Patent Publication Number: US-11651945-B2

Title: Rapid droplet introduction interface (RDII) for mass spectrometry

Description:
CROSS-REFERENCE TO RELATED APPLICATIONS 
     This application claims priority to U.S. 63/083,202 filed on Sep. 25, 2020, entitled “Rapid Droplet Introduction Interface (RDII) for Mass Spectrometry”, the entire disclosure of which incorporated herein by reference. 
    
    
     STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH AND DEVELOPMENT 
     This invention was made with government support under Contract No. DE-AC05-00OR22725 awarded by the U.S. Department of Energy. The government has certain rights in this invention. 
    
    
     FIELD OF THE INVENTION 
     The present invention relates to spectrometry, and more particularly to systems and methods for introducing an analyte into a spectrometer. 
     BACKGROUND OF THE INVENTION 
     Introduction of a real-life sample for chemical analysis by mass spectrometry (MS) can present certain challenges. In the case of atmospheric pressure ionization mass spectrometry (API-MS) with liquid introduction interfaces the sample must be in a solution that maximizes signal-to-noise (i.e. sensitivity) of the analyte of interest. In many cases, it requires vigorous sample processing which significantly extends the total analysis time. In the pharmaceutical and biochemical industries this additional time significantly increases the expense of the process. Industry participants can routinely analyze tens of thousands of samples in a day. Thus, even a small increase in sampling throughput can translate to significant monetary savings. 
     In the simplest form of liquid introduction for mass spectrometry the sample to be analyzed is pumped directly into the mass spectrometer in a process termed direct infusion (DI) MS (Lin, L.; Yu, Q.; Yan, X.; Hang, W; Zheng, J. Xing, J.; Huang, B.  Direct infusion mass spectrometry or liquid chromatography mass spectrometry for human metabonomics? A serum metabonomic study of kidney cancer. Analyst,  2010, 135, 2970-2978). Typically, the liquid sample is contained in a syringe and a syringe pump is used to deliver a regular flow of liquid. Direct infusion is suitable for use with samples that are pure or that are simple mixtures composed of only a small number of constituents. The sample must also be free of contaminating factors that might interfere with mass spectrometric measurements, such as high levels of non-volatile salts/buffers and detergents. To satisfy these conditions, offline sample preparation almost always requires extensive dilution of the original sample. 
     Another method of liquid sample introduction is injection of the sample into a stream of MS appropriate liquid using a valve system. The most commonly used example is coupling high performance liquid chromatography with MS (HPLC-MS) (Lin, L.; Yu, Q.; Yan, X.; Hang, W; Zheng, J. Xing, J.; Huang, B.  Direct infusion mass spectrometry or liquid chromatography mass spectrometry for human metabonomics? A serum metabonomic study of kidney cancer. Analyst,  2010, 135, 2970-2978). This method is used when the sample has many molecular components and/or when some molecules in the sample would interfere with the MS analysis, for example when inorganic salts and ionic buffers are present. In this case, an initial HPLC separation of the components is often essential. While this method enables separating individual sample components in time and space, thus allowing analytes from a mixture to be analyzed individually, analysis of a single sample (mixture) can take at least 1-2 min and as much as 1 hr. 
