Patent Application
20110147576
The present invention relates to mass spectrometry and mass spectrometers. More particularly, the invention relates to electrospray ion sources for and electrospray ion introduction into mass spectrometers.
In electrospray ionization, a liquid is sprayed through the tip of a needle that is held at a high electric potential of a few kilovolts. Small multiply-charged droplets containing solvent molecules and analyte molecules are initially formed and then shrink as the solvent molecules evaporate. The shrinking droplets also undergo fission—possibly multiple times—when the shrinkage causes the charge density of the droplet to increase beyond a certain threshold. This process ends when all that is left of the droplet is a charged analyte ion that can be mass analyzed by a mass spectrometer. Some of the droplets and liberated ions are directed into the vacuum chamber of the mass spectrometer through an ion inlet orifice, such as an ion transfer tube that is heated to help desolvate remaining droplets or ion/solvent clusters. A strong electric field in the tube lens following the ion transfer tube also aids in breaking up solvent clusters. The smaller the initial size of the droplets, the more efficiently they can be desolvated, and eventually, the more sensitive the mass spectrometer system becomes.
One of the design parameters that influence the initial size of the droplets is the size of the emitter orifice through which they are being formed. So-called nanospray ionization is a form of electrospray ionization that employs small-diameter tips in the order of tens of micrometers. This limits the maximum solvent flow rates to the range of tens of microliters to nanoliters per minute. It is well known in the art that, of all the variants of electrospray ionization, nanospray ionization yields the highest current per analyte concentration. This result is attributed to the small bore of the electrospray emitter needles employed, which cause the diameter of the droplets formed at the Taylor cone to be the smallest, such that the combined effects of smaller initial droplet size and higher analyte concentration (as a result of less required solvent) permit a higher proportion of ions to be inlet into a mass spectrometer. Therefore, nanospray ionization enables the most sensitive results to be obtained from a mass spectrometer.
Unfortunately, due to the small-diameter emitter needles employed in nanospray ionization, there is a maximum to the amount of liquid flow that can be accommodated. Therefore, nanospray is limited in its applications to low flow analysis. However, in LC-MS (Liquid Chromatography-Mass Spectrometry) assays, much larger flow rates are encountered, often exceeding 100 microliters per minute and occasionally as high as 5 milliliters per minute. For those flow rates, larger bore needles are conventionally employed and the electrospray variant with pneumatic assist (“sheath” or nebulizing gas) is used to enable shearing off of droplets from the liquid stream as well as to cause subsequent breakdown of the large droplets. The sheath gas may be heated in order to expedite de-solvation. Often, additional auxiliary gas flows (which could be heated) are employed to help the ions escape from the larger solvent droplets.
Still referring to
Typically the quartz tube 13 from the liquid chromatograph 12 will be 0.050 mm inner diameter. The tube 13 is sealed at its end 35 to the stainless steel tube 15, so that the liquid flowing in the tube 13 can expand into the stainless steel tube.
A gas, typically nitrogen boiled from liquid nitrogen, is introduced into the space 31 between the tubes 15, 16 from a gas source 17. The gas source 17 is connected to the outer tube 16 by a fitting 18, through which the inner quartz tube 13 passes. Other gases, such as “zero air” (i.e. air with no moisture) or oxygen can also be used.
A source 19 of electric potential is connected to the stainless steel tube 15. For negative ion operation, the stainless steel capillary may be kept at −3000 volts, and for positive ion operation at +3000 volts. The orifice plate 5 is grounded. In operation of the apparatus 1, charged droplets are emitted from the end of the stainless steel tube 15 by electrospray ionization at the same time that the gas flows through the space 31 surrounding the stainless steel tube 15. The combination of the electric field and the gas flow serves to nebulize the liquid stream. The nebulizer gas flow through the annular space 31 also allows a larger distance to be maintained between the tip of the stainless steel tube 15 and the orifice plate 5 than in the case when no gas is used, thus helping to reduce the electric field at the tip of the tube and prevent corona discharge.
