WO2006084354A1 - Procede et dispositif pour depot d'echantillons - Google Patents

Procede et dispositif pour depot d'echantillons Download PDF

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Publication number
WO2006084354A1
WO2006084354A1 PCT/CA2006/000168 CA2006000168W WO2006084354A1 WO 2006084354 A1 WO2006084354 A1 WO 2006084354A1 CA 2006000168 W CA2006000168 W CA 2006000168W WO 2006084354 A1 WO2006084354 A1 WO 2006084354A1
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WO
WIPO (PCT)
Prior art keywords
deposition surface
pump
eluant
matrix
chromatographic columns
Prior art date
Application number
PCT/CA2006/000168
Other languages
English (en)
Inventor
Thomas Covey
Peter Kovarik
Original Assignee
Mds Inc., Doing Business Through It's Mds Sciex Division
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from CA002496481A external-priority patent/CA2496481A1/fr
Application filed by Mds Inc., Doing Business Through It's Mds Sciex Division filed Critical Mds Inc., Doing Business Through It's Mds Sciex Division
Priority to JP2007553430A priority Critical patent/JP2008530521A/ja
Priority to CA002592595A priority patent/CA2592595A1/fr
Priority to EP06705124A priority patent/EP1853906A4/fr
Publication of WO2006084354A1 publication Critical patent/WO2006084354A1/fr

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Classifications

    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/02—Column chromatography
    • G01N30/84—Preparation of the fraction to be distributed
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/02—Burettes; Pipettes
    • B01L3/0241—Drop counters; Drop formers
    • B01L3/0268—Drop counters; Drop formers using pulse dispensing or spraying, eg. inkjet type, piezo actuated ejection of droplets from capillaries
    • H—ELECTRICITY
    • H01—ELECTRIC ELEMENTS
    • H01J—ELECTRIC DISCHARGE TUBES OR DISCHARGE LAMPS
    • H01J49/00—Particle spectrometers or separator tubes
    • H01J49/02—Details
    • H01J49/04—Arrangements for introducing or extracting samples to be analysed, e.g. vacuum locks; Arrangements for external adjustment of electron- or ion-optical components
    • H01J49/0431—Arrangements for introducing or extracting samples to be analysed, e.g. vacuum locks; Arrangements for external adjustment of electron- or ion-optical components for liquid samples
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2400/00—Moving or stopping fluids
    • B01L2400/02—Drop detachment mechanisms of single droplets from nozzles or pins
    • B01L2400/027—Drop detachment mechanisms of single droplets from nozzles or pins electrostatic forces between substrate and tip
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2400/00—Moving or stopping fluids
    • B01L2400/04—Moving fluids with specific forces or mechanical means
    • B01L2400/0475—Moving fluids with specific forces or mechanical means specific mechanical means and fluid pressure
    • B01L2400/0487—Moving fluids with specific forces or mechanical means specific mechanical means and fluid pressure fluid pressure, pneumatics
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/02—Column chromatography
    • G01N30/84—Preparation of the fraction to be distributed
    • G01N2030/8411—Intermediate storage of effluent, including condensation on surface
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/02—Column chromatography
    • G01N30/26—Conditioning of the fluid carrier; Flow patterns
    • G01N30/38—Flow patterns
    • G01N30/46—Flow patterns using more than one column
    • G01N30/466—Flow patterns using more than one column with separation columns in parallel
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/02—Column chromatography
    • G01N30/62—Detectors specially adapted therefor
    • G01N30/72—Mass spectrometers
    • G01N30/7233—Mass spectrometers interfaced to liquid or supercritical fluid chromatograph

Definitions

  • TITLE METHOD AND APPARATUS FOR SAMPLE DEPOSITION
  • Applicant's teachings relate to a method and apparatus of sample deposition for subsequent analysis, by, for example, mass spectrometry.
  • applicant's teachings can provide high-throughput sample deposition for subsequent analysis by MALDI mass spectrometry.
  • LC Liquid chromatography
  • an organic mixture in a specific solvent eluant
  • an absorbent material onto which compounds may be absorbed.
  • the stationary phase As the eluant and the solute mixture descend through the column the more strongly absorbed compounds coat the absorbent material, referred to as the stationary phase.
  • the compounds are therefore separated based on retention times so that compounds that interact strongly with the stationary phase are retained for a longer period in the column.
  • HPLC High Performance Liquid Chromatography
  • HPLC uses a pump system to pump the eluant through the chromatography columns.
  • the pump systems typically comprise a reservoir that receives a small amount of fluid (usually solvent or water that will form the eluant) from a source.
  • a piston is operably displaceable within the reservoir to pump the fluid from the reservoir to the chromatography column.
  • the piston is typically driven by a step-motor.
  • each pump actually comprises two similar pumps operating 180° out of phase, with one of the pumps introducing a solvent and the other pump introducing, generally water, which are mixed downstream of the pumps to form the eluant that flows through the chromatography columns.
  • liquid chromatography can be used to deposit separated analytes on a target plate for subsequent analysis. These sample records can be stored for months under appropriate conditions, allowing for characterization of additional species in subsequent experiments without additional sample processing.
  • Mass spectrometry is a prevalently used analytical method that identifies molecules in compounds based on the detection of the mass-to- charge ratio of ions generated from molecules that have been electrically charged.
  • MALDI matrix-assisted laser desorption ionization
  • samples are mixed with a UV- adsorbing compound known as a matrix, deposited on a surface, and ionized with a fast laser pulse.
  • the energy of the laser is absorbed by the matrix molecules and transferred to the sample molecules, causing them to vaporize and ionize.
