US20020019060A1 - Device for analyzing a fluid sample - Google Patents
Device for analyzing a fluid sample Download PDFInfo
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- US20020019060A1 US20020019060A1 US09/970,434 US97043401A US2002019060A1 US 20020019060 A1 US20020019060 A1 US 20020019060A1 US 97043401 A US97043401 A US 97043401A US 2002019060 A1 US2002019060 A1 US 2002019060A1
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- chamber
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- lysing
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- 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
- B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
- B01L3/502—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
- B01L7/00—Heating or cooling apparatus; Heat insulating devices
- B01L7/52—Heating or cooling apparatus; Heat insulating devices with provision for submitting samples to a predetermined sequence of different temperatures, e.g. for treating nucleic acid samples
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N1/00—Microorganisms, e.g. protozoa; Compositions thereof; Processes of propagating, maintaining or preserving microorganisms or compositions thereof; Processes of preparing or isolating a composition containing a microorganism; Culture media therefor
- C12N1/06—Lysis of microorganisms
- C12N1/066—Lysis of microorganisms by physical methods
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N13/00—Treatment of microorganisms or enzymes with electrical or wave energy, e.g. magnetism, sonic waves
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
- B01L2200/00—Solutions for specific problems relating to chemical or physical laboratory apparatus
- B01L2200/10—Integrating sample preparation and analysis in single entity, e.g. lab-on-a-chip concept
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
- B01L2300/00—Additional constructional details
- B01L2300/06—Auxiliary integrated devices, integrated components
- B01L2300/0627—Sensor or part of a sensor is integrated
- B01L2300/0654—Lenses; Optical fibres
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
- B01L2300/00—Additional constructional details
- B01L2300/06—Auxiliary integrated devices, integrated components
- B01L2300/0681—Filter
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
- B01L2300/00—Additional constructional details
- B01L2300/08—Geometry, shape and general structure
- B01L2300/0809—Geometry, shape and general structure rectangular shaped
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
- B01L2300/00—Additional constructional details
- B01L2300/08—Geometry, shape and general structure
- B01L2300/0861—Configuration of multiple channels and/or chambers in a single devices
- B01L2300/087—Multiple sequential chambers
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- 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
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- 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
- B01L2400/06—Valves, specific forms thereof
- B01L2400/0622—Valves, specific forms thereof distribution valves, valves having multiple inlets and/or outlets, e.g. metering valves, multi-way valves
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- 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
- B01L2400/06—Valves, specific forms thereof
- B01L2400/0633—Valves, specific forms thereof with moving parts
- B01L2400/0644—Valves, specific forms thereof with moving parts rotary valves
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10S435/00—Chemistry: molecular biology and microbiology
- Y10S435/81—Packaged device or kit
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10S436/00—Chemistry: analytical and immunological testing
- Y10S436/805—Optical property
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10S436/00—Chemistry: analytical and immunological testing
- Y10S436/806—Electrical property or magnetic property
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10S436/00—Chemistry: analytical and immunological testing
- Y10S436/807—Apparatus included in process claim, e.g. physical support structures
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10S436/00—Chemistry: analytical and immunological testing
- Y10S436/807—Apparatus included in process claim, e.g. physical support structures
- Y10S436/809—Multifield plates or multicontainer arrays
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10S436/00—Chemistry: analytical and immunological testing
- Y10S436/829—Liposomes, e.g. encapsulation
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
- Y10T137/00—Fluid handling
- Y10T137/8593—Systems
- Y10T137/877—With flow control means for branched passages
- Y10T137/87708—With common valve operator
- Y10T137/87716—For valve having a flexible diaphragm valving member
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
- Y10T137/00—Fluid handling
- Y10T137/8593—Systems
- Y10T137/87917—Flow path with serial valves and/or closures
- Y10T137/88046—Biased valve with external operator
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
- Y10T436/00—Chemistry: analytical and immunological testing
- Y10T436/25—Chemistry: analytical and immunological testing including sample preparation
- Y10T436/25375—Liberation or purification of sample or separation of material from a sample [e.g., filtering, centrifuging, etc.]
- Y10T436/255—Liberation or purification of sample or separation of material from a sample [e.g., filtering, centrifuging, etc.] including use of a solid sorbent, semipermeable membrane, or liquid extraction
Abstract
The present invention provides a cartridge for analyzing a fluid sample. The cartridge provides for the efficient separation of cells or viruses in the sample from the remaining sample fluid, lysis of the cells or viruses to release the analyte (e.g., nucleic acid) therefrom, and optionally chemical reaction and/or detection of the analyte. The cartridge is useful in a variety of diagnostic, life science research, environmental, or forensic applications for determining the presence or absence of one or more analytes in a sample.
Description
- This application is a divisional of U.S. application Ser. No. 09/583,807 filed May 30, 2000 which application is a continuation in part of U.S. application Ser. No. 09/331,911 filed Jun. 25, 1999. This application and U.S. application Ser. No. 09/583,807 claim priority from provisional application Ser. No. 60/136,703 filed May 28, 1999. All of the above-referenced applications are incorporated by reference herein for all purposes.
- The present invention relates generally to the field of biochemical analysis, and in particular to a cartridge for analyzing a fluid sample.
- The analysis of clinical or environmental fluid samples generally involves a series of chemical, optical, electrical, mechanical, or thermal processing steps on the samples. In recent years, there has been growing interest in developing disposable cartridges for conducting analyses of biological samples for various diagnostic and monitoring purposes. For example, U.S.
Patent 5,587,128 to Wilding discloses devices for amplifying a preselected polynucleotide in a sample by conducting a polynucleotide amplification reaction. U.S. Pat. No. 5,922,591 to Anderson et al. describes a miniaturized, integrated nucleic acid diagnostic device and system. The device is generally capable of performing one or more sample acquisition and preparation operations, in combination with one or more sample analysis operations. - Prior fluidic cartridges for processing fluid samples have focused on picoliter, nanoliter, and microliter sample volumes. These small sample volumes are not practical for many realistic diagnostic applications. Of special interest is the detection of target analytes (e.g., nucleic acid) that exist in low concentrations in many samples. For example, in detecting infectious diseases, gram negative bacteria can be present at less than 10 copies per milliliter of blood, cryptosporidium generally appears as only a few copies per gallon of drinking water, concentrated biothreat agents (e.g., anthrax) at less than 100 copies per milliliter of water, and food poisoning agents, such asE. coli and salmonella, may be manifested in less than 10 copies per gram of food.
- The present invention provides a device for analyzing a fluid sample to determine the presence or absence of an analyte in the sample. The device comprises a cartridge for separating a desired analyte from the sample and for holding the analyte for chemical reaction and optical detection. The present invention also provides an instrument that receives the cartridge for sample processing. The desired analyte is typically intracellular material (e.g., nucleic acid, proteins, carbohydrates, lipids, bacteria, or intracellular parasites). In a preferred use, the analyte is nucleic acid which the cartridge separates from the fluid sample and holds for amplification (e.g., using PCR) and optical detection.
- In a preferred embodiment, the cartridge is used with a transducer to separate an analyte from a fluid sample. The cartridge has a sample port for introducing a sample into the cartridge, and a sample flow path extending from the sample port. The cartridge also has a lysing chamber in the sample flow path. The lysing chamber contains at least one filter for capturing cells or viruses from the sample as the sample flows through the lysing chamber. The lysing chamber is defined by at least one wall having an external surface for contacting the transducer to sonicate the lysing chamber. Beads may optionally be disposed in the lysing chamber for rupturing the cells or viruses as the chamber is sonicated. The cartridge also includes a waste chamber in fluid communication with the lysing chamber via the sample flow path for receiving the remaining sample fluid after the sample flows through the lysing chamber. The cartridge further includes a third chamber connected to the lysing chamber via an analyte flow path for receiving the analyte separated from the sample. The third chamber is preferably a reaction chamber for chemically reacting and optically detecting the analyte. The cartridge also includes at least one flow controller (e.g., valves) for directing the sample into the waste chamber after the sample flows through the lysing chamber and for directing the analyte separated from the sample into the third chamber. The design of the cartridge permits the efficient processing of large sample volumes to enable the accurate detection of low concentration analytes.