Various designs have been proposed in an attempt to extend the benefits of small initial droplets—as are associated with low flow rates, for example, nanospray—to the larger flow rates required for LC-MS analysis. The concept is to use multiple low-flow rate emitters in parallel so as to divide the large flow into a large number of smaller flows, each directed to a single emitter. An example of an apparatus that employs this strategy is shown in
An issue with having a multitude of nanospray emitters is that the generated cloud of droplets starts to have dimensions that become incompatible with those of the inlet orifice of the mass spectrometer, in other words only a fraction of the mist generated is actually drawn into the inlet of the mass analyzer. This loss obviously results in decreased sensitivity of the instrument. Some possible remedies to this problem could be to provide larger or additional inlets to the mass spectrometer, but that in turn causes a larger (or more) vacuum pump(s) to be required to maintain similar pressures in the mass spectrometer. This leads to additional costs, spatial requirements, shipping weight etc. all of which are not beneficial.
In considering emitter arrays, it is desirable to be able to balance the desirable effects of small low-flow-rate emitters against the possible undesirable effects of a large number of emitters. In order to divide the total flow from a conventional liquid chromatograph among several emitters interfaced to a conventional mass spectrometer ion inlet, the distance between the individual emitters should be maintained as small as possible. However, it is also known in the art that, in order for a Taylor cone to be formed, a high electric field gradient is required. Commonly, this is obtained by having a high aspect ratio structure such as a needle. Yet, when there are multiple needles in close proximity, the spray from one needle could be negatively impacted by the electric field around a neighboring needle. Also, when multiple emitters abut one another, because of the surface tension, the eluent from the different channels could coalesce rather than form individual Taylor cones. All such issues could be resolved by using a limited number of emitters—such that the flow rate per emitter is in the range of hundreds of microliters to a few milliliters per minute—in conjunction with pneumatic assist techniques.
Arrays of electrospray emitters in close proximity to one another are known in the art. Microfabrication techniques that have been borrowed from the electronics industry and microelectromechanical systems (MEMS), such as chemical vapor deposition, molecular beam epitaxy, photolithography, chemical etching, dry etching (reactive ion etching and deep reactive ion etching), molding, laser ablation, etc., have been used to fabricate such emitter arrays. For instance,
A grid-plane region 212 of the ejection surface 210 is exterior to the nozzle 209 and to the recessed region 211 and may provide a surface on which a layer of conductive material 214 including a conductive electrode 215 may be formed for the application of an electric potential to the substrate 205 to modify the electric field pattern between the ejection surface 210, including the nozzle tip 209, and the extracting electrode 217. Alternatively, the conductive electrode may be provided on the injection surface 208 (not shown).
The electrospray device 204 further comprises a layer of silicon dioxide 213 over the surfaces of the substrate 205 through which the electrode 215 is in contact with the substrate 205 either on the ejection surface 210 or on the injection surface 208. The silicon dioxide 213 formed on the walls of the channel 206 electrically isolates a fluid therein from the silicon substrate 205 and thus allows for the independent application and sustenance of different electrical potentials to the fluid in the channel 206 and to the silicon substrate 205. Alternatively, the substrate 205 can be controlled to the same electrical potential as the fluid.
As shown in
Almost all microfabricated electrospray nozzles or other emitters have no provision for delivery of a nebulizing gas directly to the nozzle or emitter. One apparatus that is an exception to this statement is disclosed in United States Patent Application Publication 2006/0113463 A1 in the names of Rossier et al., as is illustrated in
As described in the aforementioned United States Patent Application Publication 2006/0113463 A1, the apparatus 23 comprises two plasma etched microchips made of a polyimide foil having a thickness of 75 μm, comprising one microchannel (approximately 60 μm×120 μm×1 cm) sealed by lamination of a 38 μm thick polyethylene/polyethylene terephthalate layer and one gold microelectrode (not illustrated) of approximately 52 μm diameter integrated at the bottom of the microchannel. The two polyimide chips are glued together and further mechanically cut in a tip shape, in such a manner that this multilayer system exhibits two microstructures both comprising a microchannel having an outlet at the edge of the polyimide layers, thereby forming an apparatus such that the outlets of the sample and sheath liquid microstructures are superposed. The thickness of the support separating the two microstructure outlets may be less than 50 micrometers.