     To alleviate the issues with DI-MS and LC-MS, a vertically aligned, continuous flow, coaxial-tube sampling probe was introduced recently as a simple, versatile and self-cleaning open port sampling interface (OPSI) for liquid introduction API-MS (Van Berkel, G. J.; Kertesz, V.  An open port sampling interface for liquid introduction atmospheric pressure ionization mass spectrometry. Rapid Commun. Mass Spectrom.  2015, 29, 1749-1756). This advance provides a simple sample introduction system with high throughput (seconds/sample), low material consumption, and high sensitivity. The OPSI has been used for manual liquid introduction (Van Berkel, G. J.; Kertesz, V.  Rapid sample classification using an open port sampling interface coupled with liquid introduction atmospheric pressure ionization mass spectrometry. Rapid Commun. Mass Spectrom.  2017, 31, 281-291), automated liquid introduction by a gravitation-assisted falling droplet using a regular autosampler (PAL-DROP) (Van Berkel, G. J.; Kertesz, V.; Orcutt, M.; Bentley, A.; Glick, J.; Flarakos, J.  Combined falling drop/open port sampling interface system for automated flow injection mass spectrometry. Anal. Chem.  2017, 89, 12578-12586), pneumatic liquid introduction (e.g., immediate droplet on demand technology, IDOT) (Van Berkel, G. J.; Kertesz, V.; Boeltz, H.  Immediate Droplet on Demand Technology  ( I - DOT )  coupled with mass spectrometry via an open port sampling interface. Bioanalysis  2017, 9, 1667-1679) and acoustically-assisted liquid introduction (e.g., ECHO-MS) (Habe, T.; Liu, C.; Covey, T. R.; Simon, R.; Reindl, W; Buttner, W; Winter, M.; Bischoff, D.; Luippold, A. H.; Runge. F.  Ultrahigh - Throughput ESI - MS: Sampling Pushed to Six Samples per Second by Acoustic Ejection Mass Spectrometry. Anal. Chem.  2020, 92, 18, 12242-12249). In all cases, the minute amount of the sample introduced into the OPSI (1, 5 and 500 nL using ECHO, IDOT and PAL-DROP, respectively) ensured that interference from the matrix (inorganic salts, ionic buffers, and others) was suppressed or negligible due to the ˜10-1000× dilution. However, this dilution reduces the sensitivity of the technique. 
     Beside analyzing sample droplets, metabolic analysis of single cells was demonstrated using a single cell printer (SCP) coupled to OPSI (Cahill, J. F.; Riba, J.; Kertesz, V.  Rapid, Untargeted Chemical Profiling of Single Cells in Their Native Environment. Anal. Chem.  2019, 91, 6118-6126.) This method overcomes the trade-off that exists between comprehensive chemical coverage (the number of molecular species measured) and sampling throughput (the number of cells measured per second). Several single-cell analysis techniques use molecular tags to selectively analyze one-to-&lt;50 individual molecules with high sampling throughput (&gt;0.1 cell/s), but these methods require knowing the chemistry of interest beforehand. (Spitzer, M. H. and Nolan, G. P.  Mass Cytometry: Single Cells, Many Features. Cell.  2016, 165, 780-791). Other techniques can comprehensively measure the chemistry of a single cell but lack sufficient throughput (typically &lt;&lt;0.1 cell/s) to enable statistical analysis of cell populations. (Pan, N., Rao, W, Kothapalli, N. R., Liu, R., Burgett, A. W. G., and Yang, Z.  The Single - Probe: A Miniaturized Multifunctional Device for Single Cell Mass Spectrometry Analysis. Anal. Chem.  2014, 86, 9376-9380). These techniques usually require sample preparation protocols that may perturb the chemical profile of the cell before analysis, such as changing of cell media, introduction to vacuum, and addition of molecular tags. One limitation of the SCP-OPSI method is that the sensitivity of the technique is reduced because of dilution in the OPSI probe. 
     There is a need for a liquid analysis capability that can provide high sensitivity and high throughput chemical analysis of liquid droplets. The current state of the art (OPSI) dilutes samples significantly, resulting in reduced sensitivity. This analysis capability is highly desired in the biochemical, pharmaceutical, and medical research communities. 
     SUMMARY OF THE INVENTION 
     A system for the mass spectrometry analysis of an analyte includes a spray head comprising a spray tip for ejecting the solvent as a spray, and a solvent delivery conduit for delivering solvent to the spray tip. The spray head further includes a droplet inlet opening communicating with the surrounding atmosphere for receiving liquid drops comprising the analyte. A droplet ejection device is provided for selectively ejecting a liquid analyte droplet comprising the analyte through a surrounding atmosphere and the droplet inlet opening into a solvent flowing through the solvent delivery conduit. The system can further include a mass spectrometer having an analyte inlet configured to receive a spray of the solvent containing the analyte and performing mass spectrometry analysis on the spray of the solvent containing the analyte. The analyte droplet can include a cell. The surrounding atmosphere can be the ambient atmosphere. 
     The droplet ejection device can include at least one selected from a group including a syringe, a pipette device, a piezoelectric droplet ejection device, direct pressure induced droplet ejection device, and an acoustic force induced droplet ejection device. 
