawings and claims, viewed in its entirety.

[0011] Embodiments of the disclosure include a sample comprising: an element-labeled analyte comprising an analyte bound to an element-labeled affinity reagent, wherein the element-labeled affinity reagent comprises an affinity reagent for binding to the analyte and a metal-binding moiety bound to one or more metal elements; and a stabilized solution having a total dissolved solids of at or below about 0.2%, wherein the stabilized solution comprises a salt present at a concentration of at least 5 mM.

[0012] In some cases, the salt is a non-metal salt. In some cases, the salt does not contain carbon. In some cases, the salt does not contain a metal with an atomic mass greater than 80. In some cases, the salt includes nitrogen. In some cases, the salt is ammonium nitrate. In some cases, the salt has a vapor pressure of at least 3 Pa at 100 °C. In some cases, the salt has a vapor pressure of at least 130 Pa at 150 °C. In some cases, the salt has a vapor pressure of at least 250 Pa at 160 °C. In some cases, the salt is ammonium acetate. In some cases, the analyte comprises whole cells. In some cases, the stabilizing solution induces a low enough osmotic pressure on the membrane of the analyte to avoid osmotic lysis of the analyte. In some cases, the salt is present in the stabilizing solution at a concentration of at or less than 25 mM. In some cases, the stabilizing solution has a pH between 5-9. In some cases, the stabilizing solution has a pH between 6-8. In some cases, the metal-binding moiety comprises a polymer linked to an affinity reagent and comprising at least one metal-binding pendant group comprising at least one metal atom. In some cases, the element-labeled analyte comprises a first analyte labeled with a first element tag and a second analyte labeled with a second element tag distinguishable from the first element tag by elemental analysis. In some cases, the affinity reagent comprises an antibody.

[0013] Embodiments of the present disclosure include a sample preparation kit comprising an element-labeled affinity reagent comprising an affinity reagent for binding to an analyte and a metal-binding moiety that binds to one or more metal elements; and a stabilizing solution having at or below about 0.2% total dissolved solids, wherein the stabilizing solution contains a salt present at a concentration of at least 5 mM.

[0014] In some cases, the salt is a non-metal salt. In some cases, the salt does not contain carbon. In some cases, the salt does not contain a metal with an atomic mass greater than 80. In some cases, the salt includes nitrogen. In some cases, the salt is ammonium nitrate. In some cases, the salt has a vapor pressure of at least 3 Pa at 100 °C. In some cases, the salt has a vapor pressure of at least 130 Pa at 150 °C. In some cases, the salt has a vapor pressure of at least 250 Pa at 160 °C. In some cases, the salt is ammonium acetate. In some cases, the affinity reagent can bind to a surface of a whole cell. In some cases, the stabilizing solution induces a low enough osmotic pressure on the membrane of the whole cell bound to the affinity reagent to avoid osmotic lysis of the whole cell. In some cases, the salt is present in the stabilizing solution at a concentration of or less than 25 mM. In some cases, the stabilizing solution has a pH between 5-9. In some cases, the stabilizing solution has a pH between 6-8. In some cases, the metal binding moiety includes a polymer linked to the affinity reagent and comprising at least one metal binding pendant group, the metal binding pendant group comprising at least one metal atom. In some cases, the element-labeled affinity reagent comprises a first affinity reagent labeled with a first element tag and a second affinity reagent labeled with a second element tag, the second element tag distinguishable from the first element tag by elemental analysis.

[0015] Embodiments of the present disclosure include a method comprising: receiving a sample comprising an element-labeled analyte and a stabilizing solution; transporting the sample in a downstream direction toward a plasma of an inductively coupled plasma source to ionize the sample, wherein transporting the sample comprises passing the sample through an inner wall of an injector; ionizing the sample at the plasma; and performing elemental analysis on the ionized sample to detect an element of the element-labeled analyte.

[0016] In some cases, the analyte comprises a whole cell, and wherein transporting the sample to the plasma comprises transporting the whole cell to the plasma. In some cases, transporting the sample to the plasma comprises transporting the sample through an injector having an inner diameter between about 0.5 mm and 5 mm. In some cases, receiving the sample further comprises mixing the element-labeled analyte and the stabilizing solution. In some cases, the stabilizing solution comprises a salt selected to obtain less than 2% salt deposition over a 48 hour sample run. In some cases, the stabilizing solution comprises a salt selected to maintain a percent signal drop during elemental analysis of or less than 5% over a 48 hour sample run.

[0017] Embodiments of the present disclosure include a method comprising providing an element-labeled analyte, wherein the element-labeled analyte comprises a sample of whole cells labeled with element-labeled affinity reagents, wherein each element-labeled affinity reagent comprises an affinity reagent that binds to an analyte of the sample and a metal-binding moiety that binds to one or more metal elements; and mixing the element-labeled analyte with a stabilization solution having at or below about 0.2% total dissolved solids, wherein the stabilization solution contains a salt present at a concentration of at least 5 mM.

[0018] In some cases, the salt is a non-metal salt. In some cases, the salt does not contain carbon. In some cases, the salt does not contain a metal with an atomic mass unit greater than 80. In some cases, the salt includes nitrogen. In some cases, the salt is ammonium nitrate. In some cases, the salt has a vapor pressure of at least 3 Pa at 100 °C. In some cases, the method further comprises passing the sample collection solution through an injector heated to a temperature of at least 100 °C. In some cases, the salt has a vapor pressure of at least 130 Pa at 150 °C. In some cases, the method further comprises passing the sample collection solution through an injector heated to a temperature of at least 150 °C. In some cases, the salt has a vapor pressure of at least 250 Pa at 160 °C. In some cases, the method further comprises passing the sample collection solution through an injector heated to a temperature of at least 160 °C. In some cases, the salt is ammonium acetate. In some cases, the affinity reagents can bind to the surface of the whole cells. In some cases, the stabilization solution induces a low enough osmotic pressure on the membranes of the whole cells bound to the affinity reagents to avoid osmotic lysis of the whole cells. In some cases, the salt is present in the stabilization solution at a concentration of at or below 25 mM. In some cases, the stabilization solution has a pH between 5-9. In some cases, the stabilization solution has a pH between 6-8. In some cases, the metal-binding moiety comprises a polymer linked to the affinity reagent and comprising at least one metal-binding pendant group, the metal-binding pendant group comprising at least one metal atom. In some cases, the element-labeled affinity reagents comprise a first affinity reagent labeled with a first element tag and a second affinity reagent labeled with a second element tag, the second element tag distinguishable from the first element tag by elemental analysis. In some cases, the salt is selected to obtain less than 2% salt deposition during a 48-hour sample run. In some cases, the stabilization solution comprises a salt selected to maintain a percent signal drop during elemental analysis of at or below 5% during a 48-hour sample run.

[0019] Embodiments of the present disclosure include a sample-mixable stabilized solution for use in inductively coupled plasma elemental analysis, the stabilized solution comprising: a solute and a solvent, wherein the solute is a salt present at a concentration of at least 5 mM, wherein the solution has a total dissolved solids of at or below about 0.2%, and wherein the solution is free of metals having an atomic mass unit greater than 80.

[0020] In some cases, the salt is a non-metallic salt. In some cases, the salt is free of carbon. In some cases, the salt includes nitrogen. In some cases, the salt is ammonium nitrate. In some cases, the salt has a vapor pressure of at least 3 Pa at 100 °C. In some cases, the salt has a vapor pressure of at least 130 Pa at 150 °C. In some cases, the salt has a vapor pressure of at least 250 Pa at 160 °C. In some cases, the salt is ammonium acetate. In some cases, the stabilized solution induces a low enough osmotic pressure on the membranes of whole cells of the sample to avoid osmotic lysis of the whole cells. In some cases, the salt is present in the stabilized solution at a concentration of at or less than 25 mM. In some cases, the stabilized solution has a pH between 5-9. In some cases, the stabilized solution has a pH between 6-8.

[0021] Embodiments of the present disclosure include an apparatus comprising: an inductively coupled plasma source for generating a plasma; an injector having a sample inlet for receiving a sample comprising an element-labeled analyte, wherein the injector is positioned upstream of the inductively coupled plasma source to supply the sample to the plasma; and a heat source thermally coupled to the injector for heating the injector.

[0022] In some cases, the apparatus further includes a heat transfer device thermally coupled to the injector for delivering heat from a heat source. In some cases, the heat transfer device includes a metallic jacket around at least a portion of the injector. In some cases, the heat source includes at least a portion of a spray chamber positioned upstream of the injector such that heat from the spray chamber is transferred to the injector through the heat transfer device. In some cases, the heat source includes a plasma. In some cases, the heat source includes an electrical resistance heat source. In some cases, the apparatus further includes one or more heat pipes extending along a length of the injector. In some cases, the one or more heat pipes are arranged to conduct thermal energy from a higher temperature portion of the injector to a lower temperature portion of the injector. In some cases, the apparatus further includes a mass spectrometer positioned downstream of the inductively coupled plasma source for receiving ions from the inductively coupled plasma source. In some cases, an inner diameter of the injector is between about 0.5 mm and 5 mm. In some cases, the apparatus further includes a sample source coupled to the injector for providing a sample and a stabilizing solution. In some cases, the heat transfer device is coupled to the injector to heat an inner surface of the injector to a temperature sufficient to evaporate or sublimate a solute of the stabilizing solution. In some cases, the heat transfer device is coupled to the injector to heat an inner surface of the injector to a temperature of at least 150 °C.

[0023] Embodiments of the present disclosure include methods of using one or more apparatuses disclosed above, the methods comprising: heating an injector using a heat source; passing a sample through the injector to a plasma; ionizing the sample; and performing elemental analysis on the ionized sample.

[0024] In some cases, passing the sample through the injector includes passing a solution including an element-labeled analyte and a stabilizing solution. In some cases, heating the injector includes heating the injector to a temperature suitable for obtaining less than 2% salt deposition during a 48 hour sample run. In some cases, heating the injector includes passing a current through an electrical resistance heat source, where the heat source is the electrical resistance heat source. In some cases, heating the injector includes using a heat transfer device to conduct heat from a higher temperature portion of the injector to a lower temperature portion of the injector. In some cases, heating the injector includes heating an inner wall to a temperature sufficient to evaporate or sublimate or decompose a solute of the stabilizing solution.

[0025] Embodiments of the present disclosure include a method comprising: receiving a sample including an element-labeled analyte and a stabilizing solution; delivering the sample in a downstream direction toward a plasma of an inductively coupled plasma source to ionize the sample, where delivering the sample includes passing the sample through an inner wall of an injector; and heating the inner wall of the injector.

[0026] In some cases, heating the inner wall of the injector is initiated prior to delivering the sample to the plasma. In some cases, heating the inner wall of the injector is initiated after delivering a first portion of the sample to the plasma. In some cases, the method further comprises passing the sample through a spray chamber, wherein heating the inner wall of the injector comprises conducting heat from the spray chamber through a heat transfer device. In some cases, heating the inner wall of the injector comprises generating heat at a heat source. In some cases, generating heat at the heat source comprises passing an electrical current through a resistive heat source. In some cases, heating the inner wall of the injector comprises using a heat transfer device to conduct heat from a higher temperature portion of the injector to a lower temperature portion of the injector. In some cases, heating the inner wall of the injector comprises heating the inner wall to a temperature sufficient to evaporate or sublimate a solute of the stabilization solution. In some cases, heating the inner wall of the injector comprises heating the inner wall to a temperature of at least 150°C. In some cases, the method further comprises: delivering ions of the ionized sample to a mass spectrometer; and analyzing the ions by the mass spectrometer. In some cases, the analyte comprises whole cells, and wherein delivering the sample to the plasma comprises delivering the whole cells to the plasma. In some cases, delivering the sample to the plasma comprises delivering the sample through an injector having an inner diameter between about 0.5 mm and 5 mm. In some cases, receiving the sample further comprises mixing an element-labeled analyte and a stabilization solution. In some cases, heating the inner wall of the injector comprises heating the inner wall to a temperature suitable for obtaining less than 2% salt deposition over a 48 hour sample run.

[0027] Embodiments of the present disclosure include an apparatus comprising: an injector positionable upstream of an inductively coupled plasma source and adapted to deliver a sample to a plasma of the inductively coupled plasma source, the injector having a sample inlet for receiving the sample, wherein the sample comprises an element-labeled analyte; and a heat source thermally coupled to the injector for heating the injector.