- FIG. 1 is an isometric view of a cartridge for analyzing a fluid sample according to a first embodiment of the invention.
- FIG. 2 is a lower isometric view of the cartridge of FIG. 1.
- FIG. 3 is an exploded view of the cartridge of FIG. 1.
- FIG. 4 is another exploded view of the cartridge of FIG. 1.
- FIG. 5 is a partially cut away view of an ultrasonic horn coupled to a wall of a lysing chamber formed in the cartridge of FIG. 1.
- FIG. 6 is an exploded view of a filter stack positioned in the lysing chamber of the cartridge of FIG. 1.
- FIG. 7 is a top plan view of the cartridge of FIG. 1.
- FIG. 8 is a bottom plan view of the cartridge of FIG. 1.
- FIG. 9 is a schematic block diagram of the cartridge of FIG. 1.
- FIG. 10 is an isometric view of an instrument into which the cartridge of FIG. 1 is placed for processing.
- FIG. 11 is an isometric view of the cartridge of FIG. 1 in the instrument of FIG. 10.
- FIG. 12 is a partially cut-away view of the cartridge of FIG. 1 in the instrument of FIG. 10.
- FIG. 13 is a schematic, plan view of optical sensors positioned to detect liquid levels in the cartridge of FIG. 1.
- FIG. 14 is a partially cut away, schematic, side view of a slotted optical sensor positioned to detect the liquid level in a sensor chamber of the cartridge of FIG. 1.
- FIG. 15A is a cross-sectional view of a portion of the body of the cartridge of FIG. 1 illustrating two different types of valves in the cartridge.
- FIG. 15B is a cross-sectional view of the valves of FIG. 15A in a closed position.
- FIG. 16A is another cross-sectional view of one of the valves of FIG. 15A in an open position.
- FIG. 16B is a cross-sectional view of the valve of FIG. 16A in a closed position.
- FIGS.17-19 illustrate a valve actuation system for opening and closing the valves of FIG. 15A.
- FIG. 20 is a cross sectional view of alternative valve actuators for opening and closing the valves in the cartridge of FIG. 1. FIG. 20 also shows a pressure delivery nozzle sealed to a pressure port formed in the cartridge of FIG. 1.
- FIG. 21 is a partially exploded, isometric view of a reaction vessel of the cartridge of FIG. 1.
- FIG. 22 is a front view of the vessel of FIG. 21.
- FIG. 23 is a side view of the vessel of FIG. 21 inserted between two heater plates.
- FIG. 24 is a front view of one of the heater plates of FIG. 23.
- FIG. 25 is a front view of an alternative reaction vessel according to the present invention.
- FIG. 26 is a front view of another reaction vessel according to the present invention.
- FIG. 27 is another front view of the vessel of FIG. 21.
- FIG. 28 is a front view of the vessel of FIG. 21 inserted into a heat-exchanging module of the instrument of FIG. 10.
- FIG. 29 is an exploded view of a support structure for holding the plates of FIG. 23.
- FIGS.30-31 are assembled views of the support structure of FIG. 29.
- FIG. 32 is an isometric view showing the exterior of one the optics assemblies in the heat-exchanging module of FIG. 28.
- FIG. 33 is an isometric view of the plates of FIG. 23 in contact with the optics assembly of FIG. 32.
- FIG. 34 is a partially cut away, isometric view of the reaction vessel of FIG. 21 inserted between the plates of FIG. 23. only the lower portion of the vessel is included in the figure.
- FIG. 35 is a schematic block diagram of the electronics of the heat-exchanging module of FIG. 28.
- FIG. 36 is an isometric view of an apparatus for disrupting cells or viruses according to another embodiment of the invention.
- FIG. 37 is a cross sectional view of the apparatus of FIG. 36.
- FIG. 38 is an exploded view of a container used in the apparatus of FIG. 36.
- FIG. 39 is a cross sectional view of the container of FIG. 38.
- FIG. 40 is a schematic block diagram of a fluidic system incorporating the apparatus of FIG. 36.
- FIG. 41 is a cross sectional view of another container for use in the apparatus of FIG. 36. An ultrasonic horn is in contact with a wall of the container that curves outwardly towards the horn.
- FIG. 42 is a cross-sectional view of the wall of FIG. 41.
- FIGS.43A-43B are isometric views of opposite sides of another wall suitable for use in a container for holding cells or viruses to be disrupted.
- FIG. 44 is a partially cut-away, isometric view of a container incorporating the wall of FIGS.43A-43E;.
- FIG. 45 is a bottom plan view of the container of FIG. 44.
- The present invention provides an apparatus and method for analyzing a fluid sample. In a first embodiment, the invention provides a cartridge for separating a desired analyte from a fluid sample and for holding the analyte for a chemical reaction. The fluid sample may be a solution or suspension. In a particular use, the sample may be a bodily fluid (e.g., blood, urine, saliva, sputum, seminal fluid, spinal fluid, mucus, or other bodily fluids). Alternatively, the sample may be a solid made soluble or suspended in a liquid or the sample may be an environmental sample such as ground or waste water, soil extracts, pesticide residues, or airborne spores placed in a fluid. Further, the sample may be mixed with one or more chemicals, reagents, diluents, or buffers. The sample may be pretreated, for example, mixed with chemicals, centrifuged, pelleted, etc., or the sample may be in a raw form.
- The desired analyte is typically intracellular material (e.g., nucleic acid, proteins, carbohydrates, lipids, bacteria, or intracellular parasites). In a preferred use, the analyte is nucleic acid which the cartridge separates from the fluid sample and holds for amplification (e.g., using PCR) and optical detection. As used herein, the term “nucleic acid” refers to any synthetic or naturally occurring nucleic acid, such as DNA or RNA, in any possible configuration, i.e., in the form of double-stranded nucleic acid, single-stranded nucleic acid, or any combination thereof.