  • the ions are then analyzed by a mass spectrometer, such as, for example, but not limited to, a time-of-flight (TOF) mass spectrometer.
  • TOF time-of-flight
  • the applicant's teachings provide for a method of depositing a sample for analysis.
  • the method comprises flowing a suitable eluant through a chromatographic column for separating a sample, discharging from the chromatographic column the eluant with eluted separated components of the sample, the eluant forming a droplet at the discharge end of the chromatographic column, providing a suitable deposition surface spaced from the discharge end of the chromatographic column to receive the droplet, and applying a voltage to the deposition surface to pull the droplet to the deposition surface, the voltage applied to the deposition surface at a frequency generally equal to or greater than 10 Hz.
  • the voltage can be - A -
  • applicant's teachings provide for a method of depositing multiple samples for analysis.
  • the method comprises flowing suitable eluants through respective multiple chromatographic columns, each column for separating a sample, discharging from the multiple chromatographic columns the eluants with eluted separated components of the samples, the eluants forming droplets at the discharge ends of the respective chromatographic columns, providing at least one suitable deposition surface spaced from the discharge ends of the chromatographic columns to receive the droplets, and applying a voltage to the deposition surface to pull the droplets to the deposition surface, the voltage applied to the deposition surface at a frequency generally equal to or greater than 10 Hz.
  • the voltage can be applied to the deposition surface at a frequency up to and including generally 1 kHz.
  • the voltage can be applied to the deposition surface so that successive droplets are pulled to corresponding target locations on the deposition surface.
  • the deposition surface can be movable relative to the discharge end of the chromatographic column.
  • the applicant's teachings also provide for a method of depositing multiple sample for analysis, wherein the method comprises flowing suitable eluants through multiple chromatographic columns, each column for separating a sample, discharging from the multiple chromatographic columns the eluants with eluted separated components of the samples, nebulizing the discharged eluants, and depositing the nebulized eluants on at least one suitable deposition surface to produce chromatograms.
  • At least one pneumatic pump is used to flow the suitable eluant through the chromatographic column.
  • the eluant flow rate can be controlled by a flow meter in combination with a control processor, the eluant flow rate measured and controlled to provide continuous control of the flow rate.
  • the eluant flow rate is a mixture of two fluid flows, with the flow rate of each fluid flows controlled by a respective flow meter in combination with a control processor. At least one of the fluid flows can be water; the other of the fluid flows can be a solvent.
  • a plurality of pneumatic pumps can be provided, and at least one pump is associated with each respective chromatographic column.
  • a stream of non-reactive gas can nebulize the discharged eluant.
  • the non-reactive gas can be nitrogen.
  • the method can comprise introducing a matrix to the sample, where the matrix is suitable for use in matrix-assisted laser desorption ionization.
  • the matrix can be introduced to the eluants before the step of nebulizing the discharged eluants.
  • the discharged eluants can be heated.
  • the chromatograms can be continuous traces, which, in some embodiments can be parallel to one another. Moreover, each continuous trace can correspond to a discharge from a respective chromatographic column. Further, all or a portion of the chromatograms can be ionized by a laser, and the laser can produce at least one track on the continuous trace of a select chromatogram.
  • the laser can be a high-speed laser, and each chromatogram can be rastered at a constant velocity. Further in some embodiments, the multiple laser tracks can be produced on the continuous trace of the select chromatogram. Moreover, in some embodiments, multiple laser passes can be made on a single track produced on the continuous trace of a selected chromatogram.
  • Applicant's teachings also provide for an apparatus to prepare a sample for analysis.
  • the apparatus comprises a chromatographic column to receive a sample with a suitable eluant, a pump to flow the eluant through the chromatographic column, a suitable deposition surface, the deposition surface spaced from a discharge end of the chromatographic column to receive a droplet formed at the end thereof by the flow of eluant through the chromatographic column, and a power supply to generate a voltage on the deposition surface to pull the droplets to the deposition surface, the voltage applied to the deposition surface at a frequency generally equal to or greater than 10 Hz.
  • the voltage can be applied to the deposition surface at a frequency up to and including generally 1 kHz.
  • the apparatus comprises multiple chromatographic columns to receive at least one sample with a suitable eluant, a plurality of pumps, with each pump associated with each chromatographic column, the pump to flow the eluant through the chromatographic column, the pump further including a flow meter and control processor to provide continuous control of the eluant flow rate, at least one suitable deposition surface, the deposition surface spaced from multiple discharge ends of the respective chromatographic columns, the at least one suitable deposition surface to receive droplets formed at the ends thereof by the flow of eluants through the respective chromatographic columns, and at least one power supply to generate a voltage on the deposition surface to pull the droplets to the deposition surface, the voltage applied to the deposition surface at a frequency generally equal to or greater than 10 Hz.
  • the voltage can be applied to the deposition surface at a frequency up to and including generally 1 kHz.
  • the power supply can apply a voltage to the deposition surface so that successive droplets are pulled to corresponding target locations on the deposition surface.
  • the deposition surface can be movable relative to the discharge end of the chromatographic column.
  • the pump can be a pneumatically driven pressure amplifier pump.
  • the pump can comprise a flow meter and control processor to provide continuous control of the eluant flow rate.
  • the pump can comprise a pressure source sized to hold a volume of eluant greater than the volume of the chromatographic column.
  • a nebulizer can be provided to introduce a nebulizing gas to the chromatographic column, the nebulizer nebulizing the flow of eluant as it is discharged.
  • the nebulizing gas can be a non-reactive gas.
  • the non-reactive gas can be nitrogen.
  • the nebulizer can comprise a first manifold connected to the multiple chromatographic columns to introduce the nebulizing gas to the chromatographic columns, the nebulizer nebulizing the flow of eluant as it is discharged.