[0028] In some cases, the apparatus further includes a heat transfer device thermally coupled to the injector for delivering heat from a heat source. In some cases, the heat transfer device includes a metal sleeve around at least a portion of the injector. In some cases, the heat source includes at least a portion of a spray chamber positioned upstream of the injector, such that heat from the spray chamber is transferred to the injector through the heat transfer device. In some cases, the heat source includes a plasma. In some cases, the heat source includes an electrically resistive heat source. In some cases, the apparatus further includes one or more heat pipes extending along a length of the injector. In some cases, the one or more heat pipes are arranged to conduct thermal energy from a higher temperature portion of the injector to a lower temperature portion of the injector. In some cases, the apparatus further includes a mass spectrometer positionable downstream of the inductively coupled plasma source for receiving ions from the inductively coupled plasma source. In some cases, an inner diameter of the injector is between about 0.5 mm and 5 mm. In some cases, the apparatus further includes a sample source coupled to the injector for providing a sample and a stabilizing solution. In some cases, the heat transfer device is coupled to the injector to heat an inner surface of the injector to a temperature sufficient to evaporate or sublimate a solute of the stabilizing solution. In some cases, the heat transfer device is coupled to the injector to heat an inner surface of the injector to a temperature of at least 150 °C. BRIEF DESCRIPTION OF DRAWINGS

[0029] The description herein makes reference to the following drawings, which illustrate preferred aspects of this disclosure and are in which like reference numerals

[0030] Figure 1 is a schematic diagram depicting an inductively coupled plasma (ICP) system in accordance with certain aspects of the present disclosure.

[0031] Figure 2 is a flow diagram depicting a process for ionizing a sample in accordance with certain aspects of the present disclosure.

[0032] Figure 3 is a schematic cross-sectional view of an ICP system having a heat transfer device thermally coupled to an injector in accordance with certain aspects of the present disclosure.

[0033] Figure 4 is a schematic cross-sectional view of an ICP system having an injector thermally coupled to a spray chamber in accordance with certain aspects of the present disclosure.

[0034] Figure 5 is a schematic cross-sectional view of an ICP system having a heat source thermally coupled to an injector in accordance with certain aspects of the present disclosure.

[0035] Figure 6 is a schematic front cross-sectional view of an injector having a heat transfer device thermally coupled thereto in accordance with certain aspects of the present disclosure.

[0036] Figure 7 is a schematic front cross-sectional view depicting an injector with a heat source thermally coupled thereto, in accordance with certain aspects of the present disclosure.

[0037] Figure 8 is a schematic front cross-sectional view depicting an injector with an external heating tube thermally coupled thereto, in accordance with certain aspects of the present disclosure.

[0038] Figure 9 is a schematic front cross-sectional view depicting an injector with an internal heating tube thermally coupled thereto, in accordance with certain aspects of the present disclosure.

[0039] Figure 10 is a flowchart depicting a process for preparing and ionizing a sample, in accordance with certain aspects of the present disclosure.

[0040] Figure 11 is a graph depicting the percent signal drop for a set of samples prepared with a 2 mM ammonium nitrate stabilization solution, in accordance with certain aspects of the present disclosure.

[0041] Figure 12 is a graph depicting the percent signal drop for a set of samples prepared with a 5 mM ammonium nitrate stabilization solution, in accordance with certain aspects of the present disclosure.

[0042] Figure 13 is a graph depicting the percent signal drop for a set of samples prepared with a 10 mM ammonium nitrate stabilization solution, in accordance with certain aspects of the present disclosure.

[0043] Figure 14 is a graph depicting the CD44 channel signal for a sample that has been suspended in deionized water and injected into a plasma source.

[0044] Figure 15 is a graph depicting the CD44 channel signal for a sample that has been suspended in a 25 mM ammonium nitrate stabilization solution and injected into a plasma source, in accordance with certain aspects of the present disclosure. Figure 14

[0045] Figure 16 is a graph depicting the CD44 channel signal for a sample that has been suspended in a 25 mM ammonium nitrate stabilization solution and injected into a plasma source, in accordance with certain aspects of the present disclosure. 165

[0046] Figure 17 is a graph depicting the CD44 channel signal for a sample that has been suspended in a 75 mM ammonium nitrate stabilization solution and injected into a plasma source, in accordance with certain aspects of the present disclosure. Figure 16 165

[0047] Figure 18 ​​​​is an image of the buildup on the injector when used without sufficient heating for certain aspects of the present disclosure.

[0048] Figure 19 is a flow chart depicting a process for self-cleaning an injector according to certain aspects of the present disclosure. DETAILED DESCRIPTION

[0049] Certain aspects and features of the present disclosure relate to improvements in injecting a sample into a plasma source, such as an inductively coupled plasma (ICP) source. The improvements may include one or more of a stabilizing solution that can be mixed with the sample prior to injection and a heated injector. The sample collection solution can be prepared by mixing the sample with a stabilizing solution to improve cell stability during injection. The stabilizing solution can minimize the osmotic pressure difference between the solution and the cells using a relatively low amount of dissolved solids (e.g., at or below about 0.2%). The stabilizing solution can contain a salt (e.g., ammonium nitrate) that can be present at a concentration of at least 5 mM. The injector can be heated before and / or during injection, such as using a heat source or heat transfer device. In some cases, heat from adjacent components can be directed along the injector to improve heating of the injector. Injectors heated to a sufficient temperature during use can minimize buildup and extend the usable time between cleanings. These improvements may be particularly useful in elemental analysis such as inductively coupled plasma mass spectrometry (ICP-MS) or inductively coupled plasma optical emission spectroscopy (ICP-OES). These improvements are particularly useful for ICP systems operating in suspension mode or solution mode (eg, using a microsprayer).

[0050] Certain aspects of the present disclosure are particularly useful for elemental analysis. Elemental analysis can refer to techniques for determining the elemental composition (e.g., exact or relative) of a sample, or optionally its isotopic composition (e.g., exact or relative). Non-limiting examples of elemental analysis methods include optical atomic spectroscopy, such as flame atomic absorption, graphite furnace atomic absorption, and inductively coupled plasma atomic emission, which probe the external electronic structure of atoms; mass spectrometry atomic spectroscopy, such as inductively coupled mass spectrometry, which probe the mass of atoms; and x-ray fluorescence, particle-induced x-ray emission, x-ray photoelectron spectroscopy, and Auger electron spectroscopy, which probe the internal electronic structure of atoms.

[0051] In some cases, elemental analysis involves the use of an inductively coupled plasma mass spectrometer (ICP-MS), an elemental analyzer based on sensitive mass spectrometry. Different ICP-MS configurations are distinguished primarily by the mass selection technology employed and can be, for example, quadrupole or time-of-flight (ICP-TOF) or magnetic sector (high-resolution ICP-MS). There are many commercially available ICP-MS mass spectrometer models with a wide spectrum of configurations, capabilities, and modifications.

[0052] Elemental analysis can be used to detect elemental tags associated with an analyte. Elemental tags, such as element-labeled affinity reagents or element-labeled supports or beads, can be used to label an analyte based on the presence or absence of a desired biomolecule in the analyte. An elemental tag or tag is a chemical moiety that includes an element or elements, with one or many isotopes attached to a support molecular structure (referred to as tag atoms), or capable of binding the one or more elements or isotopes. An elemental tag can also include the means by which the elemental tag is attached to a molecule of interest or target molecule (e.g., analyte). Different elemental tags can be distinguished based on the elemental composition of the tag. An elemental tag can contain many copies of a given isotope, and can have a reproducible copy number of each isotope in each tag. Suitable elemental tags can include polymers (e.g., linear or branched polymers) with metal-binding side groups such as metal-chelating moieties (e.g., tetraxetan (DOTA) or pentetic acid (DTPA)). An elemental tag can be a nanoparticle, such as a metal core packaged in a polymeric shell. An elemental tag is functionally distinguishable from other elemental tags in the same sample because its elemental or isotopic composition is different from the other tags. As used herein, the term affinity reagent can refer to a biomolecule that is capable of binding tightly to a target molecule or analyte. Some non-limiting examples of affinity reagents include aptamers, protein molecules, lectins, and polysaccharides. For example, an affinity reagent can be an antibody that recognizes and binds a particular antigen (e.g., on a protein) with high affinity. Streptavidin is a protein molecule that specifically binds biotin, and can be considered another example of an affinity reagent. In some cases, an affinity reagent is a non-oligonucleotide biomolecule.

[0053] Non-affinity reagents, such as oligonucleotides for hybridizing to target oligonucleotide (e.g., DNA, RNA) sequences, can be element-labeled and can be used to label target oligonucleotides for elemental analysis. Additional metal-containing reagents, including DNA intercalators such as iridium and barcoding reagents, can also be detected by elemental analysis as described herein.

[0054] To achieve useful results, it can be desirable to select tag atoms that are not otherwise present in a potential sample or analyte. For example, certain metals, especially lanthanides, are rare in biological samples, and thus can be particularly suitable for use in elemental tags for assaying these biological samples.

[0055] The term biological sample or tissue sample as used herein can refer to a sample obtained from a biological subject, including a biological tissue or fluid-derived sample obtained, reached, or collected in vivo or in situ. Biological samples also include samples from a region of a biological subject containing precancerous or cancerous cells or tissues. Such samples can be, but are not limited to, organs, tissues, fractions, and cells isolated from a mammal. Examples of biological samples include, but are not limited to, cell cultures, cell lines, tissues, organs, organelles, biological fluids, and the like. Examples of biological samples include, but are not limited to, skin samples, tissue biopsies, and the like.

[0056] As used herein, the term metal can mean an element having one of the following atomic numbers: 3, 4, 11-13, 19-33, 37-52, 55-84, 87-102. In some cases, the metal can be a transition element. As used herein, the term transition element can mean an element having one of the following atomic numbers: 21-30, 39-48, 57-80, and 89-92. Transition elements include rare earth metals, lanthanides, and noble metals. As used herein, the term lanthanide can refer to those transition metals having atomic numbers from 57 to 71, including La (lanthanum), Ce (cerium), Pr (praseodymium), Nd (neodymium), Pm (promethium), Sm (samarium), Eu (europium), Gd (gadolinium), Tb (terbium), Dy (dysprosium), Ho (holmium), Er (erbium), Tm (thulium), Yb (ytterbium), Lu (lutetium).

[0057] Thus, in one example, an element-labeled affinity reagent can include a distinguishable element tag (e.g., containing one element or a set of elements) bound to an antibody that has a high affinity for a particular antigen on a protein of interest. After incubating the element-labeled affinity reagent with the analyte and washing away unbound reagent, the analyte sample can be interrogated using elemental analysis to detect the presence of one or more element tags, and thus the presence of the protein of interest can be inferred.

[0058] In some cases, the analyte of interest can include a biomolecule on or within a cell. In some cases, it can be desirable to perform elemental analysis on whole cells or intact cells, such as to determine the presence, amount, or absence of element tags associated with individual cells of a sample. To enable reliable elemental analysis per cell, it can be desirable to determine lysis or other damage to individual cells prior to ionization of the cells in the plasma. Damage to cells in the cell collection by elemental analysis (e.g., elemental analysis per cell) can result in poor signal stability during the course of the sample.

[0059] Certain aspects and features of the present disclosure relate to the use of a stabilizing solution suitable for maintaining high signal stability of a sample and / or keeping individual cells of the sample intact during injection in an ICP system. As used herein, an ICP system can refer to an inductively coupled plasma source (e.g., an ICP torch), and optionally any additional equipment or components for operating the ICP source, for supplying the sample to the plasma, and / or for transporting ions for further analysis. The stabilizing solution can be selected to minimize the osmotic pressure difference between the solution and the cells, which in turn can help keep the cells intact. Alternatively or in addition, the stabilizing solution can be selected to improve the stability of metal chelates of one or more elemental tags.

[0060] However, in some cases, the stabilizing solution may increase the risk of injector clogging because solutes in the stabilizing solution may condense and accumulate in the injector (e.g., along the inner wall of the injector). In some cases, such accumulation and even clogging can be reduced or prevented by using a heated injector. In some cases, the combination of a heated injector and a stabilizing solution according to aspects of the present disclosure can improve signal stability when analyzing samples using an elemental analyzer.

[0061] In some cases, the use of a heated injector can allow the use of a higher concentration of stabilizing solution without undesirable negative effects (e.g., no accumulation or clogging, no readily noticeable accumulation or clogging, or only minimal accumulation or clogging, such as defined by a percentage of the injector cross-section). In some cases, undesirable effects associated with accumulation or clogging can be minimized by using a lower concentration of stabilizing solution, with or without the use of a heated injector. In some cases, the sample can be or be longer than 48 hours, 36 hours, 32 hours, 28 hours, 24 hours, 20 hours, 16 hours, 12 hours, 8 hours, 4 hours, 2 hours, and / or 1 hour.