- FIG. 1 shows an isometric view of a
cartridge 20 according to the preferred embodiment. Thecartridge 20 is designed to separate nucleic acid from a fluid sample and to hold the nucleic acid for amplification and detection. Thecartridge 20 has a body comprising atop piece 22, amiddle piece 24, and abottom piece 26. An inlet port for introducing a fluid sample into the cartridge is formed in thetop piece 22 and sealed by acap 30. Sixpressure ports 32 are also formed in thetop piece 22. Thepressure ports 32 are for receiving nozzles from pressure sources, e.g., pumps or vacuums. The cartridge also includesalignment legs 28 extending from thebottom piece 26 for positioning thecartridge 20 in an instrument (described below with reference to FIG. 10). Indentations ordepressions middle pieces cartridge 20. Thecartridge 20 further includesvents - FIG. 2 is an isometric view showing the underside of the
cartridge 20. Nineholes 60 are formed in thebottom piece 26 for receiving valve actuators that open and close valves in thecartridge 20. Ahole 62 is also formed in thebottom piece 26 for receiving a transducer (described in detail below with reference to FIG. 5). Thecartridge 20 also includes areaction vessel 40 extending outwardly from the body of the cartridge. Thevessel 40 has areaction chamber 42 for holding a reaction mixture (e.g., nucleic acid mixed with amplification reagents and fluorescent probes) for chemical reaction and optical detection. One of the flow paths in the cartridge carries the reaction mixture to thechamber 42 for chemical reaction and optical detection. Thevessel 40 extends outwardly from the body of thecartridge 20 so that thevessel 40 may be inserted between a pair of opposing thermal plates (for heating and cooling the chamber 42) without the need for decoupling thevessel 40 from the rest of thecartridge 20. This greatly reduces the risk of contamination and/or spilling. Thevessel 40 may be integrally formed with the body of the cartridge (e.g., integrally molded with middle piece 24). It is presently preferred, however, to produce thevessel 40 as a separate element that is coupled to the body during manufacture of the cartridge. - FIGS.3-4 show exploded views of the cartridge. As shown in FIG. 3, the
middle piece 24 has multiple chambers formed therein. In particular, themiddle piece 24 includes asample chamber 65 for holding a fluid sample introduced through theinlet port 64, awash chamber 66 for holding a wash solution, areagent chamber 67 for holding a lysing reagent, awaste chamber 68 for receiving used sample and wash solution, aneutralizer chamber 70 for holding a neutralizer, and amaster mix chamber 71 for holding a master mix (e.g., amplification reagents and fluorescent probes) and for mixing the reagents and probes with analyte separated from the fluid sample. Thesample chamber 65 optionally includes aside compartment 155 having slightly lower walls than thesample chamber 65. Theside compartment 155 is for visually indicating to a user when sufficient sample has been added to thesample chamber 65, i.e., when the liquid level in thechamber 65 is high enough to spill over into thecompartment 155. - The
top piece 22 includes thevents pressure ports 32, as previously described. An elastomeric membrane orgasket 61 is positioned and squeezed between thepieces middle piece 24 preferably includes multiple sealing lips to ensure that thegasket 61 forms an adequate seal. In particular, themiddle piece 24 preferably includes sealinglips 73 surrounding each of thechambers middle piece 24 also includessupport walls 75 around the perimeter, andintermediate sealing lips 76. The sealinglips support walls 75 locally compress thegasket 61 and achieve a seal. - As shown in FIG. 4, the
middle piece 24 has formed in its underside various channels, one of which leads to a lysingchamber 86. Thechamber 86 is aligned with thehole 62 in thebottom piece 26 so that a transducer (e.g., an ultrasonic horn) may be inserted through thehole 62 to generate pressure waves in the lysingchamber 86. Themiddle piece 24 also has ninevalve seats 84 formed in its bottom surface. The valve seats 84 are aligned with the nineholes 60 in thebottom piece 26 so that valve actuators may be inserted through theholes 60 into the valve seats 84. - An elastomeric membrane or
gasket 61 is positioned and squeezed between thepieces middle piece 24. Themiddle piece 24 preferably includes multiple sealing lips to ensure that thegasket 63 forms an adequate seal. In particular, themiddle piece 24 preferably includes sealinglips 73 surrounding the lysingchamber 86, valve seats 84, and various channels. Themiddle piece 24 also includessupport walls 75 around its perimeter, andintermediate sealing lips 76. The sealinglips support walls 75 locally compress thegasket 63 and achieve a seal. In addition to sealing various channels and chambers, thegasket 63 also functions as a valve stem by compressing, when actuated through one of theholes 60, into acorresponding valve seat 84, thus shutting one of the flow channels in themiddle piece 24. This valve action is discussed in greater detail below with reference to FIGS. 15-16. - The
gasket 63 also forms the bottom wall of the lysingchamber 86 against which a transducer is placed to effect disruption of cells or viruses in thechamber 86. Each of thegaskets gaskets - As shown in FIG. 3, the
middle piece 24 includes aslot 79 through which thereaction vessel 40 is inserted during assembly of the cartridge. Thevessel 40 has twofluid ports top piece 22 is sealed to themiddle piece 24 via thegasket 61, theports channels gasket 61 seals the respective fluidic interfaces between theports channels bottom pieces bottom pieces pieces - FIG. 4 also shows a
filter ring 88. Thefilter ring 88 compresses and holds a stack of filters in the lysingchamber 86. FIG. 6 shows an exploded view of afilter stack 87. The purpose of thefilter stack 87 is to capture cells or viruses from a fluid sample as the sample flows through the lysingchamber 86. The captured cells or viruses are then disrupted (lysed) in thechamber 86. The cells may be animal or plant cells, spores, bacteria, or microorganisms. The viruses may be any type of infective agents having a protein coat surrounding an RNA or DNA core. - The
filter stack 87 comprises agasket 93, a first filter 94, agasket 95, a second filter 97 having a smaller pore size than the first filter 94, agasket 98, athird filter 100 having a smaller pore size than the second filter 97, agasket 101, awoven mesh 102, and agasket 103. The filter stack also preferably includes a first set ofbeads 96 disposed between the first and second filters 94 and 97 and a second set ofbeads 99 disposed between the second andthird filters 97 and 100. Thefilter ring 88 compresses thefilter stack 87 into the lysingchamber 86 so that thegasket 93 is pressed against the filter 94, the filter 94 is pressed against thegasket 95, thegasket 95 is pressed against the filter 97, the filter 97 is pressed against thegasket 98, thegasket 98 is pressed against thefilter 100, thefilter 100 is pressed against thegasket 101, thegasket 101 is pressed against themesh 102, themesh 102 is pressed against thegasket 103, and thegasket 103 is pressed against the outer perimeter of the bottom wall of the lysingchamber 86. Thegasket 95 is thicker than the average diameter of thebeads 96 so that the beads are free to move in the space between the filters 94 and 97. Similarly, thegasket 98 is thicker than the average diameter of thebeads 99 so that thebeads 99 are free to move in the space between thefilters 97 and 100. A fluid sample flowing through thechannel 106 into the lysingchamber 86 first flows through filter 94, then through filter 97, next throughfilter 100, and lastly through themesh 102. After flowing through thefilter stack 87, the sample flows alongflow ribs 91 formed in the top of the lysingchamber 86 and through an outlet channel (not shown in FIG. 6). - Referring to FIG. 5, the cells or viruses captured in the filter stack (not shown in FIG. 5 for illustrative clarity) are lysed by coupling a transducer92 (e.g., an ultrasonic horn) directly to the wall of the lysing
chamber 86. In this embodiment, the wall of the lysingchamber 86 is formed by theflexible gasket 63. Thetransducer 92 should directly contact an external surface of the wall. The term “external surface” is intended to mean a surface of the wall that is external to the lysingchamber 86. Thetransducer 92 is a vibrating or oscillating device that is activated to generate pressure waves in thechamber 86. The pressure waves agitate thebeads 96, 99 (FIG. 6), and the movement of the beads ruptures the captured cells or viruses. In general, the transducer for contacting the wall of the lysingchamber 86 may be an ultrasonic, piezoelectric, magnetostrictive, or electrostatic transducer. The transducer may also be an electromagnetic device having a wound coil, such, as a voice coil motor or a solenoid device. It is presently preferred that the actuator be an ultrasonic transducer, such as an ultrasonic horn. Suitable horns are commercially available from tonics & Materials, Inc. having an office at 53 Church Hill, Newton, Connecticut 06470-1614 USA. Alternatively, the ultrasonic transducer may comprise a piezoelectric disk or any other type of ultrasonic transducer that may be coupled to the container. It is presently preferred to use an ultrasonic horn because the horn structure is highly resonant and provides for repeatable and sharp frequency of excitation and large motion of the horn tip. - As previously described in FIG. 6, the filter stack includes a gasket at both of its ends. As shown in FIG. 5, the
