Radiant energy – Ionic separation or analysis – With sample supply means
Reexamination Certificate
2001-02-14
2003-08-05
Berman, Jack (Department: 2881)
Radiant energy
Ionic separation or analysis
With sample supply means
C436S180000, C422S105000, C422S063000, C435S030000, C073S864000, C073S864810
Reexamination Certificate
active
06603118
ABSTRACT:
TECHNICAL FIELD
This invention relates generally to devices and methods for introducing a small quantity of a fluid sample into a sample vessel such as an ionization chamber or a capillary tube. More particularly, the invention relates to nozzleless acoustic ejection to form and deliver ionized droplets for mass spectrometry.
BACKGROUND
In the field of genomics and proteomics, there is a need for analytical techniques that allow for compositional analysis of minute quantities of sample materials. Mass spectrometry is a well-established analytical technique for such analysis. Mass spectrometry operates through ionization of analyte molecules and sorting the molecules by mass-to-charge ratio. For analyte molecules contained in a fluid sample, the sample fluid is typically converted into an aerosol that undergoes desolvation, vaporization, atomization, excitation and ionization in order to form analyte ions.
For fluid samples, sample introduction is a critical factor that determines the performance of analytical instrumentation such as mass spectrometers or electrophoretic devices. Analyzing the elemental constituents of a fluid sample generally requires the sample to be dispersed into a spray of small droplets or loaded in a predetermined quantity. Often, a combination of a nebulizer and a spray chamber is used in sample introduction, wherein the nebulizer produces the spray of droplets, and the droplets are then forced through a spray chamber and sorted. Such droplets may be produced through a number of methods such as those that employ ultrasonic energy and/or use a nebulizing gas. However, such nebulizers provide little control over the distribution of droplet size and no meaningful control over the trajectory of the droplets. As a result, the yield of droplets having an appropriate size and trajectory is low. In addition, the analyte molecule may be adsorbed in the nebulizer, and large droplets may condense on the walls of the spray chamber. As a result, the combination suffers from low analyte transport efficiency and high sample consumption.
Mass spectrometry has also been employed for samples that have been prepared as an array of features on a substrate. Matrix-Assisted Laser Desorption Ionization (MALDI) for example, is an ionization techniques for large and/or labile biomolecules such as nucleotidic and peptidic oligomers, polymers and dendrimers as well as non-biomolecular compounds such as fullerenes. In MALDI, a small volume of sample fluid is deposited on a photon-absorbing substrate and allowed to dry. Once solvent has been evaporated from the substrate, a laser strikes the target, and then ions and neutrals are desorbed. The substrate greatly increases the desorption performance and is considered a “soft” ionizing technique in which both positive and negative ions are produced. Surface Enhanced Laser Desoprtion Ionization (SELDI) is another surface-based ionization technique that allows for high-throughput mass spectrometry. It should be evident, then, that sample preparation for such a device requires accurate and precise placement of carefully metered amounts of sample fluids on a substrate surface in order to reduce sample waste. Often, sample deposition on to a substrate involves the use of small Eppendorf-type capillaries.
Currently, microfluidic devices have been used as chemical analysis tools as well as a means for introducing sample into clinical diagnostic tools. Their small channel size allows for the analysis of minute quantities of sample, which is an advantage where the sample is expensive or difficult to obtain. In particular, certain biomolecular samples, e.g., nucleotidic and peptide analyte molecules, are exceptionally expensive. However, microfluidic devices suffer from a number of unavoidable design limitations and drawbacks with respect to sample handling. For example, the flow characteristics of fluids in the small flow channels of a microfluidic device often differ from the flow characteristics of fluids in larger devices, as surface effects come to predominate and regions of bulk flow become proportionately smaller. Thus, in order to control sample flow, the surfaces of such devices must be adapted according to the particular sample to provide motive force to drive the sample through the devices. This means that a certain amount of sample waste must occur due to wetting of the device surfaces.
Surface wetting is a source of sample waste in other fluid delivery systems as well. For example, capillaries having a small interior channel for fluid transport are often employed in sample fluid handling by submerging their tips into a pool of sample. In order to provide sufficient mechanical strength for handling, such capillaries must have a large wall thickness as compared to the interior channel diameter. Since any wetting of the exterior capillary surface results in sample waste, the high wall thickness/channel diameter ratio exacerbates sample waste. In addition, the sample pool has a minimum required volume driven not by the sample introduced into the capillary but rather by the need to immerse the large exterior dimension of the capillary. As a result, the sample volume required for capillary submersion may be more than an order of magnitude larger than the sample volume transferred into the capillary. Moreover, if more than one sample is introduced into a capillary, the previously immersed portions of the capillary surface must be washed between sample transfers in order to eliminate cross contamination. Cross contamination in the context of mass spectrometry results in a memory effect wherein spurious signals from a previous sample compromises data interpretation. In order to eliminate the memory effect, then, increased processing time is required to accommodate the washings between sample introductions.
Accordingly, it is desired to provide a device that requires only small volumes of sample to effect efficient sample delivery into analytical devices such as mass spectrometers or capillaries, that does not lead to compromised analysis due to the above-described memory effect, and that does not require long washing times.
A number of patents have proposed different techniques for sample ionization and delivery. For example, U.S. Pat. No. 5,306,412 to Whitehouse et al. describes an apparatus that applies mechanical vibrations to an outlet port of an electrospray tip to enhance electrostatic dispersion of sample solutions into small, highly charged droplets resulting in the production of ions of solute species for mass spectrometric analysis. The technology disclosed in this patent purports to overcome the problems associated with use of inkjet technology for sample ionization and delivery. The patent discloses that due to plugging problems with nozzle orifices smaller than about 10 &mgr;m, the techniques used in inkjet printing are not practical for the production of droplets in the size range required for efficient ion production in the mass spectrometric analysis of solutions. In addition, it is also disclosed that a single small orifice diameter associated with inkjet printers would not be effective over the flow rates associated with sample introduction in electrospray mass spectrometry. Like other electrospray systems, the described apparatus is disclosed to produce droplets of appropriate size but lacks control over the droplet trajectory as they depart from the electrospray tip.
A number of patents have described the use of acoustic energy in printing. For example, U.S. Pat. No. 4,308,547 to Lovelady et al. describes a liquid drop emitter that utilizes acoustic principles in ejecting liquid from a body of liquid onto a moving document for forming characters or bar codes thereon. Lovelady et al. is directed to a nozzleless inkjet printing apparatus wherein controlled drops of ink are propelled by an acoustical force produced by a curved transducer at or below the surface of the ink. In contrast to inkjet printing devices, nozzleless fluid ejection devices as described in the aforementioned patent are not subject to clogging and the
Ellson Richard N.
Mutz Mitchell W.
Berman Jack
Picoliter Inc.
Reed Dianne E.
Reed & Eberle LLP
Wu Louis L.
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