[0062] As used herein, certain aspects of the present disclosure can prevent accumulation or blockage in an injector. The injector can have a nominal cross-sectional area, which is defined as the cross-sectional area of ​​the injector's inner diameter (e.g., A 标称 =πr 2 If accumulation or blockage occurs within the injector, the injector may have a cross-sectional area smaller than the nominal area (e.g., A) based on the degree of accumulation or blockage. 有效 =πr 2 -A clog , where A clogeffective cross-sectional area of the injector remains at or at least about 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, 90%, 89%, 88%, 87%, 86%, 85%, 84%, 83%, 82%, 81%, 80%, 79%, 78%, 77%, 76%, 75%, 74%, 73%, 72%, 71%, and / or 70% of the nominal cross-sectional area of the injector for 48 hours, 36 hours, 32 hours, 28 hours, 24 hours, 20 hours, 16 hours, 12 hours, 8 hours, 4 hours, and / or 2 hours of instrument non-stop (e.g., continuous) run. In some cases, certain aspects of the present disclosure can prevent clogging or buildup of the injector during sample run such that the effective cross-sectional area of the injector remains at or at least about 90% of the nominal cross-sectional area of the injector.

[0063] As used herein, certain aspects of the present disclosure can increase the sublimation rate and / or decrease the deposition rate of the solution through the injector, thereby preventing long-term deposition of solute on the inner surface of the injector. The increase in sublimation rate and / or decrease in deposition rate can be associated with less overall solute buildup on the inner surface of the injector during a sample run. The sublimation rate can refer to the rate at which solid solute (e.g., salt of a stabilized solution) deposited on the inner wall of the injector is converted to gas and carried away from the injector. The deposition rate can refer to the rate at which solute (e.g., salt of a stabilized solution) is deposited on the injector. Because sublimation is the primary mode of removing deposited solute from the injector during operation, the sublimation rate is approximately inversely proportional to the deposition rate. In some cases, sublimation can be described in terms of the percentage of solute that is deposited instead of ionized as the solution passes through the injector and into the plasma. For example, a 5% deposition rate can refer to 5% of the solute in the solution being deposited on the inner wall of the injector. For example, a higher sublimation rate will reduce the solute buildup on the inner wall of the injector during a sample run. In some cases, approximately 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4.5%, 4%, 3.5%, 3%, 2.5%, 2%, 1.9%, 1.8%, 1.7%, 1.6%, 1.5%, 1.4%, 1.3%, 1.2%, 1.1%, 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, or 0.1% or 0% of the solute can be deposited on the inner wall of the injector at the end of a sample run. In some cases, a sample run can be or longer than 48 hours, 36 hours, 32 hours, 28 hours, 24 hours, 20 hours, 16 hours, 12 hours, 8 hours, 4 hours, 2 hours, and / or 1 hour.

[0064] Certain stabilized solutions and optionally heated injectors as described herein can be used to transport a mixture containing a sample (e.g., whole cells) and solutes from the stabilized solution (e.g., salts from the stabilized solution) through the injector to, for example, a plasma. In some cases, the mixture exiting the injector contains at least or about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 95.5%, 96%, 96.5%, 97%, 97.5%, 98%, 98.1%, 98.2%, 98.3%, 98.4%, 98.5%, 98.6%, 98.7%, 98.8%, 98.9%, 99%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, or 99.9% of the solutes entering the injector. The mixture can be a cell collection solution. The cell collection solution can be entrained in a gas such as argon. The cell collection solution can be further entrained in a primary gas and / or a secondary gas after exiting the injector.

[0065] In some cases, the sublimation rate can be calculated as the vapor pressure of the solute at the injector (e.g., the expected vapor pressure of a given solute and the temperature of the injector). Examples of sublimation rates for exemplary solutes are described herein with reference to Table 1.

[0066] The stabilized solution (e.g., the type and concentration of salts in the stabilized solution) and / or the amount of heating of the injector (e.g., no heating or some heating) can be selected to achieve a desired sublimation rate and / or a desired deposition rate.

[0067] The stabilized solution (e.g., the type and concentration of salts in the stabilized solution) and / or the amount of heating of the injector can be selected to achieve a desired sublimation rate.

[0068] As used herein, certain aspects of the present disclosure can prevent or reduce the percentage of signal drop during a sample run. Prevention of signal drop can occur when using a stabilized solution and / or a heated injector. In some cases, prevention of signal drop can be related to keeping the injector free from buildup or clogging. In some cases, the percentage of signal drop can be at or less than about 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4.5%, 4%, 3.5%, 3%, 2.5%, 2%, 1.5%, 1%, or 0.5% according to certain aspects of the present disclosure. The percentage of signal drop can be calculated over a sample run or a portion of a sample run. In some cases, the percentage of signal drop can be calculated over a period of time that is at or about 48 hours, 36 hours, 32 hours, 28 hours, 24 hours, 20 hours, 16 hours, 12 hours, 8 hours, 4 hours, 2 hours, and / or 1 hour. The percentage of signal drop can be calculated as the average percentage of signal deviating from an initial signal measurement or average. The signal can be raw data or normalized data. In certain aspects, the percentage of signal drop can be calculated as the average signal drop across all mass channels, the maximum signal drop percentage, or the signal drop percentage for mass channels related to a particular analyte of interest.

[0069] A heated injector can be heated using any suitable technique. In some cases, a heated injector can be directly heated by a heating device. In some cases, a heated injector can be indirectly heated, such as by directing heat from other components of an ICP system or adjacent systems. A heating device (e.g., heat source) can supply heat to the injector. Various types of heating units can be used, such as resistive heating devices, thermoelectric devices, gas-powered heating devices (e.g., direct flame), convection heating devices (e.g., circulating a hot fluid, such as air), laser heating devices, or others. In some cases, heat can be applied to a portion of the heated injector (e.g., an upstream portion), allowing additional portions of the heated injector (e.g., a downstream portion or output) to be heated by conduction or convection. For example, a heat pipe can be applied to or incorporated within the injector to thermally conduct heat from a first portion to a second portion. In another example, sufficient heat can be provided to a second portion by convection through a sample fluid within the heated injector.

[0070] In some cases, the injector can be completely or partially surrounded by a heat transfer device. The heat transfer device can be any suitable device capable of conducting heat into and / or along the injector. Examples of suitable heat transfer devices include thermally conductive materials coupled to, disposed within, and / or incorporated within the injector. For example, the injector can be coated with a metal foil. In some cases, the heat transfer device can thermally couple the injector to a heat source (e.g., a direct heat source or an indirect heat source). For example, the heat transfer device can thermally couple the injector to a spray chamber of an ICP system, allowing heat to be transferred from the spray chamber into the injector. In another example, the heat transfer device can be positioned to conduct heat from a plasma into the injector. In some cases, a non-metallic heat transfer device can be used. As used herein, a heat transfer device that thermally couples the injector to another object or element (e.g., a spray chamber or a plasma) can include thermally coupling at a higher rate of heat transfer than without the heat transfer device. In other words, the heat transfer device can increase the rate of heat transfer between the injector and the other object, providing faster heat transfer than if the heat transfer device is not used (e.g., if the injector is exposed to standard ambient air or gas).

[0071] In some cases, the heat transfer device can be sized (e.g., dimensioned and / or shaped) to deliver sufficient heat from a stable heat source (e.g., a spray chamber held at 200 °C) to increase the temperature of the injector (e.g., the temperature of the inner wall of the injector) to a minimum set temperature (e.g., 160 °C). In such cases, the heat transfer device can result in a temperature gradient along the length of the injector, however the temperature at any point along the inner wall of the injector can remain at least the minimum set temperature. The minimum set temperature can be or about 160 °C. In some cases, the minimum set temperature can be or be at least about 100 °C, 110 °C, 120 °C, 130 °C, 140 °C, 150 °C, 160 °C, 170 °C, 180 °C, 190 °C, 200 °C, 210 °C, 220 °C, 230 °C, 240 °C, 250 °C, or 260 °C. In some cases, multiple heat transfer devices can be used, such as a first heat transfer device coupled to the injector and a second heat transfer device coupled to or positioned proximate to another element of the ICP system.

[0072] A heated injector can be particularly useful in certain aspects of the present disclosure, such as when the sample is combined with, mixed with, or suspended in a stabilization solution.

[0073] According to certain aspects of the present disclosure, the stabilizing solution can include a salt, such as a non-metallic salt, such as ammonium nitrate. The salt can be selected to achieve a particular vapor pressure at certain temperatures, such as certain temperatures associated with a heated injector. In some cases, ammonium nitrate is the salt used in the stabilizing solution, although other salts can also be used. In some cases, solutes based on chlorine and / or fluorine can be used, and a desired vapor pressure can be achieved. Table 1 depicts approximate vapor pressure information associated with ammonium nitrate as a function of temperature, where is the sublimation rate for a given setup in micrograms per minute.

[0074] Table 1 - Sublimation rate of ammonium nitrate at specific temperatures

[0075]

[0076]

[0077] For ammonium nitrate, at 433 Kelvin or about 160 °C, the vapor pressure reaches about 328 Pa or about 0.3% of atmospheric pressure. The mass flow rate of the evaporated solute can be estimated based on the product of the vapor pressure and the gas flow rate. When the injector flow rate is about 0.7 slpm (standard liters per minute) of argon and the sample flow rate is about 45 microliters per minute, the amount of ammonium nitrate in the carrier gas (argon) can be calculated to be 0.003% of the gas volume for a concentration of 20 mM in the solution. Thus, at this temperature, ammonium nitrate will gradually sublime from the injector walls and into the gas stream. The equilibrium between the gas phase and the solid phase of ammonium nitrate can be altered by the surface tension in small crystals. However, experiments have determined that 160 °C is sufficient to keep the injector surface free from being “fogged” by ammonium nitrate deposits, particularly at the gas flow rates commonly used in inductively coupled plasma sources.

[0078] The injector can be heated to a temperature sufficient to promote sublimation of the salt of the stabilizing solution. In some cases, the temperature to which the injector is heated can be determined or calculated based on the desired vapor pressure of the particular salt. Techniques for correlating temperature with vapor pressure for various salts are known in the art, such as described in Oxley, Jimmie, et al. “Determination of Urea Nitrate and Guanidine Nitrate Vapor Pressures by Isothermal Thermogravimetry.” For example, urea nitrate (UN), guanidine nitrate (GN), ammonium nitrate (AN), and triacetone triperoxide (TATP) can have vapor pressures and temperature relationships that approximately follow the following equation, where P is in Pascals and T is in Kelvin, at least in the range of 300-550 K.

[0079]

[0080] In some cases, the stabilizing solution can include a salt having a vapor pressure of at least 3 Pa at 100 °C, a vapor pressure of at least 130 Pa at 150 °C, and / or a vapor pressure of at least 250 Pa at 160 °C. In some cases, a salt having a vapor pressure of at or about 3 Pa, 8 Pa, 13 Pa, 18 Pa, 23 Pa, 28 Pa, 33 Pa, 38 Pa, 43 Pa, 48 Pa, 53 Pa, 58 Pa, 63 Pa, 68 Pa, 73 Pa, 78 Pa, 83 Pa, 88 Pa, 93 Pa, 98 Pa, 103 Pa, 108 Pa, 113 Pa, 118 Pa, 123 Pa, 128 Pa, 133 Pa, 138 Pa, 143 Pa, 148 Pa, 153 Pa, 158 Pa, 163 Pa, 168 Pa, 173 Pa, 178 Pa, 183 Pa, 188 Pa, 193 Pa, 198 Pa, 203 Pa, 208 Pa, 213 Pa, 218 Pa, 223 Pa, 228 Pa, 233 Pa, 238 Pa, 243 Pa, 248 Pa, 253 Pa, 258 Pa, 263 Pa, 268 Pa, 273 Pa, 278 Pa, 283 Pa, 288 Pa, 293 Pa, 298 Pa, 303 Pa, 308 Pa, 313 Pa, 318 Pa, 323 Pa, 328 Pa, 333 Pa, 338 Pa, 343 Pa, 348 Pa, and / or 350 Pa at 100 °C can be selected, although other ranges can also be used. The salt can be selected to provide a suitable sublimation at the operating temperature of the injector (e.g., with or without heating) sufficient to avoid deposition on the inner walls of the injector.

[0081] In some cases, the stabilization solution can have a neutral pH or a pH close to neutral (e.g., within 1-2 units of neutral pH). At particularly high or low pH, cells of the sample can rupture and / or metals chelated in certain elemental tags can dissociate. In some cases, the stabilization solution can be maintained at a pH between 5-9 (e.g., within 2 units of neutral pH) or 6-8 (e.g., within 1 unit of neutral pH). In some cases, the pH of the stabilization solution can be at or at least about 5, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, and / or 7, and at or below about 9, 8.9, 8.8, 8.7, 8.6, 8.5, 8.4, 8.3, 8.2, 8.1, 8, 7.9, 7.8, 7.7, 7.6, 7.5, 7.4, 7.3, 7.2, 7.1, and / or 7. In some cases, the pH of the stabilization solution can be within 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, and / or 2 units of neutral pH. The pH of the stabilization solution can be a function of the one or more solutes and their one or more concentrations. In some cases, the one or more solutes and their one or more concentrations can be selected to achieve a desired pH.