  • the first manifold can be connected to the multiple chromatographic columns by T-valves. Morever, the apparatus can comprise multiple deposition capillaries operably connected to the respective T-valves to discharge the nebulized eluants from the respective multiple chromatographic columns.
  • the nebulizer can comprise a pump to deliver the nebulizing gas to the multiple chromatographic columns.
  • the pump can comprise a pneumatic pump.
  • a matrix delivery system can be provided to introduce a matrix to the eluant, the matrix suitable for use in matrix-assisted laser desorption ionization.
  • the matrix delivery system can deliver the matrix to the eluant before the eluant is nebulized.
  • a matrix delivery system can be provided, the matrix delivery system including a second manifold connected to the multiple chromatographic columns, the second manifold to introduce a matrix to the eluants, the matrix suitable for use in matrix-assisted laser desorption ionization.
  • the second manifold can be connected to the multiple chromatographic columns by T-valves.
  • the second manifold can be operably connected to respective multiple chromatographic columns to deliver the matrix before the eluant is nebulized.
  • the matrix delivery system can comprise a pump to deliver the matrix to the multiple chromatographic columns.
  • the pump can be a syringe pump.
  • the pump is a continuous flow pump.
  • the apparatus can comprise a translational stage to receive the at least one depostion surface.
  • the translation stage can be displaceable relative to the multiple chromatographic columns so that the multiple chromatograms produced are in parallel to one another.
  • the at least one deposition surface can be a plurality of plates arranged in a deposition array on the translational stage.
  • Applicant's teachings also provides for an apparatus to prepare multiple samples for analysis, the apparatus comprising multiple chromatographic columns to receive at least one sample with a suitable eluant, a plurality of pumps, with each pump associated with each chromatographic column, a nebulizer to introduce a nebulizing gas to the multiple chromatographic columns, the nebulizer nebulizing the flow of eluants as they are discharged, and at least one suitable deposition surface to receive the discharged nebulized eluants, the discharged nebulized eluants from the multiple chromatographic columns producing respective multiple chromatograms on the at least one suitable deposition surface.
  • the pump can be a pneumatically driven pressure amplifier pump.
  • the pump can comprise a flow meter and control processor to provide continuous control of the eluant flow rate.
  • the pump can comprise a pressure source sized to hold a volume of eluant greater than the volume of the chromatographic column.
  • a nebulizer can be provided to introduce a nebulizing gas to the chromatographic columns, the nebulizer nebulizing the flow of eluant as it is discharged.
  • the nebulizing gas can be a non-reactive gas.
  • the non-reactive gas can be nitrogen.
  • the nebulizer can comprise a first manifold connected to the multiple chromatographic columns to introduce the nebulizing gas to the chromatographic columns, the nebulizer nebulizing the flow of eluant as it is discharged.
  • the first manifold can be connected to the multiple chromatographic columns by T-valves.
  • the apparatus can comprise multiple deposition capillaries operably connected to the respective T-valves to discharge the nebulized eluants from the respective multiple chromatographic columns.
  • the nebulizer can comprise a pump to deliver the nebulizing gas to the multiple chromatographic columns.
  • the pump can comprise a pneumatic pump.
  • a matrix delivery system can be provided to introduce a matrix to the eluant, the matrix suitable for use in matrix-assisted laser desorption ionization.
  • the matrix delivery system can deliver the matrix to the eluant before the eluant is nebulized.
  • the matrix delivery system can include a second manifold connected to the multiple chromatographic columns, the second manifold to introduce a matrix to the eluants, the matrix suitable for use in matrix-assisted laser desorption ionization.
  • the second manifold can be connected to the multiple chromatographic columns by T-valves.
  • the second manifold can be operably connected to respective multiple chromatographic columns to deliver the matrix before the eluant is nebulized.
  • the matrix delivery system can comprise a pump to deliver the matrix to the multiple chromatographic columns.
  • the pump can be a syringe pump.
  • the pump is a continuous flow pump.
  • the apparatus can comprise a translational stage to receive the at least one depostion surface.
  • the translation stage can be displaceable relative to the multiple chromatographic columns so that the multiple chromatograms produced are in parallel to one another.
  • the at least one deposition surface can be a plurality of plates arranged in a deposition array on the translational stage.
  • the apparatus can comprise at least one power supply to generate a voltage on the deposition surface to pull the droplets to the deposition surface, the voltage applied to the deposition surface at a frequency generally equal to or greater than 10 Hz.
  • the voltage can be applied to the deposition surface at a frequency up to and including generally 1 kHz.
  • the power supply can apply a voltage to the deposition surface so that successive droplets are pulled to corresponding target locations on the deposition surface.
  • the system comprises multiple chromatographic columns to receive at least one sample with a suitable eluant, a plurality of pumps, with each pump associated with each chromatographic column, a nebulizer to introduce a nebulizing gas to the multiple chromatographic columns, the nebulizer nebulizing the flow of eluants as they are discharged, at least one suitable deposition surface to receive the discharged nebulized eluants, the discharged nebulized eluants from the multiple chromatographic columns producing respective multiple chromatograms on the at least one suitable deposition surface, and at least one power supply to generate a voltage on the deposition surface to pull the droplets to the deposition surface, the voltage to be applied to the deposition surface at a frequency generally equal to or greater than 10 Hz.
  • the voltage can be applied to the deposition surface at a frequency generally equal to or greater than 10 Hz.
  • the power supply can apply a voltage to the deposition surface so that successive droplets are pulled to corresponding target locations on the deposition surface.
  • the pump to flow the eluant through the chromatographic column can comprise a flow meter and control processor to provide continuous control of the eluant flow rate.