     The spray tip can be an electrospray tip. The electrospray tip can be electrically connected to a high voltage source. The spray tip can be a nanoelectrospray tip. The nanoelectrospray tip can be electrically connected to the high voltage source. 
     The system can further include an inductive coil positioned near the spray tip. The inductive coil can be electrically connected to a high voltage source. The system can include an atmospheric pressure chemical ionization spray tip. The system further can further include a high voltage electrode positioned in a path of the spray from the spray tip to a mass spectrometer inlet. The spray tip can be an atmospheric pressure photoionization spray tip, and can further include a photoionization light source. 
     The droplet inlet opening of the solvent delivery conduit can be a hole in the solvent delivery conduit. The droplet ejection device ejects droplets into the hole. The droplet inlet opening can be a beveled opening in the spray tip. 
     The system can further include a guidance apparatus for guiding the droplets into the droplet inlet opening. The guidance device can be an electromagnetic field source. The guidance device can be a guidance gas stream generator. The guidance device can be a chute. The guidance device can be a funnel. 
     The solvent supply conduit can include two spaced apart conduit segments. The space between the conduits defines the droplet inlet opening. The droplets can be transported from the droplet ejection device to the droplet inlet opening by the gravitational force. 
     The system can further include a processor for monitoring the movement of droplets from the droplet ejection device to the spray head and recording droplet data comprising the timing of the droplets. The droplet ejection device can include a droplet ejection control device, and the droplet ejection control device can be responsive to control signals from the processor to release a droplet. 
     A method for the mass spectrometry analysis of an analyte can include the step of providing a spray head comprising a spray tip for ejecting the solvent as a spray, and a solvent delivery conduit for delivering solvent to the spray tip. The spray head further includes a droplet inlet opening for receiving liquid analyte droplets comprising the analyte. A solvent is flowed through the spray head and generates a spray at the spray tip. A liquid analyte droplet is selectively ejected from a droplet ejection device. The liquid analyte droplet is collected in the droplet inlet opening of the spray head. The analyte is ionized and transmitted with solvent to the inlet of a mass spectrometer. The method can include detecting and analyzing the analyte using mass spectrometry. The droplet ejection device can be selected from a syringe, a pipette device, a piezoelectric droplet ejection device, direct pressure induced droplet ejection device, or acoustic force induced droplet ejection device. The surrounding atmosphere can be the ambient atmosphere. 
     The method can further include the step of guiding the liquid analyte droplet from the droplet ejection device to the droplet inlet opening. The guiding can be by at least one of an electromagnetic field, a gas stream, a chute, and a funnel. The method can further include the step of controlling the release of liquid analyte droplets with a control device. The method can include the step of operating the control device with a processor. The method can include the step of monitoring the movement of liquid analyte droplets from the droplet ejection device to the spray head and recording droplet data comprising the timing of the liquid analyte droplets. The method can include combining liquid analyte droplet data with mass spectrometer data. 
     The liquid analyte droplets can be transported from the droplet ejection device to the droplet inlet opening by the gravitational force. The liquid analyte droplet can contain a cell. The cell can be lysed by osmotic forces upon exposure to the collection solvent, thereby releasing molecular material. The solvent flow rate can be from 10 nl/min to 1 ml/min. The ionizing can include at least of electrospray ionization, atmospheric pressure chemical ionization, inductive ionization, and atmospheric pressure photoionization. 
     A method for the chemical analysis of an analyte includes the step of providing a spray head comprising a spray tip for ejecting the solvent as a spray, and a solvent delivery conduit for delivering solvent to the spray tip, the spray head further comprising a droplet inlet opening for receiving liquid analyte droplets comprising the analyte; flowing a solvent through the spray head and generating a spray at the spray tip; selectively ejecting a liquid analyte droplet from a droplet ejection device; collecting the liquid analyte droplet in the droplet inlet opening of the spray head; forming the analyte and solvent into a spray and transmitting the analyte and solvent spray to the inlet of a chemical analysis device. The chemical analysis device can be at least one of a mass spectrometry device, a spectrophotometric device, a fluorimetric device, and an amperometric detection device. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
       There are shown in the drawings embodiments that are presently preferred it being understood that the invention is not limited to the arrangements and instrumentalities shown, wherein: 
         FIG.  1    is a schematic diagram of a system for the mass spectrometry analysis of an analyte, in a first mode of operation. 