middle cartridge piece 24 has a sealinglip 90 against which the gasket at one end of the filter stack is compressed. The gasket at the other end of the filter stack is compressed by thefilter ring 88 to form a seal. The gasket material may expand into the relief area outside of the sealinglip 90. The width of the sealinglip 90 is small (typically 0.5 mm) so that an excessive amount of force is not required to achieve a sufficient seal. - The
filter ring 88 is held between the filter stack and thecartridge gasket 63. Thecartridge gasket 63 is held between themiddle piece 24 and thebottom piece 26 by a sealinglip 406. Force is therefore transferred from thebottom piece 26 through thegasket 63 to thefilter ring 88 and finally to the filter stack. Thefilter ring 88 contains acontact lip 404 that contacts thegasket 63. Thecontact lip 404 is not a primary sealing lip (though it will seal) but a force transfer mechanism. The width of thecontact lip 404 is larger than the width of the sealinglip 90 to ensure that deformation and sealing action occurs in the filter stack and not taken up in squeezing thecartridge gasket 63. Thecartridge middle piece 24 also has a sealinglip 406 that surrounds thefilter ring 88. This is an active sealing area that should not be compromised by the presence of thefilter ring 88. For this reason, there is agap 407 between the sealinglip 406 and thecontact lip 404 on thefilter ring 88. Thegap 407 is provided to allow thegasket 63 to extrude into thegap 407 as it is compressed by the sealinglip 406 and thecontact lip 404. If thecontact lip 404 comes to a different elevation than the sealinglip 406, the seal will not be compromised because of thegap 407 and the distance between thelips - Referring again to FIG. 6, the
filter stack 87 is effective for capturing cells or viruses as a fluid sample flows through thestack 87 without clogging of any of thefilters 94, 97, 100 in the stack. The first filter 94 (having the largest pore size) filters out coarse material such as salt crystals, cellular debris, hair, tissue, etc. The second filter 97 (having the medium pore size) captures cells or viruses in the fluid sample. The third filter 100 (having the smallest pore size) captures smaller cells or viruses in the sample. Thefilter stack 87 thus enables the simultaneous capture of differently sized sample components without clogging of the filters. The average pore size of the first filter 94 is selected to be small enough to filter coarse material from the fluid sample (e.g., salt crystals, cellular debris, hair, tissue) yet large enough to allow the passage of the target cells or viruses containing the desired analyte (e.g., nucleic acid or proteins). In general, the pore size of the first filter 94 should be in the range of about 2 to 25 μm, with a presently preferred pore size of about 5 μm. - The average pore sizes of the second and third filters are selected in dependence upon the average size of the target cells or viruses that contain the desired analyte(s). For example, in one embodiment, the
filter stack 87 is used to capture gonorrhea (GC) and chlamydia (Ct) organisms to determine the presence of the diseases in the fluid sample. The GC and Ct: organisms have different average diameters, about 1 to 2 μm for GC organisms and about 0.3 μm for Ct organisms. In this embodiment, the second filter 97 has an average pore size of about 1.2 μm while thethird filter 100 has an average pore size of about 0.22 μm so that most of the GC organisms are captured by the second filter 97 while most of the Ct organisms are captured by thethird filter 100. The filter stack thus enables the simultaneous capture of differently sized target organisms and does so without clogging of the filters. The pore sizes of thefilters 97, 100 may be selected to capture desired cells or viruses of any size, and the scope of the invention is not limited to the specific example given. - The
filter stack 87 is also useful for disrupting the captured cells or viruses to release the intracellular material (e.g., nucleic acid) therefrom. The first and second sets ofbeads chamber 86. Suitable beads for rupturing cells or viruses include borosilicate glass, lime glass, silica, and polystyrene beads. - The beads may be porous or non-porous and preferably have an average diameter in the range of 1 to 200 μm. The average diameter of the
beads beads 96 in the first set may be equal to the average diameter of thebeads 99 in the second set. Alternatively, when the first set ofbeads 96 is used to rupture a type of target cell or virus that differs from the type of cell or virus to be ruptured by the second set ofbeads 99, it is advantageous to select the average diameter of the beads such that the average diameter of thebeads 96 in the first set differs from the average diameter of thebeads 99 in the second set. For example, when the filter stack is used to capture GC and Ct cells as described above, thebeads 96 are 20 μm diameter borosilicate glass beads for rupturing the GC organisms and thebeads 99 are 106 μm diameter soda lime glass beads for rupturing the Ct organisms. Each of thesilicone gaskets beads - The
mesh 102 also serves two useful purposes. First the mesh provides support to thefilter stack 87. Second, the mesh breaks up air bubbles so that the bubbles can be channeled through theflow ribs 91 and out of the lysingchamber 86. To effectively break up or reduce the size of the air bubbles, themesh 102 preferably has a small pore size. Preferably, it is a woven polypropylene mesh having an average pore size of about 25 μm. To ensure that the air bubbles can escape from the lysingchamber 86, it is desirable to use the cartridge in an orientation in which liquid flows up (relative to gravity) through thefilter stack 87 and the lysingchamber 86. The upward flow through thechamber 86 aids the flow of air bubbles out of thechamber 86. Thus, the inlet port for entry of fluids into thechamber 86 should generally be at the lowest point in the chamber, while the exit port should be at the highest. - Many different embodiments of the filter stack are possible. For example, in one alternative embodiment, the filter stack has only two filters and one set of beads disposed between the filters. The first filter has the largest pore size (e.g., 5 μm) and filters out coarse material such as salt crystals, cellular debris, hair, tissue, etc. The second filter has a pore size smaller than the first filter and slightly smaller than the target cells or viruses to be captured. Such a filter stack is described below with reference to FIG. 38. In another embodiment of the cartridge, the filter having the largest pore size (for filtering the coarse material) is positioned in a filter chamber (not shown) that is positioned upstream of the lysing
chamber 86. A channel connects the filter chamber to the lysingchamber 86. In this embodiment, a fluid sample flows first through the coarse filter in the filter chamber and then through a second filter in the lysing chamber to trap the target cells or viruses in the lysing chamber. - Further, the beads in the filter stack may have a binding affinity for target cells or viruses in the fluid sample to facilitate capture of the target cells or viruses. For example, antibodies or certain receptors may be coated onto the surface of the beads to bind target cells in the sample. Moreover, the lysing
chamber 86 may contain two different types of beads for interacting with target cells or viruses. For example, the lysing chamber may contain a first set of beads coated with antibodies or receptors for binding target cells or viruses and a second set of beads (intermixed with the first set) for rupturing the captured cells or viruses. The beads in the lysingchamber 86 may also have a binding affinity for the intracellular material (e.g., nucleic acid) released from the ruptured cells or viruses. Such beads are useful for isolating target nucleic acid for subsequent elution and analysis. For example, the lysing chamber may contain silica beads to isolate DNA or cellulose beads with oligo dT to isolate messenger RNA for RT-PCR. The lysingchamber 86 may also contain beads for removing unwanted material (e.g., proteins, peptides) or chemicals (e.g., salts, metal ions, or detergents) from the sample that might inhibit IPCR. For example, thechamber 86 may contain ion exchange beads for removing proteins. Alternatively beads having metal ion chelators such as iminodiacetic acid will remove metal ions from biological samples. - FIGS.21-22 illustrate the