[0082] The concentration of salt in the stabilizing solution can be high enough to achieve suitable results (e.g., improved stability), but can be low enough to not produce undesirable background interference. Too low a salt concentration can provide little or no benefit to cell stability, and can instead introduce some instability. Too high a salt concentration can provide a benefit to cell stability, but cause a substantial loss in signal quality due to background interference, particularly if the TDS of the salt is greater than some value (e.g., 0.2%). In some cases, the stabilizing solution can include a salt (e.g., ammonium nitrate) at a concentration of at or about 5-25 mM, such as 6-24 mM, 7-23 mM, 8-22 mM, 9-21 mM, 10-20 mM, 11-19 mM, 12-18 mM, 13-17 mM, 14-16 mM, 5-15 mM, 10-15 mM, 10-25 mM, 15-25 mM, and / or 20-25 mM. In some cases, the stabilizing solution can include a salt at a concentration of at or at least about 5 mM, 6 mM, 7 mM, 8 mM, 9 mM, 10 mM, 11 mM, 12 mM, 13 mM, 14 mM, 15 mM, 16 mM, 17 mM, 18 mM, 19 mM, 20 mM, 21 mM, 22 mM, 23 mM, and / or 24 mM. In some cases, the stabilizing solution can include a salt at a concentration of at or less than about 25 mM, 24 mM, 23 mM, 22 mM, 21 mM, 20 mM, 19 mM, 18 mM, 17 mM, 16 mM, 15 mM, 14 mM, 13 mM, 12 mM, 11 mM, 10 mM, 9 mM, 8 mM, 7 mM, and / or 6 mM. In some cases, other ranges can be used. In some cases, a stabilizing solution having a salt concentration at the lower end of the above ranges (e.g., at or about 5-10 mM, 5-9 mM, 5-8 mM, 5-7 mM, 5-6 mM, or 5 mM) can be used in the absence of a heated injector. In some cases, a stabilizing solution having a salt concentration at the upper end of the above ranges (e.g., at or about 10-25, 10-25 mM, 11-25 mM, 12-25 mM, 13-25 mM, 14-25 mM, 15-25 mM, 16-25 mM, 17-25 mM, 18-25 mM, 19-25 mM, 20-25 mM, 21-25 mM, 22-25 mM, 23-25 mM, 24-25 mM, or 25 mM) can be most effective when used with a heated injector. In some cases, higher concentrations can be used, particularly when used with a heated injector.

[0083] In some cases, the stabilizing solution can include a salt that is not a metal. In some cases, the element of the salt can have an atomic mass unit of 80 or less. In other words, the salt can be free of metals or elements having an atomic mass unit greater than 80. In some cases, the salt can have an atomic mass unit that is less than the tag atom of the element tag. In some cases, the stabilizing solution can be free of carbon or substantially free of carbon (e.g., 1% or less, 0.95%, 0.9%, 0.85%, 0.8%, 0.75%, 0.7%, 0.65%, 0.6%, 0.55%, 0.5%, 0.45%, 0.4%, 0.35%, 0.3%, 0.25%, 0.2%, 0.15%, 0.1%, 0.05%, and / or 0.01% by weight of carbon). As used herein, the term“free of” in reference to a metal or element can exclude such metal or element or include substantially small amounts of such metal or element such that the metal or element would be imperceptible or negligible during elemental analysis of a sample containing an analyte tagged with an element tag as described herein.

[0084] While ammonium nitrate can be an effective salt, other salts can also be used. In some cases, the salt can be an ammonium-based molecule. Ammonium-based salts can be highly soluble in water, which can provide beneficial results. In some cases, the salt can be ammonium acetate, ammonium phosphate, ammonium formate, or other such salts. In some cases, the stabilizing solution can include nitrogen or nitrogen-based molecules. In some cases, the stabilizing solution can include azide-based salts.

[0085] In some cases, certain salts can have elements that reduce overall performance. Examples of performance reduction can include accumulation of carbon residue on the cones, accumulation of salt residue, ion suppression due to high concentrations of easily ionizable elements (e.g., Na and K), channel loss due to ions present in the solution (e.g., ammonium iodide that floods mass channel 127 or ammonium molybdate that contains molybdenum and can flood multiple mass channels between 90-100), and other undesirable effects. In some cases, the selection of the salt (e.g., the selection of the stabilizing solution) can be made to tailor specific characteristics of the assay. For example, if there is no interest in the mass channels between 90-100 for a particular element tag used in the assay, the use of ammonium molybdate can not be problematic.

[0086] Cell stability can be desirable in various cell counting techniques, however ICP-based elemental analysis is limited due to the use of plasma to probe the cells, which is fundamentally limited by total dissolved solids (TDS). Thus, traditional solutions used in other studies to stabilize cells are ineffective or unavailable for use with elemental analysis, at least ICP-based elemental analysis. For example, in a standard ICP-MS setup, TDS is kept at 0.2% or below in order to reduce the effects of interference. For a 1x phosphate buffered saline (PBS) solution, the TDS from just the NaCl content is already 0.8%, which is four times higher than the 0.2% limit. Thus, PBS cannot be used in an ICP-MS setup without unwanted interference. In some cases, the stabilization solution can have a TDS that is at or below 0.2%, 0.19%, 0.18%, 0.17%, 0.16%, 0.15%, 0.14%, 0.13%, 0.12%, 0.11%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, and / or 0.01%, although other ranges can be used.

[0087] As used herein, the injector of an ICP system can have any suitable inner diameter. In some cases, the injector can have an inner diameter of or between about 0.5 mm and 5 mm, such as an inner diameter of or between about 1-5 mm or 1.5-5 mm. In some cases, the injector can have an inner diameter of or at least about 0.5 mm, 0.6 mm, 0.7 mm, 0.8 mm, 0.9 mm, 1 mm, 1.1 mm, 1.2 mm, 1.3 mm, 1.4 mm, 1.5 mm, 1.6 mm, 1.7 mm, 1.8 mm, 1.9 mm, 2 mm, 2.1 mm, 2.2 mm, 2.3 mm, 2.4 mm, 2.5 mm, 2.6 mm, 2.7 mm, 2.8 mm, 2.9 mm, 3 mm, 3.1 mm, 3.2 mm, 3.3 mm, 3.4 mm, 3.5 mm, 3.6 mm, 3.7 mm, 3.8 mm, 3.9 mm, 4 mm, 4.1 mm, 4.2 mm, 4.3 mm, 4.4 mm, 4.5 mm, 4.6 mm, 4.7 mm, 4.8 mm, or 4.9 mm. In some cases, the injector can have an inner diameter of or less than about 5 mm, 4.9 mm, 4.8 mm, 4.7 mm, 4.6 mm, 4.5 mm, 4.4 mm, 4.3 mm, 4.2 mm, 4.1 mm, 4 mm, 3.9 mm, 3.8 mm, 3.7 mm, 3.6 mm, 3.5 mm, 3.4 mm, 3.3 mm, 3.2 mm, 3.1 mm, 3 mm, 2.9 mm, 2.8 mm, 2.7 mm, 2.6 mm, 2.5 mm, 2.4 mm, 2.3 mm, 2.2 mm, 2.1 mm, 2 mm, 1.9 mm, 1.8 mm, 1.7 mm, 1.6 mm, 1.5 mm, 1.4 mm, 1.3 mm, 1.2 mm, 1.1 mm, 1 mm, 0.9 mm, 0.8 mm, 0.7 mm, or 0.6 mm.

[0088] In some cases, the use of a heated injector can also prevent water droplets from forming or collecting on the injector. At room temperature, especially at higher liquid flow rates (e.g., 60 pL / min) and relatively lower gas (e.g., argon) flow rates (e.g., -0.7 sLpm), the collection (or atomization) of water droplets on the injector can become an issue. Atomization and droplet formation on the injector can cause signal instability and, in some cases, even occasional plasma loss in the inductively coupled plasma source. If plasma is lost, portions of the sample being detected can not be properly ionized and, thus, can not be detected. In some cases, a heated injector can reduce or minimize the formation or collection of water droplets on the injector, which can improve signal stability and plasma reliability.

[0089] These illustrative examples are given to introduce the reader to the general subject matter discussed here and are not intended to limit the scope of the disclosed concepts. The following sections describe various additional features and examples with reference to the drawings in which like numerals indicate like elements, and directional descriptions are used to describe the illustrative implementation but, like the illustrative implementation, should not be used to limit the present disclosure. Elements included in the illustrations herein can not be drawn to scale.

[0090] Figure 1 is a schematic diagram depicting an inductively coupled plasma (ICP) system 100 in accordance with certain aspects of the present disclosure. The ICP system 100 can include an injector 108 for delivering a sample (e.g., a sample solution or a cell-harvesting solution) to a plasma 110. The plasma 110 can be, for example, a spherical, solenoid-shaped cylinder, or other shape of plasma generated by stimulating a source gas using electromagnetic induction. It should be understood that certain aspects of the present disclosure, such as a stabilized solution and / or a heated injector, can be advantageously used in conjunction with other techniques for plasma generation. Certain aspects of a standard ICP system 100, such as gas flow tubes, induction coils, and sample cones, are not shown in Figure 1

[0091] The sample 102 can include intact cells (e.g., whole cells) labeled with an elemental tag. As disclosed herein, a stabilized solution 104 can be provided. The stabilized solution 104 can include a salt as described herein, such as ammonium nitrate at a concentration of 15 mM. The sample 102 and the stabilized solution 104 can be separate or pre-mixed. When mixed, the sample 102 and the stabilized solution 104 can be considered a “sample solution” or a “cell-harvesting solution.” The sample 102 and the stabilized solution 104 can be provided to a sample source 106, either separately or as a cell-harvesting solution. The sample source 106 can be any container suitable for storing the sample 102 (e.g., a cell-harvesting solution) prior to being introduced to the injector 108. In some cases, the sample source 106 can be a vial, an injector, a beaker, a length of tubing, or any other container.

[0092] ​The injector 108 can receive the cell collection solution from the sample source 106. In some cases, the cell collection solution can pass through the spray chamber 120 before entering the injector 108, such as to atomize the cell collection solution. The injector 108 can be a length of tubing made of any suitable material, such as quartz. The injector 108 can be any suitable shape or profile, such as cylindrical. The injector 108 can direct the cell collection solution into the plasma 110 to ionize the sample 102. In some cases, ionizing the sample 102 can produce ions (e.g., a set of ions or an ion beam) that can be directed toward the elemental analyzer 112 (e.g., a mass spectrometer) for further analysis. In some cases, ionizing the sample 102 can result in light emission that can be directed toward and / or sensed by the elemental analyzer 112 (e.g., a light emission spectrometer).

[0093] In some optional cases, the heat source 118 can be coupled to (e.g., physically), disposed around, and / or disposed near the injector 108. The heat source 118 can be thermally coupled to the injector 108. For example, the heat source 118 can be a resistive heater in the form of a metal coil wrapped around the injector 108. Other heat sources 118 can be used. The heat source 118 can extend the entire length of the injector 108, or less than the entire length of the injector 108. The heat source 118 can generate heat, such as using electrical, magnetic, kinetic, or other energy.

[0094] In some optional cases, the heat transfer device 114 can be coupled to (e.g., physically), disposed around, and / or disposed near the injector 108. The heat transfer device 114 can be thermally coupled to the injector 108. The heat transfer device 114 can be any suitable device or material capable of transferring heat into and / or along the injector 108. For example, the heat transfer device 114 can transfer heat from one portion of the injector 108 to another portion of the injector 108. In another example, the heat transfer device 114 can transfer heat from another object, such as the heat source 116, into the injector 108. The heat transfer device 114 can extend the entire length of the injector 108, or less than the entire length of the injector 108. In some cases, the injector 108 can include both the heat source 118 and the heat transfer device 114. In some cases, the heat transfer device 114 can be incorporated into the injector 108, such as in the form of a heat pipe integrated into or coupled to the body of the injector 108 (e.g., integrated into a channel in a quartz tube or adhered to a surface of a quartz tube using a thermal paste).

[0095] The heat source 116 can be any suitable heat source that can be thermally coupled to the heat transfer device 114. Examples of suitable heat sources 116 can include resistive heating devices, thermoelectric devices, pneumatic heating devices (e.g., direct flame), convective heating devices (e.g., circulating hot fluids such as air), laser heating devices, or others.