         FIG.  2    is a schematic diagram of a system for the mass spectrometry analysis of an analyte, in a second mode of operation. 
         FIG.  3    is a schematic diagram of a first alternative system for the mass spectrometry analysis of an analyte. 
         FIG.  4    is a schematic diagram of a second alternative system for the mass spectrometry analysis of an analyte. 
         FIG.  5    is a schematic diagram of a third alternative system for the mass spectrometry analysis of an analyte. 
         FIG.  6    is a schematic diagram of a fourth alternative system for the mass spectrometry analysis of an analyte. 
         FIG.  7    is a schematic diagram of a fifth alternative system for the mass spectrometry analysis of an analyte. 
         FIG.  8 A  is a side elevation of a spray head;  FIG.  8 B  is a plan view of the spray head of  FIG.  8 A ;  FIG.  8 C  is a side elevation of an alternative spray head;  FIG.  8 D  is a plan view of the spray head of  FIG.  8 C ;  FIG.  8 E  is a side elevation of another alternative spray head;  FIG.  8 F  is a plan view of the spray head of  FIG.  8 E . 
         FIG.  9    is a schematic diagram of a system for the mass spectrometry analysis of an analyte, with droplet control devices and alternative analyte ionizing devices. 
     
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
     The system and methodology of the invention include the on-line analysis of small droplets containing analyte or single cells through the combination of droplet ejection with or without single cell isolation and capture into a continuously flowing open solvent stream (termed Rapid Droplet Introduction Interface (RDII)) mass spectrometry. 
     A droplet ejection device is used to selectively eject droplets with an analyte which can be a compound(s), single cell, or a cell suspension. The droplet ejection device should eject a droplet on demand or in a regulated fashion. The droplet(s) are then collected using an on-line, continuously flowing open solvent stream-mass spectrometry apparatus (RDII-MS). The droplet of sample analyte once exposed to the collection solvent of the RDII is diluted appropriately or lysed by osmotic forces releasing the molecular constituents of the cell. The packet of molecular material flowing with the solvent stream is subsequently ionized and detected using mass spectrometry. Molecular species can also be quantitatively analyzed using this technique with the addition of an internal standard to the liquid of the RDII. 
     A system for the mass spectrometry analysis of an analyte includes a droplet ejection device, a spray head comprising a spray tip for ejecting the solvent as a spray, and a solvent delivery conduit for delivering solvent to the spray tip. The spray head includes a droplet inlet opening communicating with the surrounding atmosphere for receiving liquid droplets comprising the analyte. The droplet ejection device selectively ejects a liquid analyte droplet comprising the analyte through a surrounding atmosphere and into the droplet inlet opening and into a solvent flowing through the solvent delivery conduit. The mass spectrometer can have an analyte inlet configured to receive a spray of the solvent containing the analyte and performing mass spectrometry or other chemical analysis on the spray of the solvent containing the analyte. 
     The system can be used with many different analytes that are suitable for mass spectrometry. The analyte droplet can contain an analyte compound(s), a cell or cell suspension. The cell can be lysed by osmotic forces upon exposure to the collection solvent, thereby releasing molecular material. The released molecular material can be for example lipids, amino acids, metabolites, dosed drugs, proteins, RNA, DNA. Other analytes are possible. 
     The droplet ejection device can be selected from many different kinds of droplet ejection devices. The droplet ejection device should be capable of controlling the release of the droplets in at least one of volume and frequency of the droplets. In one aspect, the droplet ejection device is controllable to release the droplets at the instruction of a processor. The droplet ejection device can be for example at least one selected from the group of a syringe, a pipette device, a piezoelectric droplet ejection device, direct pressure induced droplet ejection device, and an acoustic force induced droplet ejection device. Other droplet ejection devices are possible. 