reaction vessel 40 in greater detail. FIG. 21 shows a partially exploded view of thevessel 40, and FIG. 22 shows a front view of thevessel 40. Thevessel 40 includes the reaction chamber 42 (diamond-shaped in this embodiment) for holding a reaction mixture. Thevessel 40 is designed for optimal heat transfer to and from the reaction mixture and for efficient optical viewing of the mixture. The thin shape of the vessel contributes to optimal thermal kinetics by providing large surfaces for thermal conduction and for contacting thermal plates. In addition, the walls of the vessel provide optical windows into thechamber 42 so that the entire reaction mixture can be optically interrogated. In more detail to FIGS. 21-22, thereaction vessel 40 includes arigid frame 46 that defines theside walls reaction chamber 42. Theframe 46 also defines aninlet port 41 and achannel 50 connecting theport 41 to thechamber 42. Theframe 46 also defines anoutlet port 43 and achannel 52 connecting theport 43 to thechamber 42. Theinlet port 41 andchannel 50 are used to add fluid to thechamber 42, and thechannel 52 andoutlet port 43 are used for exit of fluid from thechamber 42. Alignment prongs 44A, 44D are used to position thevessel 40 correctly during assembly of the cartridge. - As shown in FIG. 21, the
vessel 40 also includes thin, flexible sheets attached to opposite sides of therigid frame 46 to form opposingmajor walls 48 of the chamber. (Themajor walls 48 are shown in FIG. 1 exploded from therigid frame 46 for illustrative clarity). Thereaction chamber 42 is thus defined by therigid side walls frame 46 and by the opposingmajor walls 48. The opposingmajor walls 48 are sealed to opposite sides of theframe 46 such that theside walls major walls 48 to each other. Thewalls 48 facilitate optimal thermal conductance to the reaction mixture contained in thechamber 42. Each of thewalls 48 is sufficiently flexible to contact and conform to a respective thermal surface, thus providing for optimal thermal contact and heat transfer between the thermal surface and the reaction mixture contained in thechamber 42. Furthermore, theflexible walls 48 continue to conform to the thermal surfaces if the shape of the surfaces changes due to thermal expansion or contraction during the course of the heat-exchanging operation. - As shown in FIG. 23, the thermal surfaces for contacting the
flexible walls 48 are preferably formed by a pair of opposingplates chamber 42 between them. When thechamber 42 of thevessel 40 is inserted between theplates 190A, 190DB, the inner surfaces of the plates contact thewalls 48 and the flexible walls conform to the surfaces of the plates. The plates are preferably spaced a distance from each other equal to the thickness T of thechamber 42 as defined by the thickness of theframe 46. In this position, minimal or no gaps are found between the plate surfaces and thewalls 48. The plates may be heated and cooled by various thermal elements to induce temperature changes within thechamber 42, as is described in greater detail below. - The
walls 48 are preferably flexible films of polymeric material such as polypropylene, polyethylene, polyester, or other polymers. The films may either be layered, e.g., laminates, or the films may be homogeneous. Layered films are preferred because they generally have better strength and structural integrity than homogeneous films. In particular, layered polypropylene films are presently preferred because polypropylene is not inhibitory to PCR. Alternatively, thewalls 48 may comprise any other material that may be formed into a thin, flexible sheet and that permits rapid heat transfer. For good thermal conductance, the thickness of eachwall 48 is preferably between about 0.003 to 0.5 mm, more preferably between 0.01 to 0.15 mm, and most preferably between 0.025 to 0.08 mm. - Referring again to FIG. 22, the
vessel 40 also preferably includes optical windows for in situ optical interrogation of the reaction mixture in thechamber 42. In the preferred embodiment, the optical windows are theside walls rigid frame 46. Theside walls chamber 42 through theside wall 57A and detection of light emitted from thechamber 42 through theside wall 57B. Arrows A represent illumination beams entering thechamber 42 through theside wall 57A and arrows B represent emitted light (e.g., fluorescent emission from labeled analytes in the reaction mixture) exiting thechamber 42 through theside wall 57B. - The
side walls walls wall 57A will exit throughwall 57B. In addition, the 90° angle permits a maximum amount of emitted light (e.g. fluorescence) to be collected throughwall 57B. Thewalls chamber 42. Alternatively, theangled walls walls chamber 42, such as an integrated capillary electrophoresis area. In the presently preferred embodiment, a locatingtab 58 extends from theFrame 46 below the intersection ofwalls tab 58 is used to properly position thevessel 40 in a heat-exchanging module described below with reference to FIG. 28. - Optimum optical sensitivity may be attained by maximizing the optical path length of the light beams exciting the labeled analyte in the reaction mixture and the emitted light that is detected, as represented by the equation:
- I o /I i =C*L*A,
- where Io is the illumination output of the emitted light in volts, photons or the like, C is the concentration of analyte to be detected, Ii is the input illumination, L is the path length, and A is the intrinsic absorptivity of the dye used to label the analyte.
- The thin,
flat reaction vessel 40 of the present invention optimizes detection sensitivity by providing maximum optical path length per unit analyte volume. Referring to FIGS. 23 and 27, thevessel 40 is preferably constructed such that each of thesides walls chamber 42 has a length L in the range of 1 to 15 mm, the chamber has a width W in the range of 1.4 to 20 mm, the chamber has a thickness T in the range of 0.5 to 5 mm, and the ratio of the width W of the chamber to the thickness T of the chamber is at least 2:1. These parameters are presently preferred to provide a vessel having a relatively large average optical path length through the chamber, i.e. 1 to 15 mm on average, while still keeping the chamber sufficiently thin to allow for extremely rapid heating and cooling of the reaction mixture contained therein. The average optical path length of thechamber 42 is the distance from the center of theside wall 57A to the center of thechamber 42 plus the distance from the center of thechamber 42 to the center of theside wall 57B. - More preferably, the
vessel 40 is constructed such that each of thesides walls chamber 42 has a length L in the range of 5 to 12 mm, the chamber has a width W in the range of 7 to 17 mm, the chamber has a thickness T in the range of 0.5 to 2 mm, and the ratio of the width W of the chamber to the thickness T of the chamber is at least 4:1. These ranges are more preferable because they provide a vessel having both a larger average optical path length (i.e., 5 to 12 mm) and a volume capacity in the range of 12 to 100 μl while still maintaining a chamber sufficiently thin to permit extremely rapid heating and cooling of a reaction mixture. The relatively large volume capacity provides for increased sensitivity in the detection of low concentration analytes, such as nucleic acids. - In the preferred embodiment, the
reaction vessel 40 has a diamond-shapedchamber 42 defined by theside walls frame 46, and the chamber has a volume capacity of about 100 μl. This reaction vessel provides a relatively large average optical path length of 10 mm through thechamber 42. Additionally, the thin chamber allows for extremely rapid heating and/or cooling of the reaction mixture contained therein. The diamond-shape of thechamber 42 helps prevent air bubbles from forming in the chamber as it is filled with the reaction mixture and also aids in optical interrogation of the mixture. - Referring again to FIG. 22, the
frame 46 is preferably made of an optically transmissive material, e.g., a polycarbonate or clarified polypropylene, so that theside walls transmissive walls transmissive side walls chamber 42, or to collect as much fluorescence signal from as large a fraction of the chamber volume as possible. In alternative embodiments, the optical elements may comprise gratings for selecting specific wavelengths, filters for allowing only certain wavelengths to pass, or colored lenses to provide filtering functions. The wall surfaces may be coated or comprise materials such as liquid crystal for augmenting the absorption of certain wavelengths. In the presently preferred embodiment, the opticallytransmissive walls - The
side walls chamber 42 through theside walls frame 46 defines open spaces between theside walls support ribs 53. The open spaces are occupied by ambient air that has a different refractive index than the material composing the frame (e.g., plastic). Due to the difference in the refractive indexes, the reflective faces 56 are effective for internally reflecting light trying to exit the chamber through thewalls walls transmissive side walls chamber 42, and the retro-reflective side walls - A preferred method for fabricating the
reaction vessel 40 will now be described with reference to FIGS. 21-22. Thereaction vessel 40 may be fabricated by first molding therigid frame 46 using known injection molding techniques. Theframe 46 is preferably molded as a single piece of polymeric material, e.g., clarified polypropylene. After theframe 46 is produced, thin, flexible sheets are cut to size and sealed to opposite sides of theframe 46 to form themajor walls 48 of thechamber 42. Themajor walls 48 are preferably cast or extruded films of polymeric material, e.g., polypropylene films, that are cut to size and attached to theframe 46 using the following procedure. A first piece of film is placed over one side of theframe 46. Theframe 46 preferably includes atack bar 47 for aligning the top edge of the film. The film is placed over the bottom portion of theframe 46 such that the top edge of the film is aligned with thetack bar 47 and such that the film completely covers the bottom portion of theframe 46 below thetack bar 47. The film should be larger than the bottom portion of theframe 46 so that it may be easily held and stretched flat across the frame. The film is then cut to size to match the outline of the frame by clamping to the frame the portion of the film that covers the frame and cutting away the portions of the film that extend past the perimeter of the frame using, e.g., a laser or die. The film is then tack welded to the frame, preferably using a laser. - The film is then sealed to the