[0096] In some alternatives, one or more heat transfer devices 114 can thermally couple the injector 108 to other elements of the ICP system 100 or to nearby systems (such as the spray chamber 120 or the plasma 120), although other sources can also be used. In some cases, these elements thermally coupled to the injector 108 can be considered heat sources. When thermally coupled to the spray chamber 120, the heat transfer device 114 can transfer heat energy from the spray chamber 120, which can be maintained at a constant temperature (e.g., 200°C), to the injector 108 at a suitable rate to ensure that the injector 108 is maintained at a temperature of at least a minimum set temperature (e.g., 160°C). When thermally coupled to the plasma 110, the heat transfer device 114 can receive heat indirectly from the plasma 110 (e.g., by convection due to heating of nearby gas or by radiated heat) and transfer heat to the injector 108 at a rate suitable to ensure that the injector 108 is maintained at a temperature of at least a minimum set temperature (e.g., 160°C). In some cases, achieving a suitable heat transfer rate in the heat transfer device 114 can include providing a heat transfer device 114 of a suitable size and / or shape to achieve the desired heat transfer rate. In some cases, the heat transfer device 114 can include a thermal conduction trap to appropriately slow the transfer of heat to the desired rate. The thermal conduction trap can include gaps in the material of the heat transfer device 114, which can be filled with a material that is more thermally insulating than the heat transfer device 114 itself, such as a flowing carrier gas or a ceramic material.

[0097] In some cases, the injector 108 of the ICP system 100 is not heated by any heat source 118 or heat transfer device 114. In such cases, the stabilizing solution 104 can include a salt at a suitably low concentration or a salt with a sufficiently high vapor pressure at the temperature of the injector to avoid accumulation of residue within the injector 108.

[0098] In some cases, the injector 108 of the ICP system 100 can be heated, such as by a heat source 118 or heat transfer device 114, and can be provided with a sample 102 without being provided with a stabilizing solution 104. In such cases, heating the injector 108 can provide certain benefits, such as reducing the potential accumulation of water / solvent droplets or accumulation of residue on the injector 108, without the attendant benefits of a stabilizing solution 104.

[0099] In some cases, a thermal insulation layer 115 can be provided around some or all of the injector 108. The thermal insulation layer 115 can be coupled to or positioned directly around the injector 108, or can be coupled to or positioned around the heat transfer device 114 and / or the heat source 118. The thermal insulation layer 115 can help to retain heat within the injector 108 by inhibiting radial heat dissipation. The thermal insulation layer 115 can help to maintain a constant injector temperature throughout the injector 108. In some cases, the thermal insulation layer 115 can extend completely around the injector 108, but this is not always the case. The thermal insulation layer 115 can be formed of any suitable thermal insulation material, such as fiberglass, para-aramid fiber, or aerogel. In some cases, the thermal insulation layer 115 can be an air gap or a vacuum gap. In some cases, the thermal insulation layer can be solid. In some cases, the thermal insulation layer 115 can be any suitable thermal insulation material that inhibits radial heat dissipation from the injector 108 beyond that achieved by moving a surrounding supply gas (e.g., argon) toward the plasma generator. In some cases, such as where the amount of gas (e.g., the radial thickness of the volume of gas surrounding the injector) is specifically tailored to achieve a particular desired amount of thermal insulation (such as more than in a conventional injector arrangement), the surrounding supply gas (e.g., argon) can serve as the thermal insulation layer 115.

[0100] Figure 2 is a flowchart depicting a process 200 for ionizing a sample in accordance with certain aspects of the present disclosure. The process 200 can be performed by any suitable ICP system as described herein, such as the ICP system 100 of Figure 1 FIG. 1. At block 202, an injector can be heated. The injector can be heated in accordance with any suitable technique, such as those described herein. In some cases, heating the injector at block 202 can include, at block 214, supplying heat to the injector from a directly coupled heat source (e.g., from a resistive heater wrapped around the injector). In some cases, heating the injector at block 202 can include, at block 216, passing a heated fluid through the injector (e.g., passing a heated cell-harvesting solution or another heated fluid through the injector).

[0101] In some cases, heating the injector at block 202 can include, at block 218, conducting heat to the injector. In some cases, conducting heat to the injector at block 218 can include, at block 220, conducting heat along a length of the injector. In some cases, conducting heat to the injector at block 218 can include, at block 222, conducting heat from a spray chamber of the ICP system. In some cases, conducting heat to the injector at block 218 can include, at block 224, conducting heat from a plasma generated by the ICP system.

[0102] At box 204, a sample is received. The sample may optionally include a stabilizing solution. In some cases, receiving the sample at 204 may optionally include mixing the stabilizing solution with the sample. At box 206, the sample is passed through a heated injector. At box 206, passing the sample through the heated injector may optionally include passing the sample through the heated injector as part of a cell collection solution containing the sample and the stabilizing solution. At box 206, passing the sample through the heated injector may include directing the sample to the plasma of the ICP system. In some cases, passing the sample through the heated injector at box 206 may include passing intact cells or whole cells through the injector. In some cases, the intact cells or whole cells may be passed sequentially.

[0103] At frame 208, an inductively coupled plasma can be used to ionize the sample. The ionized sample at frame 208 can result in ions being released from the sample, such as an ion beam. In some cases, the ionized sample at frame 208 can include ionizing intact cells or whole cells. In some cases, intact cells or whole cells can be ionized in sequence. At frame 210, elemental analysis can be performed on the ionized sample. The elemental analysis performed at frame 210 can include any suitable elemental analysis, such as using a mass spectrometer to measure ions (e.g., mass spectrometry) or to detect light emission (e.g., light emission spectrum) during sample ionization. At optional frame 212, the detected element can be identified based on the measurement of the elemental analysis. The detected element can be a tag atom from an element tag associated with an element-labeled sample (e.g., a sample labeled with an element tag). In some cases, the detected element identified at frame 212 may be associated with an intact cell or whole cell. The element detected for intact cells or whole cells identified at frame 212 can be repeated for multiple cells in the sample.

[0104] Figure 3 is a schematic cross-sectional view depicting an ICP system 300 having a heat transfer device 314 thermally coupled to an injector 308 in accordance with certain aspects of the present disclosure. The ICP system 300 may include an outer tube 330 for conveying a primary gas 338, such as argon. In some cases, an intermediate tube 332 may be used and may convey an auxiliary gas 336, such as argon. In some cases, the primary gas 338 and the auxiliary gas 336 are the same, optionally with different flow rates. A coil 334 positioned toward the downstream end of the outer tube 330 may function with a high frequency current suitable for exciting the gas within the bore of the coil 334 to create and / or maintain a plasma 310. A sample 328 (e.g., alone or as part of a cell collection solution with a stabilization solution) may enter the injector 308 and be transferred in a downstream direction (e.g., as Figure 3The sample 328 can be transported into the plasma 310. Resulting ions, light, or other detectable emissions or light absorption characteristics can be transported from the plasma 310 into the elemental analyzer. In some cases, the injector 308, outer tube 330, and optional intermediate tube 332 are concentric, but this is not always the case.

[0105] As Figure 3 As depicted, the injector 308 can include a heat transfer device 314 that is physically and thermally coupled thereto. The heat transfer device 314 is shown as extending to the downstream end of the injector 308, but this is not always the case. The heat transfer device 314 can be used with another heat source to heat the injector 308. However, in some cases, the heat transfer device 314 can simply transport heat through the injector 308.

[0106] In some cases, the auxiliary gas 336 and / or the primary gas 338 can be preheated to transport heat to the injector 308.

[0107] Figure 4 is a schematic cross-sectional view depicting an ICP system 400 having an injector 408 that is thermally coupled to a spray chamber 420, in accordance with certain aspects of the present disclosure. The ICP system 400 can include an outer tube 430 for transporting a primary gas 438, such as argon. In some cases, an intermediate tube 432 can be used, and it can transport an auxiliary gas 436, such as argon. In some cases, the primary gas 438 and the auxiliary gas 436 are the same, optionally with different flow rates. A coil 434 positioned toward the downstream end of the outer tube 430 can be functional with high frequency current that is suitable to excite the gas within the bore of the coil 434 to create and / or sustain a plasma 410. A sample 428 (e.g., alone or with a stabilizing solution as part of a cell harvesting solution) can enter the injector 408, and pass in a downstream direction (e.g., as indicated by the arrow from left to right as depicted) through the plasma 410. Resulting ions, light, or other detectable emissions or light absorption characteristics can be transported from the plasma 410 into the elemental analyzer. In some cases, the injector 408, outer tube 430, and optional intermediate tube 432 are concentric, but this is not always the case. Figure 4 The sample 428 can be transported into the plasma 410. Resulting ions, light, or other detectable emissions or light absorption characteristics can be transported from the plasma 410 into the elemental analyzer. In some cases, the injector 408, outer tube 430, and optional intermediate tube 432 are concentric, but this is not always the case.

[0108] As Figure 4 As depicted, the injector 408 can include a heat transfer device 414 that is physically and thermally coupled thereto. The heat transfer device 414 is shown as extending from the spray chamber 420 to the downstream end of the injector 408, but in some cases the heat transfer device 414 can not extend the entire length. The heat transfer device 414 can thermally couple the spray chamber 420 to the injector 408, thereby transporting heat from the spray chamber 420 into the injector 408.

[0109] Figure 5 is a schematic cross-sectional view depicting an ICP system 500 having a heat source 518 thermally coupled to an injector 508 in accordance with certain aspects of the present disclosure. The ICP system 500 can include an outer tube 530 for delivering a primary gas 538, such as argon. In some cases, an intermediate tube 532 can be used, and it can deliver a secondary gas 536, such as argon. In some cases, the primary gas 538 and the secondary gas 536 are the same, optionally with different flow rates. A coil 534 positioned toward a downstream end of the outer tube 530 can be functional with a high frequency current suitable for exciting the gas within the bore of the coil 534 to generate and / or sustain a plasma 510. A sample 528 (e.g., alone or with a stabilization solution as part of a cell harvesting solution) can enter the injector 508 and pass in a downstream direction (e.g., as Figure 5 depicted from left to right). The sample 528 can be delivered into the plasma 510. Resulting ions, light, or other detectable emissions or light absorption characteristics can be delivered from the plasma 510 into an elemental analyzer. In some cases, the injector 508, the outer tube 530, and the optional intermediate tube 532 are concentric, although this is not necessarily always the case.

[0110] As Figure 5 depicted, the injector 508 can include a heat transfer device 514 in physical and thermal communication therewith. The heat transfer device 514 is shown extending along the length of the injector 508 up to the downstream end of the injector 508, although this is not necessarily always the case. A resistive heater 542 is depicted as surrounding a portion of the injector 508, however in some cases the resistive heater 542 can extend along the entire length of the injector 508. The resistive heater 542 can be powered by a power source 540 to generate heat. The generated heat can be transferred through the heat transfer device 514 to the injector 508. The heat transfer device 514 can facilitate the transfer of heat along the length of the injector 508, such as from the portion of the injector 508 that the resistive heater 542 is positioned around to the downstream end of the injector 508.

[0111] Figure 6 is a schematic front cross-sectional view depicting an injector 608 having a heat transfer device 614 thermally coupled thereto in accordance with certain aspects of the present disclosure. The injector 608 can be similar to the injector 308 of Figure 3 . The heat transfer device 614 can be physically coupled to the injector 608, or can simply be disposed around or near the injector 608. The heat transfer device 614 can receive heat 644, such as from an external heat source, and transfer the heat 644 into the injector 608.

[0112] Figure 7is a schematic front cross-sectional view depicting an injector 708 having a heat source 718 thermally coupled thereto, in accordance with certain aspects of the present disclosure. The injector 708 can be similar to the injector 508 of Figure 5 , however, without the heat transfer device 514. A resistive heater 742 in the form of a coil can be disposed about the injector 708, and optionally physically coupled to the injector 708. When electricity is applied to the resistive heater 742 from a power source 740, the resistive heater 742 can generate heat to heat the injector 708.

[0113] Figure 8 is a schematic front cross-sectional view depicting an injector 808 having an external heating tube 846 thermally coupled thereto, in accordance with certain aspects of the present disclosure. The heating tube 846 can be a heat transfer device type capable of delivering heat 844 into the injector 808. In some cases, the heating tube 846 can be thermally coupled to the injector 808 using a thermal paste 848. In some cases, the heating tube 846 can be located on an inner surface of the injector 808. The heating tube 846 can extend along a portion or the entire length of the injector 808.