  • the pumps can be pneumatically driven pressure amplifier pumps.
  • the pumps can further comprise a pressure source sized to hold a volume of eluant greater than the volume of the respective chromatographic column.
  • the nebulizer can comprise a first manifold connected to the multiple chromatographic columns to introduce the nebulizing gas to the respective chromatographic columns.
  • the first manifold can be connected to the multiple chromatographic columns by T-valves.
  • the system can comprise multiple deposition capillaries operably connected to respective T-valves to discharge the nebulized eluants from the respective multiple chromatographic columns.
  • the nebulizer can comprise a pump to deliver the nebulizing gas to the multiple chromatographic columns.
  • the pump can be a pneumatic pump.
  • the nebulizing gas can be a non-reactive gas.
  • the non-reactive gas can be nitrogen.
  • the system can comprise a matrix delivery system, that can include a second manifold connected to the multiple chromatographic columns, the second manifold to introduce a matrix to the eluants, the matrix suitable for use in matrix-assisted laser desorption ionization.
  • the second manifold can be connected to the multiple chromatographic columns by T-valves.
  • the second manifold can be operably connected to respective multiple chromatographic columns to deliver the matrix before the eluant is nebulized.
  • the matrix delivery system can comprise a pump to deliver the matrix to the multiple chromatographic columns.
  • the pump can be is a syringe pump.
  • the pump can be a continuous flow pump.
  • the system can comprise a translational stage to receive the at least one deposition surface, the translation stage displaceable relative to the multiple chromatographic columns so that the multiple chromatograms produced are in parallel to one another.
  • the at least one deposition surface can be a plurality of plates arranged in a deposition array on the translational stage.
  • Figures 1a and 1b are schematic views, respectively, of a single and multiplexed sample deposition apparatus of applicant's teachings
  • Figure 2 is a flow chart illustrating fluid flow to the chromatography column;
  • Figures 3a and 3b are graphs comparing a conventional flow profile to the flow profile of the fluid flow of the system illustrated in Figure 2;
  • Figure 4 is a diagram showing discrete sample deposition
  • Figures 5a and 5b are graphs comparing detectability and throughput of conventional systems to those of applicant's teachings;
  • Figure 5c is a graph of detectability of separations of minoxidil and reserpine using applicant's teachings;
  • Figure 6 is a schematic showing a delivery system for a nebulizing gas using applicant's teachings
  • Figure 7 is a schematic illustrating deposition of discharged multiple eluants to a target plate to create multiple chromatograms
  • Figure 8 is an enlarged view of a portion of a chromatogram and showing a laser track
  • Figure 9 is an enlarged view of a portion of a chromatogram and showing multiple laser tracks
  • Figure 10 is an enlarged view of a portion of a chromatogram and showing a multiple laser passes over the same laser track;
  • Figure 11 is a chart showing the reproducibility of mass spectrometry analysis of a select chromatogram when using multiple laser passes over the same laser track;
  • Figures 12a, 12b, and 12c are charts illustrating detection limit enhancements by summing multiple laser passes over the same laser track.
  • Applicant's teachings relates to a method and apparatus of sample deposition for subsequent analysis, by, for example, but not limited to, matrix-assisted laser desorption ionization (MALDI) mass spectrometry.
  • MALDI matrix-assisted laser desorption ionization
  • High Performance Liquid Chromatography (HPLC) chromatographic separation represents a rate-limiting step in any mass spectrometry based sample analysis.
  • HPLC High Performance Liquid Chromatography
  • 2-dimensional LC is becoming essential to resolve highly complex samples.
  • 10 to 100 fractions would be collected from the first separation step and each individual fraction would then be subjected to another stage of chromatography. The time required performing this analysis in a serial fashion becomes practically prohibitive unless the chromatography in the second dimension can be multiplexed.
  • the chromatographic separation step represents the analysis bottleneck and a need for multiplexed chromatographic separations followed by high speed MALDI mass spectrometry would represent a breakthrough in the discovery process.
  • FIG. 1a shows an example of a single sample deposition apparatus of applicant's teachings and Figure 1b shows an example of a multiplexed sample deposition apparatus of applicant's teachings.
  • FIG. 1a shows an example of a single sample deposition apparatus of applicant's teachings and Figure 1b shows an example of a multiplexed sample deposition apparatus of applicant's teachings.
  • Like reference characters will be used to refer to the same components in the various aspects.
  • the apparatus 10 can provide a high throughput deposition of samples to form chromatograms 12, by, for example discrete droplet deposition, as illustrated in Figures 1a and 1b, for some aspects of applicant's teachings, and, as will hereinafter be explained, as continuous traces, as illustrated in Figure 7, for some aspects of applicant's teachings.
  • the apparatus 10 includes a sample delivery system, such as, for example, but not limited to, an autosampler (not shown).
  • the delivery system simultaneously introduces a sample (not shown) with suitable eluant into a channel fluid delivery system, comprising a pumping system, shown generally at 20, to push the eluant through a chromatographic column 14 for deposition on a suitable deposition surface 16.
  • a sample not shown
  • suitable eluant into a channel fluid delivery system, comprising a pumping system, shown generally at 20, to push the eluant through a chromatographic column 14 for deposition on a suitable deposition surface 16.
  • a channel fluid delivery system comprising a pumping system, shown generally at 20
  • the eluant is pushed through a single chromatographic column 14; for some aspects, for example only, as shown in Figure 1b, the eluant is pushed through a plurality of chromatographic columns 14.
  • deposition surfaces 16 can be provided in a deposition array 22.