In operation of the apparatus 23, when an electrical potential is applied to the electrode, a Taylor cone is formed that encompasses the outlets 29 of both the sample and sheath liquid microchannels, so that the sample solution mixes with the sheath liquid solution directly in the Taylor cone. Rossier et al. further teach that, instead of a sheath liquid, a sheath gas may be introduced into the micro-channel 26. This gas may be an inert gas such as nitrogen, argon, helium or the like, serving e.g. to favor the spray generation and/or to prevent the formation of droplets at the microstructure outlet. For some applications, a reactive gas such as oxygen or a mixture of inert and reactive gases may also be used so as to generate a reaction with the sample solution. Rossier et al. further teach that an array of such apparatuses can be constructed.
Likewise, United States Patent Application Publication US 2007/0257190 A1, in the name of inventor Li, teaches microfluidic chip structures for gas assisted ionization, these structures having an analyte channel ending in a spray tip and having up to four gas channels having outlet ends adjacent to the spray tip. For instance, Li teaches an apparatus having a spray tip having a first pair of gas channels having ends disposed at opposite sides of the spray tip and a second pair of gas channels, provided by auxiliary gas chips, also disposed at opposite ends of the spray tip.
Although the apparatuses taught by Rossier et al. and by Li appear to operate adequately, they only provide for introduction of a sheath gas at a finite number of discrete gas channel ends adjacent to a fluid channel. The nebulizing gas provided by these finite numbers of discrete gas channels thus does not exit the channels in a fashion that two-dimensionally circumferentially surrounds the fluid emitted from the fluid channel. As a result, these apparatuses are subject to potential asymmetry or non-uniformity in the sheath pressure or flow rate around the emitted droplets or other charged particles. For instance, if the sheath or nebulizing gas is supplied via a single channel aperture on one side of the Taylor cone, the supplied gas flow may not symmetrically surround the stream of emitted droplets. If the gas is supplied from multiple channels, then restricted flow or clogging in one or more of the channels may cause similar difficulties. Since sheath gas is supplied under pressure, the introduction of sheath gas in such an asymmetric or non-uniform fashion in such existing apparatuses, if not carefully controlled, may perturb the emission pattern and direction of electrospray droplets in a manner that causes fluctuations in the ability of ions to be captured by an ion inlet port of a mass spectrometer. Further, since the outlets of both the sample and sheath liquid or gas microchannels, as described in the Rossier et al. apparatus, must fit within the dimensions of an individual Taylor cone, this apparatus is limited to nanospray flow regimes and is not suitable for providing variable flow rates in the range of hundreds of microliters to a few milliliters per minute, as would be expected when dividing a total sample flow of an LC-MS among a limited number of emitters.
We herein disclose novel electrospray ion sources and methods that take all of the above issues into consideration. The conventional single electrospray emitter within a single concentric sheath gas flow tube is replaced with a plurality of electrospray assemblies, each of which carries a fraction of the total flow of analyte-bearing liquid and that receives pneumatic assistance from circumferentially surrounding sheath gas flow. As non limiting examples, the number of these electrospray emitters can be as low as 2 or 3, and can easily be envisioned to be 15 or even higher.
In a first aspect of the invention, there is disclosed an electrospray ion source for a mass spectrometer comprising: a source of an analyte-bearing liquid; a source of a sheath gas; a plurality of liquid conduits, each liquid conduit configured so as to receive a portion of the analyte-bearing liquid from the source of analyte-bearing liquid; at least one electrode for producing electrospray emission of charged droplets from an outlet of each of said liquid conduits under application of an electrical potential to the at least one electrode; a power supply electrically coupled to the at least one electrode for maintaining the at least one electrode at the electrical potential; and a plurality of sheath gas conduits, each sheath gas conduit comprising: an inlet configured to receive a sheath gas portion from the source of sheath gas; and an outlet configured to emit a sheath gas flow that circumferentially surrounds, in at least two dimensions, a portion of the charged droplets emitted from a respective one of the liquid conduit outlets.