[0114] Figure 9 is a schematic front cross-sectional view depicting an injector 908 having an internal heating tube 946 thermally coupled thereto, in accordance with certain aspects of the present disclosure. The heating tube 946 can be a heat transfer device type capable of delivering heat 944 into the injector 908. In some cases, the heating tube 946 can be thermally coupled to the injector 908 using a thermal paste 948. The heating tube 946 can be located within a channel 950 of the injector 908. In some cases, the heating tube 946 can be completely enclosed by the injector 908, including cross-sectional and / or longitudinal enclosures. In some cases, the heating tube 946 can be located in the channel 950 positioned on an inner surface of the injector 908. The heating tube 946 can extend along a portion or the entire length of the injector 908.

[0115] Figure 10 is a flowchart depicting a process 1000 for preparing and ionizing a sample, in accordance with certain aspects of the present disclosure. The process 100 can utilize any suitable ICP system, such as the ICP system 100 of Figure 1 . At block 1002, an element-labeled analyte is provided. The element-labeled analyte can include an analyte on or within a whole cell or intact cell that has been labeled or traced with an elemental tag. At block 1004, a stabilization solution can be provided. The stabilization solution can be any suitable stabilization solution as described herein, such as a solution containing 15 mM ammonium nitrate. At block 1006, the element-labeled analyte can be mixed with the stabilization solution to produce a sample collection solution (e.g., a cell collection solution).

[0116] The sample collection solution can include intact cells or whole cells in suspension with a stabilizing solution containing a salt, such as ammonium nitrate, as described herein. The intact cells or whole cells of the sample collection solution can be labeled with elemental tags, such as by including element-labeled analytes.

[0117] At block 1008, the sample collection solution is transferred into the plasma of the ICP system using the injector at block 1008. The sample collection solution can be pressurized through the injector using a fluid, such as the sample collection solution and / or a carrier gas. In some cases, transferring the sample collection solution into the plasma using the injector can include passing the sample collection solution through a heated injector and / or heating the injector.

[0118] At block 1010, the ionized sample solution can be analyzed, such as by elemental analysis (e.g., mass spectrometry or optical emission spectroscopy). In some cases, at optional block 1012, solutes retained on the injector, such as solutes from the stabilizing solution, can be evaporated or sublimated. Evaporation or sublimation of the solutes can be achieved by heating the injector. In some cases, evaporation or sublimation of the solutes at block 1012 can occur after or concurrently with transferring the sample collection solution into the plasma using the injector at block 1008.

[0119] Figures 11-13 Graphs 1100, 1200, 1300 showing the percent signal drop for a particular sample when prepared with different molar concentrations of ammonium nitrate stabilizing solution are depicted. The sample contains various element-labeled affinity reagents and element-labeled beads. The element-labeled affinity reagents in this sample include 145Nd-CD4 (specific for CD4 antigen and containing element tag 145 Nd affinity reagent), 145Nd-CD4 (specific for CD4 antigen and containing element tag 145 Nd affinity reagent), 146Nd-CD8 (specific for CD8 antigen and containing element tag 148 Nd affinity reagent), 147Sm-CD20 (specific for CD20 antigen and containing element tag 147 Sm affinity reagent), 154Sm-CD45 (specific for CD45 antigen and containing element tag 154 Sm affinity reagent), 155Gd-CD27 (specific for CD27 antigen and containing element tag 155 Gd affinity reagent), 159Tb-CD11c (specific for CD11c antigen and containing element tag 159 Tb affinity reagent), 160Gd-CD14 (specific for CD14 antigen and containing element tag 160Gd affinity reagent), 170Er-CD3 (specific for CD3 antigen and containing an elemental tag 170 Ir affinity reagent for a first identifiable DNA string and containing an elemental tag 191 Ir affinity reagent for a second identifiable DNA string and containing an elemental tag 193 Ir affinity reagent). The element-labeled beads in this sample include beads containing known amounts of 140 Ce, 142 Ce, 151 Eu, 153 Eu, 165 Ho, 175 Lu, 176 Lu. Each of the foregoing elements or isotopes can be measured by an elemental analyzer. In some cases, each of the foregoing elements or isotopes can be measured using a different channel of the elemental analyzer that is specific to the element or isotope.

[0120] In each of the graphs 1100, 1200, and 1300, the percent signal drop in the raw data measurements during a sample run (e.g., a 30 minute sample run) is shown, along with the percent signal drop after the data has been normalized. Data normalization can include adjusting the measured signal intensity of individual channels of the elemental analyzer based on the signal drift detected in a known standard. In some cases, one or more element-labeled beads, such as those identified above, can be used as the known standard. For example, if element-labeled beads containing 165 Ho are used as the known standard, the element-labeled beads can contain a known amount of 165 Ho, and can be present at a known concentration, which should produce a constant signal intensity throughout the sample run. In the event that any drift from the expected signal intensity is detected, a correction can be applied to bring the 165 Ho signal back to the expected signal intensity, and similar corrections can be made to the other channels of the elemental analyzer. In some cases, even within a common time interval, the element-labeled beads can be normalized to other element-labeled beads, such as to account for drift from moment to moment in the detectors of the elemental analyzer within the time interval.

[0121] Figure 11is a graph 1100 depicting the percent signal drop for a set of samples prepared with a 2 mM ammonium nitrate stabilization solution according to certain aspects of the present disclosure. The graph 1100 shows the percent signal drop for a number of element-labeled affinity reagents when the samples are prepared with a 2 mM ammonium nitrate stabilization solution. As depicted by the graph 1100, the percent signal drop for almost all channels remains below about 15%, and many channels remain below about 10% or 5%.

[0122] Figure 12 is a graph 1200 depicting the percent signal drop for a set of samples prepared with a 5 mM ammonium nitrate stabilization solution according to certain aspects of the present disclosure. The graph 1200 shows the percent signal drop for a number of element-labeled affinity reagents when the samples are prepared with a 5 mM ammonium nitrate stabilization solution. As is evident when compared to the graph 1100 for the 2 mM ammonium nitrate stabilization solution, increasing to a 5 mM ammonium nitrate stabilization solution results in a decrease in signal drift. As depicted by the graph 1200, the percent signal drop for all channels remains below about 6%, and most channels remain below about 2% or 3%.

[0123] Figure 13 is a graph 1300 depicting the percent signal drop for a set of samples prepared with a 10 mM ammonium nitrate stabilization solution according to certain aspects of the present disclosure. The graph 1300 shows the percent signal drop for a number of element-labeled affinity reagents when the samples are prepared with a 10 mM ammonium nitrate stabilization solution. As is evident when compared to the graph 1200 for the 5 mM ammonium nitrate stabilization solution, increasing to a 10 mM ammonium nitrate stabilization solution does not greatly affect stability. As depicted by the graph 1300, the percent signal drop for all channels remains below about 4% or 5%, and most channels remain below about 1% or 2%.

[0124] Figure 14 and 15 Graphs 1400, 1500 depict the signal intensity within a particular channel of an elemental analyzer showing over the course of a 30 minute sample run. In this case, the particular channel is used to identify the CD44 antigen. The element-labeled affinity reagent specific for CD44 is labeled with Yb. 171 Yb. With respect to Figure 14 and 15 The sample used during the 30 minute sample run contains cells labeled with an affinity reagent labeled with this element due to its specificity for CD44. The CD44 channel of the elemental analyzer is tuned to have a signal intensity for the Yb element that is at or approximately equivalent to 171Yb or ions of atomic mass of or about 171 amu. For each of the plots 1400 and 1500, the x-axis represents time during the element analysis process, and the y-axis represents the expression intensity (e.g., the number of detected tag atoms) for the selected CD44 channel for detected events (each event is represented by a dot on the plot). These particular channels, antigens, and / or elements are selected to provide examples, however any other suitable channels, antigens, and / or elements can be used.

[0125] Figure 14 is a plot 1400 depicting CD44 channel signals for a sample that has been suspended in deionized water and injected into a plasma source. The brighter region in the middle of the band represents the population of the most frequent cellular events. In plot 1400, a relatively wide variation and downward trend on the y-axis is apparent, indicating some degree of instability in the cells during storage and / or injection. The downward trend can also indicate that an accumulation occurred within the injection tube, which can have negatively impacted the signal intensity over time. Furthermore, if the cells in this non-stable sample were damaged during storage and / or injection, the element-labeled affinity reagents can have detached from the remainder of the cells to which they were attached, which can have created an unwanted fluctuation in the signal intensity, as tag atoms that were expected to have landed on the detector very close in time to other tag atoms of that particular cell can have instead landed on the detector early or late. Thus, a portion of the signal is not accounted for in the response of individual events. As a result, the measurements depicted in plot 1400 can occupy a relatively wide band on the y-axis.

[0126] Figure 15 is a plot 1500 depicting CD44 channel signals for a sample that has been suspended in a 25 mM ammonium nitrate stabilization solution and injected into a plasma source, in accordance with certain aspects of the present disclosure. The brighter region in the middle of the band represents the population of the most frequent cellular events. The effect of the stabilization solution is evidenced by the significantly different clustering of the measured signal intensities in plots 1400 (e.g., without the stabilization solution) and 1500 (e.g., with the stabilization solution). The band of measured signals depicted in plot 1500 is much narrower than the band depicted in plot 1400, indicating a significant increase in stability, which can indicate that fewer or no cells were damaged during storage and / or injection. The band in plot 1500 provides a more dense combination of measured values and a more clear and accurate average. Furthermore, the band in plot 1500 shows a relatively constant level trend, as opposed to the downward trend of the band in plot 1400.

[0127] Figure 16 and 17Depicted are diagrams 1600, 1700 showing the signal intensity within a particular channel of an elemental analyzer during a 30 minute sample run. In this case, the particular channel is used to identify an element standard in the form of element-labeled beads. The element-labeled beads used in diagrams 1600 and 1700 are 165 Ho. The channel pairs used to obtain the signal strengths depicted in diagrams 1600 and 1700 have a value of or approximately equal to 165 Ho or ions with an atomic mass of or about 165 amu respond. Figure 16 and 17 The samples used during the 30-minute sample run contained the sampled cells and element-labeled beads. 165 Ho element-labeled beads serve as element standards because they are not present in cells or in any element-labeled affinity reagents used with cells. 165 Ho. For each of the graphs 1600 and 1700, the x-axis represents the time during the element analysis, and the y-axis represents the time for the selected element. 165 The expression intensity of the Ho channel (e.g., the number of label atoms detected). These specific channels and / or elements are selected to provide examples, however any other suitable channels and / or elements can be used. In some cases, element-labeled beads (which can contain any suitable element or isotope (such as those described above)) are selected as element standards. 165 Ho) can be used to normalize signal intensity in the analyzer's detector. Element-labeled beads containing a known amount of an element or isotope can be expected to present a known amount of labeled atoms to the detector over a period of time, and therefore, if the signal of the element-labeled beads drops below the expected signal intensity, any drift in signal intensity due to natural drift in the detector can be identified, and the identified drift can be used to correct or normalize signal intensities in other channels.

[0128] Figure 16 is a graph depicting a sample that has been suspended in a 25 mM ammonium nitrate stabilized solution and injected into a plasma source according to certain aspects of the present disclosure. 165 Graph 1600 of the Ho channel signal. The dense set of measurements forming a thin band near the top of graph 1600 represents those events associated with the elementally labeled beads, and the large band of measurements near the bottom of graph 1600 represents background noise from events in cells in the 25 mM ammonium nitrate stabilization solution. Since there are no cells in the sample 165The source of Ho, the only measured source in the selected channel should be the element-labeled beads. Therefore, as expected, the background noise in graph 1600 is relatively minimal, and no areas of high intensity are shown except for the expected intensity of the element-labeled beads and 0 (e.g., the expected atomic intensity of cells in the sample). At 25 mM ammonium nitrate, the background signal does not overwhelm the signal of interest, and the signal of interest is clearly discernible.

[0129] Figure 17 is a graph depicting a sample that has been suspended in a 75 mM ammonium nitrate stabilized solution and injected into a plasma source according to certain aspects of the present disclosure. 165 Graph 1700 of the Ho channel signal. The thin band near the top of graph 1700 represents those measurements associated with the element-labeled beads, and the large band of measurements near the bottom of graph 1700 represents background noise in a 75 mM ammonium nitrate stabilized solution. At 75 mM ammonium nitrate, the background signal begins to swamp the signal of interest and may begin to interfere with the ability to clearly distinguish the signal of interest. Specifically, a population of readings that would be expected to have an intensity at or around 0 instead show an intensity above 0, indicating that the detector is detecting signals from sources other than the element-labeled beads. 165 Ho. Due to the absence of 165 Ho, it is obvious that the background signal interferes with the detection in the elemental analyzer.

[0130] Graph 1700 shows that when higher concentrations of ammonium nitrate (or other salts) are used, they may begin to cause undesirable background interference when compared to graph 1600. Therefore, it may be desirable to provide a stabilization solution that is high enough to improve cell stability, but low enough to avoid overwhelming background interference.