     The spray tip takes solvent flowing through the solvent delivery conduit and forms the flowing solvent into an aerosol. This aerosol is directed into the chemical analysis device, such as a mass spectrometer. The spray tip can be an electrospray tip, and the electrospray tip can be electrically connected to a high voltage source. The electrospray tip can be a nanoelectrospray tip. The nanoelectrospray tip is electrically connected to a high voltage source. The system can include an inductive coil positioned near the spray tip, and the inductive coil can electrically connect to a high voltage source such that spray droplets pass through the inductive coil and are subjected to the electromagnetic field created by the inductive coil. The spray tip can be an atmospheric pressure chemical ionization spray tip. The atmospheric pressure chemical ionization system further includes a high voltage electrode positioned in a path of the spray from the spray tip to a mass spectrometer inlet. The spray tip can be an atmospheric pressure photoionization spray tip. The atmospheric pressure photoionization system can further include a photoionization light source directed so as to ionize the analyte. The ionization of the analyte can be performed by any suitable method. Other ionizing devices and processes are possible. 
     The droplet inlet opening opens in some fashion to the surrounding atmosphere such that droplets emanating from the droplet ejection device travel through the surrounding atmosphere and enter the solvent stream flowing through the solvent delivery conduit. The droplet inlet opening can take many different forms. The droplet inlet opening does not have to open directly to the surrounding atmosphere, so long as the droplet inlet opening operates at the pressure of the surrounding atmosphere and connects to a structure which connects to the surrounding atmosphere in a manner so as to receive the droplets from the droplet ejection device. The surrounding atmosphere can be ambient (room pressure) or can be at some other pressure surrounding the system such as under vacuum. 
     The solvent delivery conduit can have an opening of the solvent delivery conduit, and the droplet ejection device ejects droplets into this opening that functions as the droplet inlet opening. The droplet inlet opening can be a beveled opening in the spray tip. The droplet inlet opening can be formed by another conduit leading into the solvent delivery conduit, so long as the other conduit is open to the surrounding atmosphere. 
     The system can further include guidance apparatus for guiding the droplets into the droplet inlet opening. The guidance device can be a guidance gas stream generator. The guidance device can be a chute. The guidance device can be a funnel. The guidance device in the case of a charged solvent or analyte in the droplets emanating from the droplet ejection device can be an electromagnetic field source. The solvent supply conduit can include two spaced apart conduit segments. The space between the conduits defines the droplet inlet opening. The droplets can be transported from the droplet ejection device to the droplet inlet opening by the gravitational force. 
     The system can further include a processor for monitoring the movement of droplets from the droplet ejection device to the spray head and recording droplet data comprising the timing of the droplets. The droplet ejection device can have a droplet ejection control device. The droplet ejection control device can be responsive to control signals from the processor to release a droplet. The droplet ejection control device can be a valve or similarly acting structure which can be used to control the ejection of droplets from the droplet ejection device. 
     A method for the mass spectrometry analysis of an analyte includes the step of providing a spray head comprising a spray tip for ejecting the solvent as a spray, and a solvent delivery conduit for delivering solvent to the spray tip. The spray head further includes a droplet inlet opening for receiving liquid analyte droplets comprising the analyte from the surrounding atmosphere. A solvent is flowed through the spray head and the spray tip generates a spray that is directed to a mass spectrometer inlet. A liquid analyte droplet is selectively ejected from a droplet ejection device through the surrounding atmosphere, and the liquid analyte droplet is collected in the droplet inlet opening of the spray head. The analyte is ionized, and the solvent and the ionized analyte are transmitted to the inlet of a mass spectrometer. The analyte is detected and analyzed using mass spectrometry. 
     The method can include the step of guiding the liquid analyte droplet from the droplet ejection device to the droplet inlet opening. The guiding can be by at least one selected from the group of a gas stream, a chute, a funnel, and an electromagnetic field. 
     The method can include the step of controlling the release of liquid analyte droplets with a control device. The control device can be operated with a processor. The movement of liquid analyte droplets from the droplet ejection device to the spray head can be monitored. Droplet data comprising the timing of the liquid analyte droplets can be recorded. The liquid analyte droplet data can be combined with mass spectrometer data. 
     The solvent flow rate can vary. The solvent flow rate can be from 10 nl/min to 1 ml/min. The solvent flow rate can be 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 525, 550, 575, 600, 625, 650, 675, 700, 725, 750, 775, 800, 825, 850, 875, 900, 925, 950, 975 and 1000 nl/min, and can be within a range of any high value and low value selected from these values. 
     In general, a droplet-on-demand droplet ejection system is aligned such that the ejected droplets are collected in the droplet inlet opening. Proper solvent in the solvent delivery conduit and high voltage applied allows optimal spray conditions and lysis in case of single cells for the consecutive online mass spectrometer analysis. 