In a second aspect of the invention, there is disclosed an electrospray ion source for a mass spectrometer comprising: a source of an analyte-bearing liquid; a source of a sheath gas; a plurality of liquid conduits, each liquid conduit configured so as to receive a portion of the analyte-bearing liquid from the source of analyte-bearing liquid; at least one electrode for producing electrospray emission of charged droplets from an outlet of each of said liquid conduits under application of an electrical potential to the at least one electrode; a power supply electrically coupled to the at least one electrode for maintaining the at least one electrode at the electrical potential; and a sheath gas conduit comprising: an inlet configured to receive the sheath gas from the source of sheath gas; and an outlet configured to emit a sheath gas flow that circumferentially surrounds, in at least two dimensions, a portion of the charged droplets emitted from every one of the plurality of liquid conduit outlets.
In another aspect the invention, a method for providing ions to a mass spectrometer is disclosed, the method comprising: providing a source of an analyte-bearing liquid; providing a source of a sheath gas; providing a plurality of liquid conduits, each liquid conduit configured so as to receive a portion of the analyte-bearing liquid from the source of analyte-bearing liquid; providing at least one electrode associated with the plurality of liquid conduits; providing a plurality of sheath gas conduits, each sheath gas conduit comprising a sheath gas outlet configured to emit a sheath gas flow that circumferentially surrounds, in at least two dimensions, an outlet of a respective one of the liquid conduits; distributing the analyte-bearing liquid among the plurality of liquid conduits; distributing the sheath gas among the plurality of sheath gas conduits; and maintaining the at least one electrode at an electrical potential such that charged liquid droplets are emitted from the plurality of liquid conduits.
In yet another aspect of the invention, a method for providing ions to a mass spectrometer is disclosed, the method comprising: providing a source of an analyte-bearing liquid; providing a source of a sheath gas; providing a plurality of liquid conduits, each liquid conduit configured so as to receive a portion of the analyte-bearing liquid from the source of analyte-bearing liquid and having a respective outlet; providing at least one electrode associated with the plurality of liquid conduits; providing a sheath gas conduit comprising a sheath gas outlet configured to emit a sheath gas flow that circumferentially surrounds, in at least two dimensions, the outlets of the plurality of liquid conduit outlets; distributing the analyte-bearing liquid among the plurality of liquid conduits; providing the sheath gas to the sheath gas conduit; and maintaining the at least one electrode at an electrical potential such that charged liquid droplets are emitted from the plurality of liquid conduits.
In accordance with the present teachings, the diameters of each of a plurality of electrospray emitting capillaries may be smaller than is the case for a conventional single capillary. Such smaller capillaries can generate smaller initial droplets which are more readily de-solvated. Further, the smaller capillary size enables all of the electrospray emitters to be in close proximity to one another so that ions are directed to an ion inlet of a mass spectrometer. Although the emitters are in close mutual proximity, nonetheless, they are each surrounded by nebulizing sheath such that their individual Taylor cones are not perturbed and also coalescence of liquid from different sprayers does not occur. In various embodiments, each liquid capillary or conduit may be configured so as to admit a flow rate of an analyte-bearing liquid portion of between 1 microliter per minute and 1 milliliter per minute through the capillary or conduit. The total flow rate, summed over all capillaries or conduits, may range from approximately 10 microliters per minute up to approximately 10 milliliters per minute.