[0131] Figure 18 is an image depicting an injector 1800 showing a significant buildup due to insufficient heating as a result of certain aspects of the present disclosure. The injector 1800 is not heated or is not heated sufficiently, and therefore residue has accumulated within the injector. The residue may be a result of salts from the stabilizing solution. When using a stabilizing solution, it may be desirable to heat the injector to avoid residue buildup, such as Figure 18 Depicted.

[0132] Figure 19 19 is a flow chart depicting a process 1900 for self-cleaning an injector according to certain aspects of the present disclosure. Self-cleaning of an injector can be used to remove buildup on an injector of an inductively coupled plasma system, such as residues of salts from a stabilization solution or accumulations of water droplets. In some cases, self-cleaning can occur before, after, or during transfer of a sample (e.g., a cell) through the injector for ionization by the plasma of the inductively coupled plasma system.

[0133] At optional block 1902, a sample collection solution (e.g., a solution containing cells, and optionally a stabilization solution) can be transferred into the plasma by the injector. During the transfer of the sample collection solution at block 1902 by the injector, residue can accumulate on the injector.

[0134] At block 1904, a self-cleaning routine can be performed. In some cases, the self-cleaning routine can be performed automatically after the transfer of the sample collection solution at block 1902 is complete, such as after a quantity of sample collection solution is transferred, after all of the sample collection solution is transferred, or after a period of time of sample collection solution is transferred. In some cases, the self-cleaning routine can be performed automatically before the transfer of the sample collection solution at block 1906 is initiated. At optional block 1904, a sample collection solution (e.g., a solution containing cells, and optionally a stabilization solution) can be transferred into the plasma by the injector. In some cases, the sample collection solution transferred at block 1904 includes a remaining portion of the sample collection solution that has not yet been transferred at block 1902.

[0135] In some cases, the self-cleaning routine performed at block 1904 can be triggered. In such cases, at optional block 1914, a need for self-cleaning can be determined, and in response to determining that there is a need for self-cleaning, the self-cleaning routine at block 1904 can be performed automatically. The need for self-cleaning can be based on a detected injector condition (e.g., based on a vision sensor related to the injector) or based on an inferred injector condition. The inferred injector condition can be based on an expected outcome (e.g., after a preset amount of fluid has passed through the injector or after a preset amount of run time) or can be based on a post-injector measurement (e.g., a change in a characteristic of an expected output of an elemental analyzer related to the inductively coupled plasma source). For example, a calibrated sample can be passed through the injector, ionized, and then analyzed by an elemental analyzer. The measurements of the elemental analyzer can be used to produce an inference that the injector needs self-cleaning. In other cases, when a sample collection solution is passed through the injector, ionized, and analyzed by an elemental analyzer, the measurements of the elemental analyzer can change over time in an identifiable pattern that can be used to infer that the injector needs self-cleaning. In some cases, the need for self-cleaning can exist when an accumulated measured or inferred amount present in the injector is equal to or above a threshold amount of accumulation, such as based on a percentage amount of cross-sectional area that is free of accumulation as described herein.

[0136] The self-cleaning routine at block 1904 can include heating the injector at block 1908. At block 1910, solutes or other residue on the injector can be evaporated or sublimated due at least in part to the increased temperature of the injector. At block 1912, fluid can be passed through the injector. The fluid passed through the injector at block 1912 can be a sample collection solution (e.g., the sample collection solution of block 1902 or 1906) or another fluid, such as deionized water or argon gas. In some cases, block 1912 can occur simultaneously with and / or after block 1910. In some cases, heating the injector 1908 can occur before and / or simultaneously with any of blocks 1910 and 1912.

[0137] In some cases, transferring the sample collection solution at block 1902 and / or block 1904 can occur without heating the injector.

[0138] The foregoing description of implementations of embodiments, including the specific embodiments, is provided for the purpose of illustration and description. It is not intended to be exhaustive or to be limited to the precise form disclosed. Many modifications, adaptations, and uses of the embodiments will be apparent to those skilled in the art.

[0139] As used in the following, any reference to a series of embodiments should be understood as a reference to each of those embodiments individually (e.g., “embodiments 1-4” should be understood as “embodiments 1, 2, 3, or 4”).

[0140] Embodiment 1 is a sample comprising: an element-labeled analyte containing an analyte bound to an element-labeled affinity reagent, wherein the element-labeled affinity reagent comprises an affinity reagent for binding to the analyte and a metal-binding moiety bound to one or more metal elements; and a stabilized solution having a total dissolved solids of at or below about 0.2%, wherein the stabilized solution contains a salt. In some cases, the salt of the sample according to embodiment 1 is present at a concentration of at least 5 mM.

[0141] Embodiment 2 is the sample according to embodiment 1, wherein the salt is a non-metal salt.

[0142] Embodiment 3 is the sample according to embodiment 1 or 2, wherein the salt does not contain carbon.

[0143] Embodiment 4 is the sample according to embodiments 1-3, wherein the salt does not contain a metal with an atomic mass unit greater than 80.

[0144] Embodiment 5 is the sample according to embodiments 1-4, wherein the salt includes nitrogen.

[0145] Embodiment 6 is the sample according to embodiments 1-5, wherein the salt is ammonium nitrate.

[0146] Example 7 is the sample according to Examples 1-6, wherein the salt has a vapor pressure of at least 3 Pa at 100 °C.

[0147] Example 8 is the sample according to Examples 1-7, wherein the salt has a vapor pressure of at least 130 Pa at 150 °C.

[0148] Example 9 is the sample according to Examples 1-8, wherein the salt has a vapor pressure of at least 250 Pa at 160 °C.

[0149] Example 10 is the sample according to Examples 1-5 or 7-9, wherein the salt is ammonium acetate.

[0150] Example 11 is the sample according to Examples 1-10, wherein the analyte comprises whole cells.

[0151] Example 12 is the sample according to Example 11, wherein the stabilizing solution induces a low enough osmotic pressure on the membrane of the analyte to avoid osmotic lysis of the analyte.

[0152] Example 13 is the sample according to Examples 1-12, wherein the salt is present in the stabilizing solution at a concentration of or less than 25 mM.

[0153] Example 14 is the sample according to Examples 1-13, wherein the stabilizing solution has a pH between 5-9.

[0154] Example 15 is the sample according to Examples 1-13, wherein the stabilizing solution has a pH between 6-8.

[0155] Example 16 is the sample according to Examples 1-15, wherein the metal-binding moiety comprises a polymer linked to an affinity reagent and comprising at least one metal-binding pendant group, the metal-binding pendant group comprising at least one metal atom.

[0156] Example 17 is the sample according to Examples 1-16, wherein the elementally labeled analyte comprises a first analyte labeled with a first elemental tag and a second analyte labeled with a second elemental tag, the second elemental tag distinguishable from the first elemental tag by elemental analysis.

[0157] Example 18 is the sample according to Examples 1-17, wherein the affinity reagent comprises an antibody.

[0158] Example 19 is a sample preparation kit comprising an element-labeled affinity reagent comprising an affinity reagent for binding to an analyte and a metal-binding moiety that binds to one or more metal elements; and a stabilizing solution having a total dissolved solids of at or below about 0.2%, wherein the stabilizing solution contains a salt. In some cases, the salt of the sample preparation kit according to Example 19 is present at a concentration of at least 5 mM.

[0159] Example 20 is the sample preparation kit according to Example 19, wherein the salt is a non-metal salt.

[0160] Example 21 is the sample preparation kit according to Examples 19-20, wherein the salt does not contain carbon.

[0161] Example 22 is the sample preparation kit according to Examples 19-21, wherein the salt does not contain a metal with an atomic mass unit greater than 80.

[0162] Example 23 is the sample preparation kit according to Examples 19-22, wherein the salt includes nitrogen.

[0163] Example 24 is the sample preparation kit according to Examples 19-23, wherein the salt is ammonium nitrate.

[0164] Example 25 is the sample preparation kit according to Examples 19-24, wherein the salt has a vapor pressure of at least 3 Pa at 100 °C.

[0165] Example 26 is the sample preparation kit according to Examples 19-25, wherein the salt has a vapor pressure of at least 130 Pa at 150 °C.

[0166] Example 27 is the sample preparation kit according to Examples 19-26, wherein the salt has a vapor pressure of at least 250 Pa at 160 °C.

[0167] Example 28 is the sample preparation kit according to Examples 19-23 or 25-27, wherein the salt is ammonium acetate.

[0168] Example 29 is the sample preparation kit according to Examples 19-28, wherein the affinity reagent can bind to the surface of a whole cell.

[0169] Example 30 is the sample preparation kit according to Example 29, wherein the stabilizing solution induces a low enough osmotic pressure on the membrane of a whole cell to which the affinity reagent is bound to avoid osmotic lysis of the whole cell.

[0170] Example 31 is the sample preparation kit according to Examples 19-29, wherein the salt is present in the stabilizing solution at a concentration of at or below 25 mM.

[0171] Example 32 is the method according to Examples 19-31, wherein the stabilizing solution has a pH between 5-9.

[0172] Example 33 is the method according to Examples 19-31, wherein the stabilizing solution has a pH between 6-8.

[0173] Example 34 is the sample preparation kit according to Examples 19-33, wherein the metal-binding moiety comprises a polymer linked to the affinity reagent and comprising at least one metal-binding pendant group, the metal-binding pendant group comprising at least one metal atom.

[0174] Example 35 is the sample preparation kit according to Examples 19-34, wherein the element-labeled affinity reagent comprises a first affinity reagent labeled with a first element tag and a second affinity reagent labeled with a second element tag, the second element tag being distinguishable from the first element tag by elemental analysis.

[0175] Example 36 is a method comprising: receiving a sample comprising an element-labeled analyte and a stabilizing solution; transporting the sample in a downstream direction toward a plasma of an inductively coupled plasma source to ionize the sample, wherein transporting the sample comprises passing the sample through an inner wall of an injector; ionizing the sample at the plasma; and performing elemental analysis on the ionized sample to detect an element of the element-labeled analyte.

[0176] Example 37 is the method according to Example 36, wherein the analyte comprises a whole cell, and wherein transporting the sample toward the plasma comprises transporting the whole cell toward the plasma.

[0177] Example 38 is the method according to Examples 36 or 37, wherein transporting the sample toward the plasma comprises transporting the sample through an injector having an inner diameter between about 0.5 mm and 5 mm.

[0178] Example 39 is the method according to Examples 36-38, wherein receiving the sample further comprises mixing the element-labeled analyte and the stabilizing solution.

[0179] Example 40 is the method according to Examples 36-39, wherein the stabilizing solution comprises a salt, the salt being selected to obtain a salt deposition of less than 2% of the total flow of salt material in the injector during a 48 hour sample run.

[0180] Example 41 is the method according to Examples 36-40, wherein the stabilizing solution comprises a salt, the salt being selected to maintain a percent signal drop during elemental analysis of or less than 5% during a 48 hour sample run.

[0181] Example 42 is a method comprising providing an element-labeled analyte, wherein the element-labeled analyte comprises a sample having whole cells labeled with element-labeled affinity reagents, wherein each element-labeled affinity reagent comprises an affinity reagent bound to an analyte of the sample and a metal-binding moiety bound to one or more metal elements; and mixing the element-labeled analyte with a stabilized solution having at or below about 0.2% total dissolved solids, wherein the stabilized solution contains a salt. In some cases, the salt of the method according to Example 42 is present at a concentration of at least 5 mM.

[0182] Example 43 is the method according to Example 42, wherein the salt is a non-metal salt.

[0183] Example 44 is the method according to Example 42 or 43, wherein the salt does not contain carbon.

[0184] Example 45 is the method according to Examples 42-44, wherein the salt does not contain a metal having an atomic mass unit greater than 80.

[0185] Example 46 is the method according to Examples 42-45, wherein the salt includes nitrogen.

[0186] Example 47 is the method according to Examples 42-46, wherein the salt is ammonium nitrate.

[0187] Example 48 is the method according to Examples 42-47, wherein the salt has a vapor pressure of at least 3 Pa at 100 °C.

[0188] Example 49 is the method according to Example 48, further comprising passing the sample collection solution through an injector heated to a temperature of at least 100 °C.

[0189] Example 50 is the method according to Examples 42-49, wherein the salt has a vapor pressure of at least 130 Pa at 150 °C.

[0190] Example 51 is the method according to Example 50, further comprising passing the sample collection solution through an injector heated to a temperature of at least 150 °C.

[0191] Example 52 is the method according to Examples 42-51, wherein the salt has a vapor pressure of at least 250 Pa at 160 °C.

[0192] Example 53 is the method according to Example 52, further comprising passing the sample collection solution through an injector heated to a temperature of at least 160 °C.

[0193] Example 54 is the method according to Examples 42-46 or 48-53, wherein the salt is ammonium acetate.