     To illustrate the analytical utility of this coupling, a commercially available single cell droplet ejection system (Single-cell Printer™, Cytena GmbH, Freiburg, Germany) was used as an external actuator to eject droplets from a cartridge filled with ˜50 μL of aqueous solution of 5 mM drug propranolol. 10 droplets (˜50 μm diameter each) were deposited into the beveled end of a 21 G×3⅛″ hypodermic needle with a 15° beveled angle (Rose GmbH, Tier, Germany), acting as the spray head. The spray head was then manually transferred in front of an ion-trap mass spectrometry system (LTQ XL, Thermo, San Jose, USA) and provided 100/0.1 methanol/formic acid solvent at a 5 μL/min flow rate through the needle. A high voltage (2.8 kV) was applied to it to create nanoelectrospray. Extracted ion chronogram of propranolol demonstrated appropriate signal from the deposited drug solution droplets. The viability was tested in an offline manner, but can work in an online manner. The throughput of the system was about 3-5 s/sample (droplet with or without a single cell), and could be further accelerated using multichannel methods with multiple probes capturing the droplets sequentially. A sampling throughput of 1 sample/s is achievable. 
     Chemical analysis of liquids or single cells often requires choosing between having sensitivity, comprehensive chemical coverage or having high sampling throughput. The benefits of the inventive system are that it provides a way to quantitatively measure the chemistry of system-generated liquid droplets or single cells in an untargeted or targeted manner with high sampling throughput and with high sensitivity. Further, no sample preparation steps are needed before analysis which significantly reduces experimental complexity and allows for the measure of cells in their native state. The inventive system is useful in many applications, such as the on-line measurement of the chemistry of single droplets generated with multiple droplet-on-demand sample introduction systems (IDOT, ECHO, SCP) with minimized sample dilution with mass spectrometric detection. The system can be used for the on-line measurement of the chemistry of single cells such as algae, bacteria, and mammalian cells, and in suspension using SCP with mass spectrometric detection. The invention can also be used with droplet ejection coupled to liquid capture for consecutive mass spectrometric, spectrophotometric, fluorimetric, and amperometric detection, as well as other forms of detection. 
     There is shown in  FIG.  1    a system  10  for mass spectrometry analysis. The system  10  includes a droplet ejection device  14 , a spray head  18 , and a mass spectrometer  22 . The droplet ejection device  14  includes a container  26  and an opening  30  for ejection of the analyte. The control device  34  can be associated with the droplet ejection device  14  to control the ejection of droplets from the opening  30 . 
     The spray head  18  includes a solvent delivery conduit  38  and a spray tip  42 . The solvent delivery conduit  38  includes open interior for the transport of solvent  46  in the direction shown by arrow  50 . The spray tip  42  comprises a droplet inlet opening communicating with the surrounding atmosphere for receiving liquid droplets comprising the analyte. The mass spectrometer  22  includes a mass spectrometer inlet assembly  58  with an inlet opening  60 . Solvent  46  flowing through the conduit  38  is formed into a spray  52  at the spray tip  42 . Particles  54  of the spray  52  enter the inlet opening  60  of the mass spectrometer  22 . 
     In operation, as shown in  FIG.  2   , droplets  66  are released by the droplet ejection device  14 . The analyte droplets are diluted in the solvent and formed into spray particles  70  along with the solvent particles  52 . Some of the analyte particles  70  enter the inlet opening  60  of the mass spectrometer  22  together with solvent spray particles  52 . The analyte particles  70  and solvent particles  52  enter the mass spectrometer inlet opening  60  as a plug generally defined by area  78 . The plug  78  is an area where there is a concentrated mixture of analyte particles  70  with solvent particles  52 . The stream of solvent particles  52  immediately in front of or downstream of the plug  78 , indicated by area  77 , and in back of or upstream of the plug  78 , indicated by area  79 , are substantially devoid of analyte particles. 