  • Two deposition surfaces 16 are provided in an array 22 for purposes of illustration of applicant's teachings shown in Figures 1a and 1b; four deposition surfaces 16 are provided in an array 22 for purposes of illustration for some aspects of applicant's teachings, for example only, as shown in Figure 7.
  • the deposition surfaces can be arranged in an array of n x n deposition surfaces as desired.
  • the array 22 of deposition surfaces can be provided on a translational stage 36, such as an x-y-z stage, as will hereinafter be explained. Providing an array 22 of deposition surfaces on a translational stage 36 facilitates the high throughput deposition of the chromatograms 12 for multiplexed systems shown in Figure 1b, as will hereinafter be explained.
  • At least one sample is introduced with a suitable eluant into multiple chromatographic columns 14. It can be appreciated, however, that some aspects of applicant's teachings contemplate one sample divided amongst the multiple chromatographic columns 14 to produce multiple chromatograms 12 of the same sample for analysis, as well as each chromatographic column 14 receiving a separate sample with suitable eluant, and various combinations of these as needed.
  • the pumping system 20 needs to provide precise gradients at nanoliter per minute rates and respond rapidly to flow rate changes, and particularly for each chromatographic column 14 as shown in Figure 1b.
  • a suitable pump that has these characteristics is a pneumatic pump such as a pneumatically driven pressure amplifier pump. It is to be understood however, that other pumping systems that achieve similar results are contemplated for use with applicant's teachings.
  • the pumping system 20 has a pump
  • the pumps 21 of the pumping system 20 precisely measure flow rates and control flow of the eluants through respective chromatographic columns 14. This allows the pumps 21 to quickly respond to step changes in flow rates, pump against substantial back pressures, identify leaks and blockages, and adjust flow rates accordingly in the respective chromatographic columns 14 of Figure 1b, on a one-to-one basis.
  • FIG. 2 illustrates a suitable pump 21 for various embodiments of applicant's teachings.
  • pump 21 is actually two pumps 21 A and 21 B that combine their respective fluid flows, however, for purposes of applicant's teachings, pumps 21 A and 21 B operate identically.
  • Pump 21A and 21 B feature a source 102a, 102b, respectively, of a large volume of fluid (such as solvent or water) and a discharge channel 104a, 104b, respectively, connected to the source and through which the fluid travels to the chromatographic column 14 associated with that pump.
  • the fluid can be pneumatically driven from the source 102a, 102b, where the pump 21 is a pneumatic pump, for example.
  • the fluids retained in the sources 102a, 102b are sufficient in volume to feed the respective chromatographic column 14 for the entire desired run.
  • Flow meters 106a, 106b are provided in channels 104a, 104b, respectively. Flow meters 106a, 106b measure the flow rates of the fluids through channels 104a, 104b, respectively. The fluid flow rates measured by the flow meters 106a, 106b, are monitored by control processors 108a, 108b, respectively, which then adjust the discharge of the fluids from sources 102a,
  • microfluidic flow control is precise and rapid to generate the desired flow through a given chromatographic column 14.
  • pump is precise and rapid to generate the desired flow through a given chromatographic column 14.
  • 21 can provide flow rates from 1 nl per minute to 100 ⁇ l per minute.
  • pump 21 comprises two pumps 21 A and 21 B to deliver the suitable fluids to a liquid chromatography column 14.
  • Pump 21 A for example, operates to dispense a suitable fluid, such as water, to the liquid chromatography column 14. Water can serve to both flush the column for cleaning, as well as to dilute the solvent.
  • Pump 21 B can operate to pump a suitable solvent to the liquid chromatography column 14 to effect the separation of the compounds within the column.
  • water from pump 21A is mixed in predefined amounts with solvent from pump 21 B, as at 110, to form the eluant that flows at a controlled rate by the pumps 21A 1 21 B, respectively, into the respective liquid chromatography column 14.
  • the pump system shown in Figure 2 provides extremely precise gradient control. Having regard to Figures 3a, and 3b, it can be seen that the pumps 21 A and 21 B can be adjusted very quickly to mix the flow rates and provide a very precise and steep gradient.
  • Figure 3a shows the flow profile of a pump having a discontinuous flow rate, such as a piston driven pump that generates pulses of fluid flow.
  • Line 112a illustrates the flow profile of water by such a pump
  • line 112b illustrates the flow profile of a suitable solvent from a second piston driven pump.
  • Line 112a shows that only water is initially channeled into the liquid chromatography column. After a period of time, as shown at 113, a predefined amount of solvent, as shown by line 112b, is then added to the mixture and proportionally the flow of the water is reduced over the same time so that the total flow rate of the entire system remains constant. Towards the end of the run, the amount of water introduced to the flow rate is minimal.
  • Figure 3b shows the flow profile of pump 21, which, as previously described, allows for precise measurement of the flow rates and control of the flow of the eluants through respective chromatographic columns 14.
  • Line 114a illustrates the flow profile of water by, for example, pump 21A
  • line 114b illustrates the flow profile of a suitable solvent from pump 21 B.
  • Lines 114a and 114b reveal very steep gradients compared to lines 112a and 112b of Figure 3a.
  • the adding of solvent to the mixture commences generally immediately, as shown at 115 and increases very sharply.
  • the proportionate reduction of the water flow commences generally immediately.
  • the flow rates between water and solvent as shown by lines 114a and 114b, respectively is for illustrative purposes only, and that applicant's teachings contemplates additional fluid mixtures as well.
  • Figure 3b This can be compared to the gradual commencement of fluid flow as shown at 113 for line 112b in Figure 3a, and similar gradual stopping of fluid flow as shown at 119 for line 112a in Figure 3a.