The above noted and various other aspects of the present invention will become apparent from the following description which is given by way of example only and with reference to the accompanying drawings, not drawn to scale, in which:
The present invention provides methods and apparatus for an improved ionization source for mass spectrometry. The following description is presented to enable one of ordinary skill in the art to make and use the invention and is provided in the context of a particular application and its requirements. It will be clear from this description that the invention is not limited to the illustrated examples but that the invention also includes a variety of modifications and embodiments thereto. Therefore the present description should be seen as illustrative and not limiting. While the invention is susceptible of various modifications and alternative constructions, it should be understood that there is no intention to limit the invention to the specific forms disclosed. On the contrary, the invention is to cover all modifications, alternative constructions, and equivalents falling within the essence and scope of the invention as defined in the claims. To more particularly describe the features of the present invention, please refer to the attached
Analyte-bearing liquid is delivered to each respective capillary tip through an interior bore of the respective capillary 32. Preferably, each capillary tip protrudes outward slightly relative to the end of the respective enclosing tube. In a similar fashion, each tube 34 delivers a sheath or nebulizing gas to vicinity of a respective emitter capillary tip. Thus, each capillary 32 may be considered as a particular example of a liquid conduit through which the analyte-bearing liquid flows and each tube 34 may be considered as a particular example of a sheath gas conduit through which the sheath or nebulizing gas flows. Clearly, other forms of liquid conduit and sheath gas conduit may be employed, some of which are specifically discussed in regard to subsequent examples provided later in this document.
Still referring to
As envisaged, the flow of an analyte-bearing liquid is divided approximately equally among the electrospray emitter capillaries 32 comprising the array. Therefore, according to the configuration shown in
Twelve channel and emitter capillary pairs are illustrated in
In the apparatus shown
The electrospray emitter array apparatus 50 shown in
The electrospray emitter array apparatus 60 shown in
As shown in the bottom half of
The apparatus 91 shown in
A plate or second partition element or wall 110 separates the intermediate-vacuum chamber 104 from either the high-vacuum chamber 106 or possibly a second intermediate-pressure region (not shown), which is maintained at a pressure that is lower than that of chamber 104 but higher than that of high-vacuum chamber 106. Ion optical assembly or ion lens 119 provides an electric field that guides and focuses the ion stream leaving ion transfer tube 116 through an aperture 122 in the second partition element or wall 110 that may be an aperture of a skimmer 120. A second ion optical assembly or lens 124 may be provided so as to transfer or guide ions to the mass analyzer 128. The ion optical assemblies or lenses 119, 124 may comprise transfer elements, such as, for instance a multipole ion guide, so as to direct the ions through aperture 122 and into the mass analyzer 128. The mass analyzer 128 comprises one or more detectors 130 whose output can be displayed as a mass spectrum. Vacuum port 112 is used for evacuation of the intermediate-vacuum chamber and vacuum port 114 is used for evacuation of the high-vacuum chamber 106.
The mass spectrometer system 100 shown in
A power supply 136 electrically connected to emitter electrodes of the emitter array apparatus 150 as well as to a counter electrode 142 so as to create a voltage difference and, thus, an electric field between the emitters and the counter electrode that serves to separate positively charged from negatively charged ions in the liquid and to cause ions of a desired polarity to be emitted in the direction of the ion transfer tube 116. The ion transfer tube 116 may itself be electrically connected to power supply 136 and used as a counter electrode. In such a case, a separate counter electrode may not be required. To capture positively charged analyte ions, the emitter electrode or electrodes are held at a positive potential, relative to the counter electrode (or the ion capillary) which may be held at ground potential. Alternatively, the emitter electrode or electrodes may be grounded and the counter electrode maintained at a negative potential. These polarities are reversed in case to capture negative ions.
The mass spectrometer system 300 shown in
The discussion included in this application is intended to serve as a basic description. Although the present invention has been described in accordance with the various embodiments shown and described, one of ordinary skill in the art will readily recognize that there could be variations to the embodiments and those variations would be within the spirit and scope of the present invention. The reader should be aware that the specific discussion may not explicitly describe all embodiments possible; many alternatives are implicit. Accordingly, many modifications may be made by one of ordinary skill in the art without departing from the spirit, scope and essence of the invention. As one non-limiting example, the additional electrodes described in reference to the electrospray emitter array apparatus 50 (
Neither the description nor the terminology is intended to limit the scope of the invention. Any publications, patents or patent application publications mentioned in this specification are explicitly incorporated by reference in their respective entirety.