     There is shown in  FIG.  3    an alternative embodiment of a spray head  80  having a solvent delivery conduit  84  with an open end  88 . A spray tip  92  has an open end  96 . The open end  88  of the solvent delivery conduit  84  is spaced from the open end  96  of the spray tip  92  defining an opening  100  which serves as the droplet inlet opening. Solvent  104  travels through the solvent delivery conduit  84  in the direction of arrow  112  and reaches the droplet inlet opening  100  such that a portion  108  of the solvent stream  104  is exposed to the surrounding atmosphere. The analyte droplets  66  enter the exposed solvent portion  108  of the flowing solvent stream  104 . 
     The spray tip  92  has a beveled end  116  which generates a spray  120  of solvent  104 . Analyte spray particles  124  are generated as the droplets  66  are also turned into a spray. Analyte spray particles  124  enter the inlet opening  60  of the mass spectrometer  22  and are confined as a plug  132 . A portion  134  of the solvent stream immediately downstream and a portion  135  immediately upstream are substantially devoid of analyte spray particles  124 . 
     There is shown in  FIG.  4    an alternative embodiment a spray head  140 . A solvent delivery conduit  144  has a spray tip with a beveled end  148 . A solvent stream  160  flows through the solvent delivery conduit  144  in the direction of arrow  162 . An opening  156  in the solvent delivery conduit  144  exposes a portion  168  of the solvent stream  160  to the surrounding atmosphere. Droplets  66  from the droplet ejection device  14  enter the opening  156  and thereby solvent stream  160 . The solvent stream  160  at the spray tip  148  is formed into a spray  152 . Analyte spray particles  172  are also generated. Analyte particles  172  enter the inlet opening  60  of the mass spectrometer  22  as a plug  180 . A portion  182  of the solvent stream immediately downstream of the plug  180  and a portion  185  immediately upstream of the plug  180  are substantially devoid of analyte particles. 
     There is shown in  FIG.  5    an alternative embodiment of a spray head  200  with a solvent delivery conduit  204  and a spray tip in the form of a beveled end  208 . A solvent stream  212  flows through the solvent delivery conduit  204  in the direction of arrow  214  and is turned into a spray  216 . Droplets  66  from the droplet ejection device  14  are released and encounter a chute  180  having curved surface  184  which guides analyte droplets  66  to the beveled end  208 . The analyte droplets  66  are turned into analyte spray particles  220  and travel with the solvent spray  216  to the mass spectrometer  22 . Analyte particles  220  enter the inlet opening  60  the mass spectrometer  22  as a plug  228  mixed with solvent particles  216 . A portion  230  of the solvent particle stream immediately downstream and a portion  231  immediately upstream of the plug  228  are substantially devoid of analyte spray particles  220 . 
     There is shown in  FIG.  6    an alternative embodiment of a spray head  250  with a solvent delivery conduit  254  and a spray tip comprising a beveled end  258 . Solvent stream  262  moves through the solvent delivery  254  in the direction of arrow  264 . A funnel  244  receives analyte droplets  66  and directs the droplets through open interior  245  of funnel body  248  into a solvent spray  268  generated at the spray tip  258 . The analyte droplets  66  are turned into analyte spray particles  272  by the spray tip  258  and the solvent particles  268  and analyte particles  272  travel to the inlet opening  60  of the mass spectrometer  22 . Analyte spray particles  272  with the solvent spray particles  268  enter the inlet opening  60  as a plug  280 . A portion  282  of the solvent spray particles  268  immediately downstream and a portion  283  immediately upstream of the plug  280  are substantially devoid of analyte particles. 
     There is shown in  FIG.  7    an alternative embodiment of the spray head  330  having a solvent delivery conduit  334  and a spray tip comprising a beveled end  338 . A solvent stream  342  travels through the solvent delivery conduit  334  in the direction shown by arrow  346 . A funnel  300  communicates with a funnel body  302  with an open interior  304 . The funnel body  300  has a curved portion  308  and enters the solvent delivery conduit  334  at an opening  312 . A portion  316  of the funnel body  302  is within the solvent delivery conduit  334  such that droplets  66  of the analyte are directed through the funnel  300  and into the flowing solvent stream  342 . An open end  318  of the funnel  300  can be directed so as to release the droplets  66  in the direction of the solvent stream  342  indicated by arrow  346 . The solvent stream  342  is turned into a spray of solvent spray particles  350  by the spray tip  338 . The solvent droplets  66  will be also be turned into a spray of analyte spray particles  354 . The solvent spray particles  350  and analyte spray particles  354  will travel to the inlet opening  60  of the mass spectrometer  22 . Analyte spray particles  354  mixed with solvent spray particles  350  will enter the inlet opening  60  as a plug  362 . A portion  364  of the solvent spray particles  350  immediately downstream and a portion  365  immediately upstream of the plug  362  will be substantially devoid of analyte particles. 