  • Figures 1a, 1b, and 4 show some aspects of applicant's teachings to collect discrete droplets of discharged eluants from respective chromatographic column 14 ( Figure 1a) or columns 14 ( Figure 1b) at high frequencies, generally equal to or greater than 10 Hz, and up to and including about 1kHz, as will hereinafter be explained.
  • the eluant from the chromatographic column 14 flows through capillary 112 to the discharge end 114 of the capillary.
  • the discharge end 114 is spaced from facing 38 of the deposition surface 16.
  • Figure 4 illustrates an exaggerated spacing of the discharge end 114 from facing 38 of the deposition surface 16. It is to be understood, however, that the discharge end 114 of the capillary 112 is much closer to facing 38 of the deposition surface 16, as illustrated in Figures 1a and 1b.
  • the deposition surface 16 can be a plate 116, such as, the target plates used in MALDI analysis, and preferably microtiter plates. But other configurations of the deposition surface may be contemplated and include, but are not limited to a disk, tape, or drum.
  • the facing 38 of the deposition surface 16 may include, but is not limited to, a metal surface consisting of stainless steel, gold, silver, chrome, nickel, aluminum, and copper.
  • the depositon surface 16, such as a target plate 116 may be removable from the array 22, for later analysis by MALDI mass spectrometry.
  • Plate 116 is typically held by suitable plate holder 118, which, in turn, can be supported by a motion table, such as a depositional array 22 (see Figure 1).
  • the depositional array 22 can be provided on a translational stage 36, such as an x-y-z stage.
  • the translational stage 36 is displaceable relative to the chromatographic column 14. It is understood that the depositional array 22, and hence the deposition surfaces 16, generally move relative to the chromatographic column 14 of Figure 1a or chromatographic columns of 14 of Figure 1b, however, alternatively the chromatographic column or columns 14 may move relative to the oppositional array 22.
  • the discharged eluant from the chromatographic column 14 forms a droplet 115 to be deposited to the deposition surface 16.
  • Applicant's teachings removes drop 115 from the discharge end 114 of the capillary 112 by providing an electric field between the deposition surface 16 and the droplet 115. This electric field acts to pull the droplet onto the deposition surface 16.
  • a suitable power supply 120 is provided to allow for adjustment of the output voltage.
  • the power supply can include electrodes that are connected to ground or zero potential.
  • the power supply is configured to energize either the deposition surface 16 or the droplet 115, to create a potential difference between the droplet and the deposition surface 16.
  • the deposition surface 16 is charged and the droplet 115 at the discharge end 114 of the capillary 112 is grounded as at 121.
  • a voltage pulse is provided to the deposition surface 16, and in this application, the voltage pulse creates a potential difference between the droplet and the deposition surface 16 to thereby pull the droplet 115 onto the deposition surface 16 and into a predesignated location, such as a well or divot 125 (see Figures 1a and 1b) provided in the facing 38 of the deposition surface 16.
  • a predesignated location such as a well or divot 125 (see Figures 1a and 1b) provided in the facing 38 of the deposition surface 16.
  • a well or divot 125 see Figures 1a and 1b
  • each of these wells or divots is an independently addressable target location and the deposition of the droplet into the suitable well or divot is controlled by a microprocessor that, controls the relative position of the deposition surface 16 relative to the droplet 115 to be deposited.
  • the voltage pulse required to create a sufficient potential difference between the droplet and the deposition surface 16 to thereby pull the droplet 115 onto the deposition surface 16 and into a predesignated location, such as a well or divot 125 (see Figures 1a and 1b) is of the order of 1 ,000 volts per 0.2 mm, or about 5,000 volts per cm. At this voltage, relays are not an option because of the switching speed and the reliability of mechanical parts.
  • the voltage requirement can be achieved by a series arrangement of FET's or IGTB's (not illustrated) that are available in ratings of up to 1 ,200 volts. This divides the voltage across a number of devices. For example, and for purposes of illustration only, two sets of five FET's or IGTB's can be used to either connect the output to a 4,000-volt power supply or ground. The maximum voltage across each device is 800 volts, well within the maximum voltage rating.
  • the devices are controlled so that they switch in unison by, for example, generating an RF signal at 8 Mhz and applying it to a coil printed on one side of the printed circuit board (not illustrated) of the FET's or IGTB's and detect this signal with another coil on the other side of the printed circuit board. This allows the control single to ride on top of whatever voltage is on the switching device.
  • Op amps (not illustrated) can be used to generate the control signals.
  • a function generator (not illustrated) can be used for the internal clock
  • a CMOS circuit (not illustrated) can be used for interlocking and application of the external pulse input.
  • the voltage pulse to the different plates can be at very high frequencies, generally equal to or greater than 10 Hz, and up to and including about 1kHz, thereby allowing extremely fast electrostatic deposition of the eluant onto the target plates of the deposition surface 16, which accommodates the high throughput of the eluant flows through the chromatographic column. Therefore an apparatus is provided that allows for a high throughput of depositing samples that can be analyzed by for example, but not limited to, MALDI mass spectrometry.
  • Figures 1a and 1b also provides a MADLI matrix delivery system 40, that operates to deliver a matrix to the eluant in capillary 112 before the eluant is discharged from the capillary 112.
  • the matrix is introduced through a load valve 41.
  • the matrix delivery system is described in greater detail below in relation to some aspects of applicant's teachings.
  • Figures 5a and 5b illustrate how the combination of the pumping system to achieve high throughput flow rates and the deposition system described, at frequencies generally equal to or greater than 10 Hz 1 and up to and including about 1 kHz, produce chromatograms that, when analyzed, produce sharper peaks in shorter run times.
  • Figure 5a illustrates signal traces of three compounds separated using conventional pumping and deposition technologies. The run times to achieve the peaks are seen to be upwards of five minutes.