[0194] Example 55 is the method according to Examples 42-54, wherein the affinity reagent is bondable to the surface of the whole cell.

[0195] Example 56 is the method according to Examples 42-55, wherein the stabilizing solution induces a low enough osmotic pressure on the membrane of the whole cell bound to the affinity reagent to avoid osmotic lysis of the whole cell.

[0196] Example 57 is the method according to Examples 42-56, wherein the salt is present in the stabilizing solution at a concentration of or less than 25 mM.

[0197] Example 58 is the method according to Examples 42-57, wherein the stabilizing solution has a pH between 5-9.

[0198] Example 59 is the method according to Examples 42-57, wherein the stabilizing solution has a pH between 6-8.

[0199] Example 60 is the method according to Examples 42-59, wherein the metal binding moiety comprises a polymer linked to the affinity reagent and comprising at least one metal binding pendant group, the metal binding pendant group comprising at least one metal atom.

[0200] Example 61 is the method according to Examples 42-60, wherein the element-labeled affinity reagent comprises a first affinity reagent labeled with a first element tag and a second affinity reagent labeled with a second element tag, the second element tag being distinguishable from the first element tag by elemental analysis.

[0201] Example 62 is the method according to Examples 42-61, wherein the salt is selected to obtain less than 2% salt deposition during a 48 hour sample run.

[0202] Example 63 is the method according to Examples 42-62, wherein the stabilizing solution comprises a salt, the salt being selected to maintain a percent signal drop during elemental analysis of or less than 5% during a 48 hour sample run.

[0203] Example 64 is a stabilizing solution mixable with a sample for use in inductively coupled plasma elemental analysis, the stabilizing solution comprising: a solute and a solvent, wherein the solute is a salt, wherein the solution has a total dissolved solids of or below about 0.2%, and wherein the solution is free of metals having an atomic mass unit greater than 80. In some cases, the salt of the stabilizing solution according to Example 64 is present at a concentration of at least 5 mM.

[0204] Example 65 is the solution according to Example 64, wherein the salt is a non-metal salt.

[0205] Example 66 is the solution according to Examples 64 or 65, wherein the salt is free of carbon.

[0206] Example 67 is the solution according to Examples 64-66, wherein the salt comprises nitrogen.

[0207] Example 68 is the solution according to Examples 64-67, wherein the salt is ammonium nitrate.

[0208] Example 69 is the solution according to Examples 64-68, wherein the salt has a vapor pressure of at least 3 Pa at 100 °C.

[0209] Example 70 is the solution according to Examples 64-69, wherein the salt has a vapor pressure of at least 130 Pa at 150 °C.

[0210] Example 71 is the solution according to Examples 64-70, wherein the salt has a vapor pressure of at least 250 Pa at 160 °C.

[0211] Example 72 is the solution according to Examples 64-67 or 69-71, wherein the salt is ammonium acetate.

[0212] Example 73 is the solution according to Examples 64-72, wherein the stabilizing solution induces a sufficiently low osmotic pressure across the membrane of whole cells of the sample to avoid osmotic lysis of the whole cells.

[0213] Example 74 is the solution according to Examples 64-73, wherein the salt is present in the stabilizing solution at a concentration of or less than 25 mM.

[0214] Example 75 is the solution according to Examples 64-74, wherein the stabilizing solution has a pH between 5-9.

[0215] Example 76 is the solution according to Examples 64-75, wherein the stabilizing solution has a pH between 6-8.

[0216] Example 77 is an apparatus comprising: an inductively coupled plasma source for generating a plasma; an injector having a sample inlet for receiving a sample comprising an element-labeled analyte, wherein the injector is positioned upstream of the inductively coupled plasma source to supply the sample to the plasma; and a heat source thermally coupled to the injector for heating the injector.

[0217] Example 78 is the apparatus according to Example 77, further comprising a heat transfer device thermally coupled to the injector for transferring heat from the heat source.

[0218] Example 79 is the apparatus according to Example 78, wherein the heat transfer device comprises a metal jacket surrounding at least a portion of the injector.

[0219] Example 80 is the apparatus of Examples 78 or 79, wherein the heat source comprises at least a portion of a spray chamber positioned upstream of the injector, such that heat from the spray chamber is transferred to the injector by the heat transfer device.

[0220] Example 81 is the apparatus of Examples 78-80, wherein the heat source comprises a plasma.

[0221] Example 82 is the apparatus of Examples 77-81, wherein the heat source comprises an electrical resistance heat source.

[0222] Example 83 is the apparatus of Examples 77-82, further comprising one or more heat pipes extending along a length of the injector.

[0223] Example 84 is the apparatus of Example 83, wherein the one or more heat pipes are arranged to conduct thermal energy from a higher temperature portion of the injector to a lower temperature portion of the injector.

[0224] Example 85 is the apparatus of Examples 77-84, further comprising a mass spectrometer positioned downstream of the inductively coupled plasma source for receiving ions from the inductively coupled plasma source.

[0225] Example 86 is the apparatus of Examples 77-85, wherein the injector has an inner diameter of between about 0.5 mm and 5 mm.

[0226] Example 87 is the apparatus of Examples 77-86, further comprising a sample source coupled to the injector for providing a sample and a stabilizing solution.

[0227] Example 88 is the apparatus of Example 87, wherein the heat transfer device is coupled to the injector to heat an inner surface of the injector to a temperature sufficient to evaporate or sublimate a solute of the stabilizing solution.

[0228] Example 89 is the apparatus of Examples 77-88, wherein the heat transfer device is coupled to the injector to heat an inner surface of the injector to a temperature of at least 150 °C.

[0229] Example 90 is a method of using the apparatus of Examples 77-89, the method comprising: heating the injector using the heat source; passing a sample through the injector to the plasma; ionizing the sample; and performing elemental analysis on the ionized sample.

[0230] Example 91 is the method of Example 90, wherein passing the sample through the injector comprises passing a solution comprising an element-labeled analyte and a stabilizing solution.

[0231] Example 92 is the method according to Example 91, wherein heating the injector comprises heating the injector to a temperature suitable to obtain less than 2% salt deposition during a 48 hour sample run.

[0232] Example 93 is the method according to Examples 90-92, wherein heating the injector comprises passing an electrical current through a resistive heat source, wherein the heat source is the resistive heat source.

[0233] Example 94 is the method according to Examples 90-93, wherein heating the injector comprises using a heat transfer device to conduct heat from a higher temperature portion of the injector to a lower temperature portion of the injector.

[0234] Example 95 is the method according to Examples 90-94, wherein heating the injector comprises heating the inner wall to a temperature sufficient to evaporate or sublimate or decompose a solute of the stabilized solution.

[0235] Example 96 is a method comprising: receiving a sample comprising an element-labeled analyte and a stabilized solution; transporting the sample in a downstream direction toward a plasma of an inductively coupled plasma source to ionize the sample, wherein transporting the sample comprises passing the sample through an inner wall of an injector; and heating the inner wall of the injector.

[0236] Example 97 is the method according to Example 96, wherein heating the inner wall of the injector is initiated prior to transporting the sample toward the plasma.

[0237] Example 98 is the method according to Example 96, wherein heating the inner wall of the injector is initiated after transporting the sample toward the plasma.

[0238] Example 99 is the method according to Examples 96-98, further comprising passing the sample through a spray chamber, wherein heating the inner wall of the injector comprises conducting heat from the spray chamber through a heat transfer device.

[0239] Example 100 is the method according to Examples 96-99, wherein heating the inner wall of the injector comprises generating heat at a heat source.

[0240] Example 101 is the method according to Example 100, wherein generating heat at the heat source comprises passing an electrical current through a resistive heat source.

[0241] Example 102 is the method according to Examples 96-101, wherein heating the inner wall of the injector comprises using a heat transfer device to conduct heat from a higher temperature portion of the injector to a lower temperature portion of the injector.

[0242] Example 103 is the method according to Examples 96-102, wherein heating the inner wall of the injector comprises heating the inner wall to a temperature sufficient to evaporate or sublimate a solute of the stabilized solution.

[0243] Example 104 is the method according to Examples 96-103, wherein heating the inner wall of the injector comprises heating the inner wall to a temperature of at least 150°C.

[0244] Example 105 is the method according to Examples 96-104, further comprising: transporting ions of the ionized sample to a mass spectrometer; and analyzing the ions by the mass spectrometer.

[0245] Example 106 is the method according to Examples 96-105, wherein the analyte comprises whole cells, and wherein transporting the sample to the plasma comprises transporting the whole cells to the plasma.

[0246] Example 107 is the method according to Examples 96-106, wherein transporting the sample to the plasma comprises transporting the sample through an injector having an inner diameter between about 0.5 mm and 5 mm.

[0247] Example 108 is the method according to Examples 96-107, wherein receiving the sample further comprises mixing the elementally labeled analyte and the stabilizing solution.

[0248] Example 109 is the method according to Examples 96-108, wherein heating the inner wall of the injector comprises heating the inner wall to a temperature suitable to obtain less than 2% salt deposition during a 48 hour sample run.

[0249] Example 110 is an apparatus comprising: an injector positionable upstream of an inductively coupled plasma source and suitable to transport a sample into a plasma of the inductively coupled plasma source, the injector having a sample inlet for receiving the sample, wherein the sample comprises an elementally labeled analyte; and a heat source thermally coupled to the injector for heating the injector.

[0250] Example 111 is the apparatus according to Example 110, further comprising a heat transfer device thermally coupled to the injector for transporting heat from the heat source.

[0251] Example 112 is the apparatus according to Example 111, wherein the heat transfer device comprises a metal sleeve surrounding at least a portion of the injector.

[0252] Example 113 is the apparatus according to Examples 111 or 112, wherein the heat source comprises at least a portion of a spray chamber positioned upstream of the injector, such that heat from the spray chamber is transferred to the injector through the heat transfer device.

[0253] Example 114 is the apparatus according to Examples 111-113, wherein the heat source comprises a plasma.

[0254] Example 115 is the apparatus according to Examples 110-114, wherein the heat source comprises an electrical resistance heat source.

[0255] Example 116 is the apparatus of Examples 110-115, further comprising one or more heat pipes extending along a length of the injector.

[0256] Example 117 is the apparatus of Example 116, wherein the one or more heat pipes are arranged to conduct thermal energy from a higher temperature portion of the injector to a lower temperature portion of the injector.

[0257] Example 118 is the apparatus of Examples 110-117, further comprising a mass spectrometer positionable downstream of the inductively coupled plasma source for receiving ions from the inductively coupled plasma source.

[0258] Example 119 is the apparatus of Examples 110-118, wherein the injector has an inner diameter between about 0.5 mm and 5 mm.

[0259] Example 120 is the apparatus of Examples 110-119, further comprising a sample source coupled to the injector for providing the sample and the stabilizing solution.

[0260] Example 121 is the apparatus of Example 120, wherein a heat transfer device is coupled to the injector to heat an inner surface of the injector to a temperature sufficient to evaporate or sublimate a solute of the stabilizing solution.

[0261] Example 122 is the apparatus of Examples 110-121, wherein a heat transfer device is coupled to the injector to heat an inner surface of the injector to a temperature of at least 150 °C.

Claims

1. A device comprising: an inductively coupled plasma source, the inductively coupled plasma source being used to generate plasma; an injector having a sample inlet for receiving a sample comprising an elementally labeled analyte, wherein the injector is positioned upstream of the inductively coupled plasma source to supply the sample to the plasma; as well as A heat source is thermally coupled to the injector for heating the injector.

2. The apparatus of claim 1 further comprising a heat transfer device thermally coupled to the injector for transferring heat from the heat source.

3. The device according to claim 2, wherein The heat transfer device includes a metal jacket surrounding at least a portion of the injector.

4. The device according to claim 2, wherein The heat source includes at least a portion of a spray chamber positioned upstream of the injector such that heat from the spray chamber is transferred to the injector through the heat transfer device.

5. The apparatus according to claim 2, wherein The heat source includes the plasma.

6. The apparatus according to claim 1, wherein The heat source includes a resistive heat source.

7. The apparatus of claim 1 further comprising one or more heat pipes extending along a length of the injector.

8. The apparatus according to claim 7, wherein The one or more heat pipes are arranged to conduct thermal energy from a higher temperature portion of the injector to a lower temperature portion of the injector.

9. The apparatus of claim 1, further comprising a mass spectrometer positioned downstream of the inductively coupled plasma source for receiving ions from the inductively coupled plasma source.

10. A method comprising: receiving a sample comprising an elementally labeled analyte and a stabilization solution; transporting the sample in a downstream direction toward a plasma of an inductively coupled plasma source to ionize the sample, wherein transporting the sample includes passing the sample through an inner wall of an injector; and The inner wall of the injector is heated.

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