     There is shown in  FIGS.  8 A- 8 F  different embodiments of a spray head according to the invention. There is shown in  FIGS.  8 A-B  a spray head  400  with a solvent delivery conduit  402  and a spray tip comprising a curved, beveled end  404  culminating in a point  408 . The spray head  400  has an open interior  412 . There is shown in  FIGS.  8 C- 8 D  a spray head  420  having a solvent delivery conduit  422  and a spray tip comprising a beveled end  424 . A droplet inlet opening  428  is provided and communicates with an open interior  432 . There is shown in  FIGS.  8 E- 8 F  a spray head  450  with a solvent delivery conduit  452 . The spray head  450  has a straight open end  454  and a droplet inlet opening  458 . Other spray head designs are possible. 
     There is shown in  FIG.  9    an example system  500  which shows several alternative embodiments of the invention. The system  500  includes droplet ejection device  504 , a spray head  508 , and a mass spectrometer  512 . A processor  516  can be provided to control operation of the system  500 . The droplet ejection device  504  includes an analyte container  520 , a droplet ejection opening  524 , and possibly a droplet ejection valve  528 . The droplet ejection valve  528  can be controlled by the processor  516  through a control line  532 . Sensors can be provided to monitor the injection of droplets  536 . Such a sensor can be a light source  540  and a detector  542  which are connected to the processor through a control line  544 . 
     The spray head  508  can include a solvent delivery conduit  546  which has flowing stream of solvent  548  from a suitable solvent source  550 , and flows in the direction of arrow  552 . The flow of solvent  548  from source  550  can be controlled by control line  558  communicating with the processor  516 . The spray head  508  includes a spray tip including a beveled end  556  which generates a spray of solvent spray particles  560 . The analyte droplets  536  are also converted to spray such as analyte spray particles  562 . The solvent spray particles  560  and analyte spray particles  562  are concentrated into a plug  566  which enters an inlet opening  570  of the mass spectrometer  512 . A portion of the solvent stream downstream of the plug  566  as indicated by area  568  and upstream from the plug  566  as indicated by area  569  are substantially devoid of analyte spray particles  562 . 
     The manner in which the analyte droplets  536  and subsequently the analyte spray particles  562  are ionized can vary. An electrode pin  574  can for example be positioned near to solvent spray particles  560  and analyte spray particles  562  with high voltage to create a corona discharge creating gas-phase ions which ionize analyte particles. The electrode  574  can communicate with the processor  516  through control line  576 . An inductive ring  578  can communicate with the processor  516  through a control line  580 . The solvent spray particles  560  and analyte spray particles  562  can be directed through the inductive ring  578 , whereupon the analyte particles will be ionized in the inductive field. A photoradiation source  582  can communicate with the processor  516  through control line  584 . The photoradiation source will direct radiation at the analyte particles and will directly ionize analyte particles or will ionize dopants which ionize the analyte particles. The solvent delivery conduit  546  can communicate with the processor  516  through control line  559 . The solvent delivery conduit  546  can act as an electrode with high voltage controlled by the processor  516  to ionize solvent spray particles  560  and analyte spray particles  562  by electrospray or nanoelectrospray. 
     The droplet guidance apparatus  588  can be provided and connected to the processor  516  by a control line  590 . The droplet guidance apparatus  588  can be pneumatic, electromagnetic or other or a positionable funnel or chute that can be controlled by the processor  516  through suitable actuators. 
     The invention as shown in the drawings and described in detail herein disclose arrangements of elements of particular construction and configuration for illustrating preferred embodiments of structure and method of operation of the present invention. It is to be understood however, that elements of different construction and configuration and other arrangements thereof, other than those illustrated and described may be employed in accordance with the spirit of the invention, and such changes, alternations and modifications as would occur to those skilled in the art are considered to be within the scope of this invention as broadly defined in the appended claims. In addition, it is to be understood that the phraseology and terminology employed herein are for the purpose of description and should not be regarded as limiting.