  • Figure 5b shows a similar run using the pumping system and deposition techniques in accordance with the applicant's teachings.
  • the run time is seen to be less than one minute, which is five times faster than that obtained using conventional methods.
  • the samples for analysis are more concentrated resulting in sharper peaks.
  • Applicant's teachings provides a dramatic increase in throughput and detectability.
  • Figure 5c shows a signal trace from LC MADLI for the separation of minoxidil (trace 57) and reserpine (trace 59) at 20 ⁇ L/minute using the deposition described for Figures 1a and 1b and run at a rate of about 10 Hz.
  • the individual points from the discrete droplets recorded are shown in Figure 5c as at 51.
  • Figure 6 illustrates some aspects of applicant's teachings that provides for rapid and continuous sample deposition. The results from the various embodiments are also shown in Figure 5c, and are represented by the line 55 that represents a signal obtained from a continuous trace recording of the individual points from the discrete droplets recorded as at 51.
  • Figure 6 adds a nebulizer 24 to introduce a nebulizing gas to the chromatographic columns 14 to nebulize the eluants in the chromatographic columns as they are being discharged from the chromatographic columns.
  • the nebulizer gas evaporates the eluants in the chromatographic columns 14.
  • the discharged nebulized eluants are deposited onto the deposition surface 16.
  • the nebulizer gas is a non-reactive gas, and may include, but is not limited to, nitrogen, dried air, the noble gases, or any other appropriate gas. It is understood that other means to nebulize the samples are possible and are well known in the art.
  • the nebulizer 24 includes a manifold 26 connected to the chromatographic columns 14 to deliver the nebulizing gas to the eluants in the chromatographic columns 14.
  • the manifold 26 is a tubing manifold.
  • T-valves 28 connect the manifold 26 to the multiple chromatographic columns 14 to allow the introduction of the nebulizing gas to the chromatographic columns 14. Nebulizing of the eluants occurs as the eluants are discharged from the chromatographic columns 14, so, in some embodiments, the manifold 26 that delivers the nebulizer gas is connected by the T-valves 28 at or near the discharge end 30 of the chromatographic columns 14.
  • Figure 6 shows an apparatus adapted to prepare multiple chromatograms 12 for analysis by a MALDI mass spectrometer, and therefore features an additional matrix manifold, as will hereinafter be explained, between the end 30 of the chromatographic columns 14 and the T-valves 28 of the nebulizer 24.
  • the discharge end of the chromatographic columns 14 can encompass the discharge from the chromatographic columns or the discharge from, for example, a matrix delivery system, if present, or any other delivery system that could be present before the nebulizer 24.
  • the T-valves 28 of the nebulizer 24 can be operably connected at discharge end 32 to deposition capillaries 34.
  • Deposition capillaries 34 discharge the nebulized eluants from the respective multiple chromatographic columns 14 to the suitable surface 16.
  • the deposition capillaries can operate 1-5 mm from the suitable surface, which is not shown in Figure 6 for clarity.
  • the nebulizer 24 further includes a pump (not shown) to deliver the nebulizing gas to the chromatographic columns 14.
  • the pump comprises a pneumatic pump, but applicant's teachings is not intended to be limited to such a pump.
  • the discharged eluant may also be heated to accelerate desolvation by the nebluizer 24. As illustrated in Figure 6, the discharged eluant is heated by flowing, as at 27, a suitable heated gas from a source to the T-valves 28. It can be appreciated, however, that other methods and structures for heating the discharged eluants are contemplated by applicant's teachings.
  • FIG. 6 illustrates a matrix delivery system 40 for when the chromatograms 12 are analyzed by MALDI mass spectrometry.
  • the matrix delivery system 40 can include a manifold 42 connected to the chromatographic columns 14 to introduce a matrix to the eluants.
  • respective T-valves 44 connect the manifold 42 to the chromatographic columns 14.
  • the T-valves 44 can be operably connected to the chromatographic columns 14 to deliver the matrix to the eluants before the eluants are nebulized by the nebulizer 24 (see Figure 6).
  • the matrix delivery system can include a pump 60 system (illustrated schematically in Figure 2 to deliver the matrix to the load valve 41, and then through the manifold 42 and T-valves 44, to the chromatographic columns 14.
  • the pump can be, for example, a syringe pump, or alternatively, but not limited to, a continuous flow pump.
  • FIG. 2 schematically illustrates a suitable pump system 60 for delivering the matrix.
  • System 60 comprises a pump 62 featuring a source 64 of matrix and a discharge channel 66 connected to the source and through which the matrix travels to the load valve 41 and ultimately chromatographic column 14.
  • Flow meter 68 is provided in channel 66 to measure the flow rate of the matrix through channel 66.
  • the fluid flow rate measured by the flow meter 68 is monitored by a control processor 70, which adjusts the discharge of the matrix from source 64.
  • the appropriate matrix materials for use in MALDI are well known in the art. Examples of commonly used matrix materials include, but are not limited to, 2,5-dihydroxybenzoic acid derivatives, sinapinic acid derivatives, and indoleacrylic acid derivatives.
  • the nebulized eluants with eluted separated components of the samples are discharged to at least one depostion surface 16, to produce multiple chromatograms 12, as shown, for example on surface 16a.
  • the deposition array 22 can carry multiple surfaces 16 in a translation stage 36, the method can produce mutiple chromatograms simultaneously on a plurality of surfaces, and in particular surface 16a and 16b as shown in Figure 7.
  • the apparatus and method of applicant's teachings produces multiple chromatograms 12 deposited onto the suitable surfaces 16 that can be in continuous and uninterrupted traces.