frame 46, preferably by heat sealing. Heat sealing is presently preferred because it produces a strong seal without introducing potential contaminants to the vessel as the use of adhesive or solvent bonding techniques might do. Heat sealing is also simple and inexpensive. The heat sealing may be performed using, e.g., a heated platen. An identical procedure may be used to cut and seal a second sheet to the opposite side of theframe 46 to complete thechamber 42. Many variations to this fabrication procedure are possible. For example, in an alternative embodiment, the film is stretched across the bottom portion of theframe 46 and then sealed to the frame prior to cutting the film to size. After sealing the film to the frame, the portions of the film that extend past the perimeter of the frame are cut away using, e.g., a laser or die. - Although it is presently preferred to mold the
frame 46 as a single piece, it is also possible to fabricate the frame from multiple pieces. For example, theside walls side walls frame 46. Theflexible walls 48 may then be attached to opposite sides of theframe 46 as previously described. - Referring again to FIG. 3, it is presently preferred to use a
gasket 61 to seal theports vessel 40 to correspondingchannels 80, 81 (FIG. 4) in the cartridge body. Alternatively, fluidic seals may be established using a luer fitting, compression fitting, or swaged fitting. In another embodiment, the cartridge body and frame of thevessel 40 are molded as a single part, and the flexible major walls of the vessel are heat-sealed to opposite sides of the frame. - Referring again to FIG. 22, the
chamber 42 is filled by forcing liquid (e.g., a reaction mixture) to flow through theport 41 and thechannel 50 into thechamber 42. The liquid may be forced to flow into thechamber 42 using differential pressure (i.e., either pushing the liquid through theinlet port 41 or aspirating the liquid by applying a vacuum to the outlet port 43). As the liquid fills thechamber 42, it displaces air in the chamber. The displaced air exits thechamber 42 through thechannel 52 and theport 43. For optimal detection of analyte in thechamber 42, the chamber should not contain air bubbles. To help prevent the trapping of air bubbles in thechamber 42, the connection between thechamber 42 and theoutlet channel 52 should be at the highest point (with respect to gravity) in thechamber 42. This allows air bubbles in thechamber 42 to escape without being trapped. Thus, thevessel 40 is designed to be used in the vertical orientation shown in FIG. 22. - FIG. 25 shows another
vessel 206 designed to be used in a horizontal orientation. Thevessel 206 has aninlet port 41 and aninlet channel 50 connecting theinlet port 41 to the bottom of thechamber 42. The vessel also has anoutlet port 43 and anoutlet channel 50 connecting theoutlet port 43 to the top of thechamber 42. Thus, any air bubbles in thechamber 42 may escape through theoutlet channel 52 without becoming trapped. FIG. 26 shows anothervessel 207 having twoinlet ports outlet port 43.Inlet channels respective inlet ports chamber 42, and outlet.channel 52 connects thechamber 42 tooutlet port 43. Many other different embodiments of the vessel are also possible. In each embodiment, it is desirable to evacuate thechamber 42 from the highest point (with respect to gravity) in the chamber and to introduce liquid into the chamber from a lower point. - FIGS.15A-15B illustrate two types of valves used in the cartridge. As shown in FIG. 15A, there are two types of fundamental concepts to the valve action, and hence two types of valves. The first valve uses a cone-shaped or
conical valve seat 160 formed in themiddle cartridge piece 24. Thevalve seat 160 is a depression, recess, or cavity molded or machined in themiddle piece 24. Thevalve seat 160 is in fluid communication with achamber 167 through a port orchannel 157 that intersects the center of theconical valve seat 160. As shown in FIG. 15B, avalve actuator 164 having a spherical surface is forced against theelastic membrane 63 and into thevalve seat 160, establishing a circular ring of contact between themembrane 63 and thevalve seat 160. The kinematic principle is that of a ball seated into a cone. The circular seal formed by themembrane 63 andvalve seat 160 prevents flow between the channel 157 (and hence the chamber 167) and aside channel 158 extending from a side of thevalve seat 160. Theside channel 158 is defined by themembrane 63 and themiddle cartridge piece 24. - As shown in FIG. 15A, the other type of valve controls the cross flow between the
channel 158 and anotherside channel 159 formed between themembrane 63 and themiddle cartridge piece 24. In this case, a circular ring of contact would be ineffective. Instead, the second valve comprises a recess depression orcavity 161 formed in themiddle cartridge piece 24. Thecavity 161 separates thechannels channel 158 is positioned on one side of thecavity 161, and an end of thechannel 159 is positioned on the opposite side of thecavity 161. Thecavity 161 is defined by a first,curved surface 162A positioned adjacent the end of thechannel 158, a secondcurved surface 162B positioned adjacent the end of thechannel 159, and athird surface 163 between the first and secondcurved surfaces membrane 63 to seal off the flow between thechannels valve seats - As shown in FIG. 16A, the first and second
curved surfaces valve actuator 164 has also has a spherical surface for pressing themembrane 63 tightly against thesurfaces surfaces valve actuator 164 plus the thickness T of themembrane 63. - For example, if the radius of curvature R2 of the surface of the
valve actuator 164 is 0.094 inches and themembrane 63 has a thickness T of 0.031 inches, then the radius of curvature R1 of each of thesurfaces - As shown in FIG. 16B, the
third surface 163 is recessed from the first andsecond surfaces gap 166 between themembrane 63 and thethird surface 163 when themembrane 63 is pressed against the first andsecond surfaces surfaces surface 163. Thegap 166 ensures that themembrane 63 contacts primarily the valve seats 162A, 162B rather than the entire surface of thecavity 161 so that maximum pressure is applied to thevalve seats membrane 63. This provides a very strong seal with minimal actuator force required. - Referring again to FIG. 15B, in both types of valves the respective kinematic principle defines the location of the mating parts. In both the ball-in-cone concept and the ball-against-two-spherical-surfaces concept, the ball or spherical shaped valve actuator is permitted to seek its own location as it is forced against the valve seat(s). There is a deliberate clearance (e.g., 0.01 to 0.03 inches) between the valve actuator and the hole in the
bottom cartridge piece 26 in which theactuator 164 travels so that only the valve seat action defines the location of the mating pieces. - The valve actuators can be controlled by a variety of mechanisms. FIGS.17-19 illustrate one such mechanism. As shown in FIG. 17, a
valve actuator 172 has a spherical surface for pressing thegasket 63 into a valve seat. Theactuator 172 also has aflange 177 on its bottom portion. The cartridge includes an elastic body, such as aspring 174, that pushes against a ledge in thelower cartridge piece 26 to bias the valve actuator against thegasket 63. Thespring 174 is sufficiently strong to close the valve unless a deliberate force is applied to pull down theactuator 172. The valves in the cartridge may be kept closed in this manner for shipping and storage before the cartridge is used. Thus, the cartridge may be preloaded during manufacture with the necessary reagents and wash solutions to analyze a fluid sample without the fluids leaking out of the cartridge during shipping and storage. - The actuator pull-down mechanism is usually located in an instrument into which the cartridge is placed for sample analysis (one such instrument is described in detail below with reference to FIG. 10). The mechanism comprises a sliding
guide 175 that rotates a hinged pull-down member 180 having ajaw 181 for receiving theflange 177 of theactuator 172. As shown in FIG. 18, the slidingguide 175 rotates the hinged pull-down member 180 until theflange 177 is positioned within thejaw 181. As shown in FIG. 19, asolenoid 146 pulls down themember 180 and thus thevalve actuator 172 so that thegasket 63 is released from the valve seat, thus opening the valve and permitting fluid flow between thechannels - FIG. 20 illustrates the manner in which fluid flow into and out of the sample chamber, wash chamber, neutralizer chamber, and reagent chambers is controlled in the cartridge. Each of these chambers, as illustrated by a
