Acoustic sample introduction for analysis and/or processing

Details Acoustic sample introduction for analysis and/or processing Acoustic sample introduction for analysis and/or processing

2002-01-30

2004-03-23

Berman, Jack (Department: 2881)

Radiant energy

Ionic separation or analysis

With sample supply means

C436S180000, C422S105000, C422S063000, C435S030000, C073S864000, C073S864810

Reexamination Certificate

active

06710335

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, a capillary tube or a microfluidic device. More particularly, the invention relates to the use of nozzleless acoustic ejection to form and deliver droplets from a reservoir containing a small amount of fluid such as a microplate well, a capillary or a microfluidic device into a sample vessel for analysis and/or processing. The invention is particularly useful in mass spectrometry.
BACKGROUND
In the fields of genomics and proteomics, there is a need to manipulate, analyze and/or process minute quantities of sample materials. For example, microfluidic devices have been used as chemical analytic tools as well as means for introducing samples 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 rare. 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. Another limitation of microfluidic devices is the difficulty and expense of replicating the performance of some sophisticated chemical analytical instruments or chemical processing device within the microfluidic device. In these cases, it would be beneficial to have a method to remove a sample from the microfluidic device and load it directly into a more conventional analytical instrument or chemical reactor.
Surface wetting is a source of sample waste in other fluid delivery systems as well. For example, capillaries, Eppendorf-type or otherwise, having a small interior channel are often employed for 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 to 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 may result in a memory effect wherein spurious signals from a previous sample compromise data interpretation. In order to eliminate the memory effect, increased processing time is required to accommodate the washings between sample introductions.
Thus, there is a need in the art for techniques for manipulating minute amounts of fluids in conjunction with established analytical techniques. Mass spectrometry is a well-established analytical technique used for such analysis. In this technique, sample molecules are ionized and the resulting ions are sorted by mass-to-charge ratio. For sample 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 mass spectrometers, electrophoretic devices, and other analytical instruments. Analyzing the elemental constituents of a fluid sample may require the sample to be dispersed into a spray of small droplets or loaded in a predetermined quantity. A combination of a nebulizer and a spray chamber is commonly used for sample introduction, wherein the nebulizer produces the spray of droplets, and the droplets are then forced through a spray chamber and sorted by size and trajectory. Such droplets may be produced through a number of methods, such as those that employ ultrasonic energy and/or use a nebulizing gas. Such nebulizers, however, 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 a desired size and trajectory is low. In addition, the sample molecule may be adsorbed in the nebulizer, and large droplets may condense on the walls of the spray chamber. Such systems thus suffer 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 technique for large and/or labile biomolecules, such as nucleotidic and peptidic oligomers, polymers, and dendrimers, as well as for nonbiomolecular compounds such as fullerenes. MALDI is considered a “soft” ionizing technique in which both positive and negative ions are produced. The technique involves depositing a small volume of sample fluid containing an analyte on a substrate comprised of a photon-absorbing matrix material. The sample fluid typically contains a solvent and the analyte. Once solvent has been evaporated from the substrate, the analyte remains on the substrate at the location where the sample fluid is deposited. Photons from a laser strike the substrate at the location of the analyte and, as a result, ions and neutral molecules are desorbed from the substrate. Notably, the substrate matrix material is selected to provide enhanced desorption performance.
Surface Enhanced Laser Desoprtion Ionization (SELDI) is another example of a surface-based ionization technique that allows for high-throughput mass spectrometry. Typically, SELDI is used to analyze complex mixtures of proteins and other biomolecules. SELDI employs a chemically reactive surface such as a “protein chip” to interact with analytes, e.g., proteins, in solution. Such surfaces selectively interact with analytes and immobilize them thereon. Thus, analytes can be partially purified on the chip and then quickly analyzed in the mass spectrometer. By providing different reactive moieties at different sites on a substrate surface, throughput may be increased.
It should be evident, then, that sample preparation for surface-based ionization devices requires accurate and precise placement of carefully metered amounts of sample fluids on a substrate surface in order to reduce sample waste. Waste reduction is an important concern when sample fluids are expensive or difficult to obtain. In particular, certain biomolecular samples, e.g., nucleotidic and peptidic sample molecules, are exceptionally expensive. Thus, sample deposition on to a substrate often involves the use of small Eppendorf-type capillaries. These capillaries, of course, suffer from the disadvantages as discussed above.
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 and 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 present 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

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