Radiant energy – Ionic separation or analysis – With sample supply means
Reexamination Certificate
2002-05-24
2004-11-02
Wells, Nikita (Department: 2881)
Radiant energy
Ionic separation or analysis
With sample supply means
Reexamination Certificate
active
06812456
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a microfluidic device, which can be interfaced to a mass spectrometer (MS). The device comprises a microchannel structure, which has a first port (inlet port) and a second port (outlet port). A sample to be analysed is applied to the first port and presented to the mass spectrometer in the second port. This second port will be called an MS-port. There may be additional inlet and outlet ports, and also additional identical or similar microchannnel structures. During passage through the microchannel structure the sample is prepared to make it suitable for analysis by mass spectrometry.
The sample presented in an MS-port will be called an MS-sample. An analyte in an MS-sample is an MS-analyte. “Sample” and “analyte” without prefix will primarily refer to a sample applied to an inlet port.
Conductive and non-conductive properties are with respect to conducting electricity.
The present invention concerns mass spectrometry in which the MS-samples are subjected to Energy Desorption/Ionisation from a surface by input of energy (EDI MS). Generically this kind of process will be called EDI and the surface an EDI-surface in the context of the invention. Typically EDIs are thermal desorption/ionisation (TDI), plasma desorption/ionisation (PDI) and various kinds of irradiation desorption/ionisation (IDI) such as by fast atom bombardment (FAB), electron impact etc. In the case a laser is used the principle is called laser desorption/ionisation (LDI). Desorption may be assisted by presenting the MS analyte together with various helper substances or functional groups on the surface. Common names are matrix assisted laser desorption/ionisation (MALDI) including surface-enhanced laser desorption/ionisation (SELDI). For MALDI see the publications discussed under Background Publications below. For SELDI see WO 0067293 (Ciphergen Biosystems).
The term “EDI-area” comprises the EDI-surface as such and the part of a substrate covered by this surface, e.g. the part of the substrate that is under the EDI-surface. Compare the description of FIG.
4
.
The term “microformat” means that in at least a part of a microchannel structure the depth and/or width is in the microformat range, i.e. <10
3
&mgr;m, preferably <10
2
&mgr;m. The depth and/or width are within these ranges essentially everywhere between an inlet port and an outlet port, e.g. between a sample inlet port and an MS-port. The term “microchannel structures” includes that the channels are enclosed in a substrate.
The term “microfluidic device” means that transport of liquids and various reagents including analytes are transported between different parts within the microchannel structures by a liquid flow.
BACKGROUND PUBLICATIONS.
For some time there has been a demand for microfluidic sample handling and preparation devices with integrated MS-ports. This kind of devices would facilitate automation and parallel experiments, reduce loss of analyte, increase reproducility and speed etc.
WO 9704297 (Karger et al) describes a microfluidic device that has an outlet port that is claimed useful when conducting electrospray ionisation mass spectrometry (ESI MS), atmospheric pressure chemical ionisation mass spectrometry (APCI MS), matrix assisted laser desorption/ionisation mass spectrometry (MALDI MS) and a number of other analytical principles.
U.S. Pat. No. 5,705,813 (Apffel et al) and U.S. Pat. No. 5,716,825 (Hancock et al) describe a microfluidic chip containing an MS-port. After processing a sample within the chip the sample will appear in the MS-port. The whole chip is then placed in an MALDI-TOF MS apparatus. The microfluidic device comprises
(a) an open ionisation surface that may be used as the probe surface in the vaccum gate of an MALDI-TOF MS apparatus (column 6, lines 53-58 of U.S. Pat. No. 5,705,813), or
(b) a pure capture/reaction surface from which the MS-analyte can be transferred to a proper probe surface for MALDI-TOF MS (column 12, lines 13-34, of U.S. Pat. No. 5,716,825).
These publications suggest that means for transporting the liquid within a microchannel structure of the device are integrated with or connected to the device. These means are electrical connections, pumps etc, which impose an extra complexity on the design and use and may negatively influence the production costs, easiness of handling etc.
Although both U.S. Pat. No. 5,705,813 (Apffel et al) and U.S. Pat. No. 5,716,825 (Hancock et al) explicitly concern microfluidic devices, they are scarce about
the proper fluidics around the MALDI ionisation surface,
the proper crystallisation on the MALDI ionisation surface,
the proper geometry of the port in relation to crystallisation, evaporation, the incident laser beam etc,
the conductive connections to the MALDI ionisation surface for MALDI MS analysis.
These features are important in order to manage with interfacing a microfluidic device to an MALDI mass spectrometer.
WO 9704297 (Karger et al) and WO 0247913 (Gyros A B) suggest a radial or spoke arrangement of the microchannel structures of a microfluidic device.
WO 9721090 (Mian et al) (page 30, lines 3-4, and page 51, line 10) and WO 0050172 (Burd Mehta) (page 55, line 14) suggest in general terms that their microfluidic systems might be used for preparing samples that are to be analysed by mass spectrometry. WO 9721090 is explicitly related to a system in which centrifugal force is used for driving the liquid flow.
A number of publications referring to the use of centrifugal force for moving liquids within microfluidic systems have appeared during the last years. See for instance WO 9721090 (Gamera Bioscience), WO 9807019 (Gamera Bioscience) WO 9853311 (Gamera Bioscience), WO 9955827 (Gyros A B), WO 9958245 (Gyros A B), WO 0025921 (Gyros A B), WO 0040750 (Gyros A B), WO 0056808 (Gyros A B), WO 0062042 (Gyros A B), WO 0102737 (Gyros A B), WO 0147637, (Gyros A B), WO 0154810 (Gyros A B), WO 0147638 (Gyros A B), WO 0146465 (Gyros A B).
U.S. Ser. No. 60/315,471 and the corresponding International Patent Application WO 02074438 discuss various designs of microfluidic functions, some of which can be applied to the present invention.
Kido et al., (“Disc-based immunoassay microarrays”, Anal. Chim. Acta 411 (2000) 1-11) has described microspot immunoassays on a compact disc (CD). The authors suggest that a CD could be used as a continuous sample collector for microbore HPLC and subsequent detection for instance by MALDI MS. In a preliminary experiment a piece of a CD manufactured in polycarbonate was covered with gold and spotted with a mixture of peptides and MALDI matrix.
OBJECTS OF THE INVENTION.
A first object is to provide improved means and methods for transporting samples, analytes including fragments and derivatives, reagents etc in microfluidic devices that are capable of being interfaced with a mass spectrometer that require energy desorption/ionisation of an MS-analyte from a surface by input of energy.
A second object is to provide improved microfluidic methods and means for sample handling before presentation of a sample analyte as an MS-analyte. Sub-objects are to provide an efficient concentration, purification and/or transformation of a sample within the microfluidic device while maintaining a reproducible yield/recovery, and/or minimal loss of precious material.
A third object is to provide improved microfluidic methods and means that will enable efficient and improved presentation of an MS-sample/MS-analyte. This object applies to MS-samples that are presented on an EDI-surface.
A fourth object is to enable reproducible mass values from an MS-sample that is presented on an EDI surface that is present in a microfluidic device
A fifth object is to provide improved microfluidic means and methods for parallel sample treatment before presentation of the MS-analyte from an EDI-surface to mass spectrometry. The improvements of this object refer to features such as accuracy in concentrating, in chemical transformation, in required time for individual steps and for the total treatment protocol etc. By parallel s
Andersson Per
Gustafsson Magnus
Hellermark Cecilia
Palm Anders
Wallenborg Susanne
Fulbright & Jaworski LLP
Gyros AB
Kalivoda Christopher M.
Wells Nikita
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