chamber 414 in FIG. 20, is covered by ahydrophobic membrane 410 that allows the passage of gas but not liquid therethrough. Thehydrophobic membrane 410 is positioned between thechamber 414 and apressure port 32. Thepressure port 32 is formed in theupper cartridge piece 22 and positioned over thechamber 414. Themembrane 410 holds liquids in thechamber 414 during shipping and storage of the cartridge, even if the cartridge is turned upside down. Thepressure port 32 is sized to receive apressure nozzle 182 that is connected to a pressure source (e.g., a vacuum or pneumatic pump) usually located in the external instrument. Thenozzle 182 includes an o-ring 184 and aflange 415. Aspring 185 pushes against theflange 415 to force thenozzle 182 into thepressure port 32 so that the o-ring 184 establishes a seal around theport 32. In operation, positive air pressure or a vacuum is applied to thechamber 414 through thepressure port 32 to force liquids out of or into, respectively, thechamber 414. - A conical valve seat160 (previously described with reference to FIGS. 15A-15B) is formed in the
middle cartridge piece 24 below thechamber 414 to control the flow of liquid between thechamber 414 and a connectingchannel 411. The valve is opened and closed by avalve actuator 188 having aflange 187 and aspring 188 pressing against the flange to hold the valve closed until a downward force is applied to theactuator 186. The downward force is preferably supplied by a solenoid that pulls down theactuator 186 to open the valve. Thevalve actuator 186 and solenoid are preferably located in the instrument. - FIGS.7-8 show top and bottom plan views, respectively, of the cartridge. FIG. 9 is a schematic block diagram of the cartridge. As shown in any of FIGS. 7-9, the cartridge includes a
sample chamber 65 having a port for adding a fluid sample to the cartridge and a sample flow path extending from thesample chamber 65. The sample flow path extends from thesample chamber 65 through avalve 107 and into achannel 106. Thechannel 106 includes asensor region 136 in which thechannel 106 has a flat bottom enabling easy optical detection of the presence of liquid in the channel. The sample flow path continues from thechannel 106 into the lysingchamber 86 and through thefilter stack 87. The sample flow path also includes achannel 109 for exit of fluid from the lysingchamber 86, achannel 110 having a flat-bottomeddetection region 137, avalve 111, and achannel 112 leading to the ventedwaste chamber 68 through avalve 114. - The cartridge also includes the
wash chamber 66 for holding wash solution and thereagent chamber 67 for holding lysing reagent. Thewash chamber 66 is connected to the lysingchamber 86 through avalve 115,channel 117, andchannel 106. Thereagent chamber 67 is connected to the lysingchamber 86 through avalve 119,channel 117, andchannel 106. Sample components (e.g., cells or viruses in the sample) are captured in thefilter stack 87 and lysed in thechamber 86 to release target analyte (e.g., nucleic acid) from the sample components. The cartridge also includes an analyte flow path extending from the lysingchamber 86 for carrying the analyte separated from the fluid sample to thereaction vessel 40 for chemical reaction and optical detection. The analyte flow path extends from thechamber 86 through thechannel 109,channel 110, andvalve 111. After passing through thevalve 111, the analyte flow path diverges from the sample flow path. While the sample flow path extends thoughchannel 112 into thewaste chamber 68, the analyte flow path diverges into theU-shaped channel 122. The analyte flow path then extends into and out of theneutralizer chamber 70 through avalve 124. The analyte flow path also passes into and out of themaster mix chamber 71 through avalve 126. From themaster mix chamber 71, the analyte flow path extends along the channel L22, through avalve 127, throughchannel 80, and into thereaction vessel 40 through theport 41. - The
reaction vessel 40 includes theport 41 for adding a reaction mixture to the vessel, and theport 43 for exit of fluids (e.g., air or excess reaction mixture) from the vessel. The cartridge also includeschannel 81 in fluid communication with theport 43. Thechannel 81 includes a flat-bottomeddetection region 130 for detecting the presence of liquid in the channel. Thechannel 81 connects to a channel 131 (channel 131 extends straight down perpendicular to the page in the top plan view of FIG. 7).Channel 131 connects to achannel 132 which in turn connects to achannel 134 through a valve 133 (channel 134 extends straight up perpendicular to the page in the top plan view of FIG. 7). Thechannel 134 leads to thevent 36 which has a hydrophobic membrane to permit the escape of gas but not liquid from the cartridge. The channels, vent and valve positioned downstream from thereaction vessel 40 are used to pressurize thechamber 42 of the vessel, as is described in the operation section below. - The cartridge also includes a
first pressure port 105 positioned above thesample chamber 65, asecond pressure port 116 positioned above thewash chamber 66, athird pressure port 118 positioned above thereagent chamber 67, afourth pressure port 123 positioned above theneutralizer chamber 70, afifth pressure port 125 positioned above themaster mix chamber 71, and asixth pressure port 128 positioned at the end of theU-shaped channel 122. The cartridge further includessensor chambers waste chamber 68. Thesensor chambers waste chamber 68, as is described in detail below. - Referring to FIG. 10, the cartridge is preferably used in combination with an
instrument 140 designed to accept one or more of the cartridges. For clarity of illustration, theinstrument 140 shown in FIG. 10 accepts just one cartridge. It is to be understood, however, that the instrument may be designed to process multiple cartridges simultaneously. Theinstrument 140 includes acartridge nest 141 into which the cartridge is placed for processing. Theinstrument 140 also includes the transducer 92 (e.g., an ultrasonic horn) for generating pressure waves in the lysing chamber of the cartridge, ninevalve actuators 142 for actuating the nine valves in the cartridge, nine correspondingsolenoids 146 for pulling down the valve actuators, and sixispressure nozzles 145 for interfacing with six corresponding pressure ports formed in the cartridge. In addition, the instrument includes or is connected to one or more regulated pressure sources for supplying pressure to the cartridge through thepressure nozzles 145. Suitable pressure sources include syringe pumps, compressed air sources, pneumatic pumps, or connections to external sources of pressure. The instrument further includes three slottedoptical sensors 143 and three reflectiveoptical sensors 144. - FIG. 13 illustrates the slotted
optical sensors 143 positioned to detect liquid in thesensor chambers reagent chamber 67. Eachsensor 143 includes a built in LED and photodiode positioned on opposite sides of the sensor. The LED emits a beam that is detected by the photodiode if the beam is not substantially refracted. Such slotted optical sensors are commercially available from a number of suppliers. The cartridge is shaped so that the slotted optical sensors fit around thechambers optical sensors 143 are therefore useful for determining the presence or absence of liquid in thechambers - FIG. 14 shows a cut-away, schematic side view of the
sensor chamber 120 in fluid communication with thewaste chamber 68 and surrounded by the slottedoptical sensor 143. Thesensor chamber 120 andsensor 143 are used to indicate when a predetermined volume of liquid is present in thewaste chamber 68. Thesensor chamber 120 is partially separated from thewaste chamber 68 by awall 151 having aspillover rim 152. The height of the wall is selected so that when the predetermined volume of liquid is received in thewaste chamber 68, the liquid spills over thespillover rim 152 and into thesensor chamber 120. The liquid in thesensor chamber 120 is then detected by thesensor 143. - Referring again to FIG. 13, the cartridge may also include a
second sensor chamber 121 in fluid communication with thewaste chamber 68. Thesecond sensor chamber 121 is also separated from thewaste chamber 68 by awall 153 having a spillover rim. Thewall 153 is taller than thewall 152 so that liquid does not spill over thewall 153 until a second predetermined volume of fluid in addition to the first predetermined volume of fluid has been received in thewaste chamber 68. Thesensor chambers optical sensors 143 are useful for controlling the operation of the cartridge. The height of thewall 152 is preferably selected such that when a fixed volume of fluid sample from thesample chamber 65 has flowed through the sample flow path to thewaste chamber 68, the sample liquid spills over into thesensor chamber 120 and is detected. The detection inchamber 120 triggers the release of wash solution from thewash chamber 66 which flows through the sample flow path to thewaste chamber 68. When an incremental volume of the wash solution is received in thechamber 68, liquid spills over thewall 153 into thesensor chamber 121 and is detected. The detection of liquid in thechamber 121 then triggers the release of lysing reagent from thechamber 67. Thesensor 143 surrounding thechamber 67 may then be used to indicate when thechamber 67 is empty, triggering the start of ultrasonic lysis. In an alternative embodiment, the cartridge may have two waste chambers, one for sample and one for wash, with each waste chamber having a respective sensor chamber connected thereto. - In-line reflective