  • the traces of the chromatograms 12 in Figure 7 are generally parallel to one another, it can be appreciated, however, that the continuous traces may be deposited in any line or any pattern.
  • the deposition of the chromatograms 12 can be formed in continuous, uninterrupted traces that are uniform and void of gaps.
  • the homogeneity of the continuous traces preserves an intact signal without loss of data, accuracy, and chromatographic fidelity when the chromatogram 12 is subject to analysis by MALDI mass spectrometry.
  • a select chromatogram 12 from the apparatus, as described above for Figures 1a, 1b, and 6, is ionized and then the ions analyzed by mass spectrometer (not illustrated).
  • the chromatograms are suitable for soft ionization mass spectrometry, such as, for example, but not limited to MALDI.
  • MALDI it is preferable to use a high-repetition nitrogen laser (not illustrated) to irradiate and ionize all or a portion of a select chromatogram 12.
  • each trace is rastered at a constant velocity so as to image the chromatogram at high chromatographic resolution when analyzed by mass spectrometry.
  • the laser can be operated to produce at least one track 46 on the continuous trace of a select chromatogram 12. It can be appreciated, however, that multiple laser tracks 46a, 46b, 46c, can be produced on a single continuous trace of the select chromatogram 12 — as illustrated in Figure 9. Alternatively, however, multiple laser passes can be made on a single track 47 produced on the continuous trace of a selected chromatogram 12 (see Figure 10).
  • Figure 11 shows an example of exemplary reproducibility when multiple passes are conducted on the same laser track 47 on the select chromatogram 12 (as illustrated in Figure 10).
  • the data resulting from the first, third, and fifth passes over the same track is shown over a 6 second interval.
  • Figures 12a, 12b, 12c show the detection limit enhancement by summing multiple passes over the same laser track 47 on the select chromatogram 12. For these Figures, eight single passes over the same laser track are added together. It is found that there is approximately a four times improvement in signal-to-noise ratio in comparison to a single laser pass.
  • the nebulizer can be shut-off and through use of a suitable power source 120, a voltage pulse can be applied to the deposition surface 16 so that the device is operated in electrostatic mode with extremely fast discrete droplet deposition.
  • the power source can be shut-off and a nebulizing gas can be introduced through nebulizer 24 to nebulize the eluants in the chromatographic columns that can produce a generally continuous trace.
  • a nebulizing gas can be introduced through nebulizer 24 to nebulize the eluants in the chromatographic columns that can produce a generally continuous trace.
  • the various embodiments of Figure 6 can achieve high resolution digitization by pulsing the fluid emanating from the chromatographs by applying a voltage to the target plate that operates at frequencies equal to or greater than about 10 Hz, and up to and including about 1 KHz.
  • Various embodiment of Figure 6 also allows for analogue recording (i.e., approaching infinite resolution) by nebulizing the fluid coming from the columns and simultaneously collecting it on a target plate as a continuous trace.
  • sample throughputs can be increased by recording multiple chromatograms simultaneously and to allow the individual chromatographs to be operated at high speed thereby producing sample transients that are less than one second in duration from multiple chromatographs simultaneously.
  • Recording of the transients (chromatographic peaks) in a digital fashion (spotting) requires high frequency sampling in order to retain the data integrity and in situations where sample transients (peaks) are extremely fast analogue recording may be invoked.
  • the records of such chromatograms can be read by using a mass spectrometer with, for example, MALDI ionization, or any other forms of ionization, including fast atom bombardment, secondary ion mass spectrometry (SIMS), thermal desorption with electron impact, photoionization, desorption electrospray (DESI), atmospheric pressure chemical ionization, or other means of ionizing compounds from a surface.
  • MALDI ionization or any other forms of ionization, including fast atom bombardment, secondary ion mass spectrometry (SIMS), thermal desorption with electron impact, photoionization, desorption electrospray (DESI), atmospheric pressure chemical ionization, or other means of ionizing compounds from a surface.

Abstract

Cette invention concerne un procédé et un dispositif de préparation d'un ou de plusieurs échantillons pour analyse ultérieure. Sont décrits deux dispositifs de dépôt d'échantillons, l'un simple, l'autre multiplexé. Avec ces dispositifs, le système permet de déposer des échantillons à cadence élevée pour la formation de chromatogrammes par dépôt séparé de gouttelettes ou sous forme de traces continues. Ce système rend possible une numérisation à haute résolution par pulsation du fluide provenant des chromatographes, avec application à la plaque cible d'une tension sous des fréquences égales ou supérieures à 10 Hz environ, et jusqu'à environ 1 KHz. Le système autorise également un enregistrement analogue (c'est-à-dire proche d'une résolution infinie) par nébulisation du fluide provenant de colonnes multiples et collecte simultanée dudit fluide sur une plaque cible sous forme de trace continue.
PCT/CA2006/000168 2005-02-08 2006-02-08 Procede et dispositif pour depot d'echantillons WO2006084354A1 (fr)

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JP2007553430A JP2008530521A (ja) 2005-02-08 2006-02-08 サンプルの沈着の方法および装置
CA002592595A CA2592595A1 (fr) 2005-02-08 2006-02-08 Procede et dispositif pour depot d'echantillons
EP06705124A EP1853906A4 (fr) 2005-02-08 2006-02-08 Procede et dispositif pour depot d'echantillons

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US65136205P 2005-02-08 2005-02-08
US60/651,362 2005-02-08
CA002496481A CA2496481A1 (fr) 2005-02-08 2005-02-09 Methode et dispositif de depot d'echantillon
CA2,496,481 2005-02-09
US65120305P 2005-02-10 2005-02-10
US60/651,203 2005-02-10

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