optical sensors 144 are used to determine the presence or absence of liquid in the flat-bottomeddetection regions channels sensor 144 has a built in emitter and detector that is positioned over a flat-bottomed detection region. The emitter emits a beam that is reflected from the cartridge and detected by the detector. The sensor detects a change in signal when as an air/liquid interface passes through the detection region. Optionally, dual emitter reflective optical sensors may be used for a more reliable detection operation. Both types of reflective optical sensors are well known in the art and commercially available. - Referring again to FIG. 10, the
instrument 140 also includes a heat-exchangingmodule 147 having aslot 148 for receiving the reaction vessel of the cartridge. Themodule 147 is described in detail below with reference to FIG. 28. Theinstrument 140 further includes alatch mechanism 149 for latching alid 150 over a cartridge. Thecartridge nest 141 includes alignment holes 401 for receiving the legs of the cartridge. The alignment holes 401 ensure proper positioning of the cartridge in thenest 141 so that thepressure nozzles 145,transducer 92, andvalve actuators 142 fit into the corresponding ports in the cartridge and so that the reaction vessel fits into theslot 148. Thetransducer 92 should be positioned in theinstrument 140 such that when the cartridge is placed in thenest 141, the transducer contacts the bottom wall of the lysingchamber 86, as shown in the cut-away view of FIG. 5. In addition, the instrument may include a spring or similar mechanism to bias thetransducer 92 against the wall of the lysingchamber 86. - The
instrument 140 also includes various conventional equipment not shown in FIG. 10 including a main logic board having a microcontroller for controlling the operation of thesolenoids 146,transducer 92, heat-exchangingmodule 147, andoptical sensors nozzles 145. Theinstrument 140 is preferably computer-controlled using, e.g., the microcontroller which is programmed to perform the functions described in the operation section below. Alternatively, the instrument may controlled by a separate computer, or controlled by a combination of a separate computer and an on-board microcontroller. - FIG. 11 shows an isometric view of the
cartridge 20 placed in theinstrument 140 for processing. FIG. 11 shows a partial cut-away view of theinstrument 140 with thelid 150 closed. Referring again to FIG. 11, a memory or microprocessor chip may optionally be incorporated as part of thecartridge 20. This chip preferably contains information such as the type of cartridge, program information such as specific protocols for the processing of the cartridge, tolerances for accept and reject, serial numbers and lot codes for quality tracking, and provision for storing the results of the processing. Integrated electronic memory on thecartridge 20 allows for rapid, easy, and error-free set-up of theinstrument 140 for different fluidic processing protocols. When thecartridge 20 is inserted into theinstrument 140, the instrument may electronically address the memory on the cartridge, and thus automatically receive the appropriate set of instructions for controlling the time-sequence of fluidic operations to be carried out with the inserted cartridge. Theinstrument 140 may simply sequentially retrieve and execute each step in the cartridge's memory, or download its contents so that the user may edit the sequence using, e.g., the controller computer. - If suitable memory is included on the cartridge, such as writable memory (e.g., erasable programmable read-only memory (EPROM), electrically erasable programmable read-only memory (EEPROM), etc., intermediate and final results, based on the sample introduced into the cartridge, could be written by the instrument into the cartridge's memory for co-located storage with the physical sample after processing. This is particularly advantageous in applications where archiving of samples and results is necessary, such as forensics. In addition, other information can be stored in the memory on the cartridge, in unalterable (or alterable) forms. For example, cartridge serial number, lot manufacture information, and related information could be pre-programmed and unalterable. User data, technician identification number, date of test, location of test and instrument serial number could be unalterably written into the cartridge. This allows for easy identification of the “chain of custody” in the handling of a specimen. Engineers skilled in the art of data storage will recognize that other memory means than electronic can be used, such as optically-addressed printed regions (e.g., ink-jet or thermal), magnetic strips, etc.
- FIG. 28 shows the heat-exchanging
module 147 of the instrument into which thereaction vessel 40 is inserted for thermal processing and optical detection of target analyte(s) in the reaction mixture. Themodule 147 preferably includes ahousing 208 for holding the various components of the module. Themodule 147 also includes thethermal plates 190 described above. Thehousing 208 includes a slot (not shown in FIG. 28) above theplates 190 so that the reaction chamber of thevessel 40 may be inserted through the slot and between the plates. The heat-exchangingmodule 147 also preferably includes a cooling system, such as afan 212. Thefan 212 is positioned to blow cooling air past the surfaces of theplates 190 to cool the plates and hence cool the reaction mixture in thevessel 40. Thehousing 208 preferably defines channels for directing the cooling air past theplates 190 and out of themodule 147. - The heat-exchanging
module 147 further includes anoptical excitation assembly 216 and anoptical detection assembly 218 for optically interrogating the reaction mixture contained in thevessel 40. Theexcitation assembly 216 includes afirst circuit board 220 for holding its electronic components, and thedetection assembly 216 includes asecond circuit board 222 for holding its electronic components. Theexcitation assembly 216 includes one or more light sources (e.g., an LED). laser, or light bulb) for exciting fluorescently-labeled analytes in thevessel 40. Theexcitation assembly 216 also includes one or more lenses for collimating the light from the light sources, as well as filters for selecting the excitation wavelength ranges of interest. Thedetection assembly 218 includes one or more detectors (e.g., a photodiode, photomultiplier tube, or CCD) for detecting the light emitted from thevessel 40. Thedetection assembly 218 also includes one or more lenses for focusing and collimating the emitted light, as well as filters for selecting the emission wavelength ranges of interest. Suitable optical excitation and detection assemblies for use in the heat-exchangingmodule 147 are described in International Publication Number WO 99/60380 (International Application Number PCT/US99/11182) published Nov. 25, 1999, the disclosure of which is incorporated by reference herein. - The
optics assemblies housing 208 such that when the chamber of thevessel 40 is inserted between theplates 190, theexcitation assembly 216 is in optical communication with thechamber 42 through the opticallytransmissive side wall 57A (see FIG. 22) and thedetection assembly 218 is in optical communication with the chamber through the opticallytransmissive side wall 57B (FIG. 22). In the preferred embodiment, theoptics assemblies optics assemblies plates 190 so that when the chamber of the vessel is placed between the plates, theoptics assemblies - FIG. 34 shows a partially cut-away, isometric view of the chamber of the vessel inserted between the
plates transmissive side walls plates first plate 190A has a firstbottom edge 250A and a second bottom edge 2190B. Similarly, the bottom portion of thesecond plate 190B has a firstbottom edge 252A and a secondbottom edge 252B. The first and second bottom edges of each plate are preferably angularly offset from each other by the same angle that theside walls plates first side wall 57A is positioned substantially adjacent and parallel to each of the firstbottom edges second side wall 57B is positioned substantially adjacent and parallel to each of thesecond bottom edges 2190B, 252B. This arrangement provides for easy optical access to the opticallytransmissive side walls side walls - Referring again to FIG. 28, the
optics assemblies vessel 40 includes a locating tab 58 (see FIG. 22) that fits into a slot formed between theoptics assemblies vessel 40 for optical detection. For improved detection, themodule 147 also preferably includes a light-tight lid (not shown) that is placed over the top of thevessel 40 and made light-tight to thehousing 208 after the vessel is inserted between theplates 190. - Although it is presently preferred to locate the
optics assemblies plates 190, many other arrangements are possible. For example, optical communication may be established between theoptics assemblies vessel 40 via optical fibers, light pipes, wave guides, or similar devices. One advantage of these devices is that they eliminate the need to locate theoptics assemblies plates 190. This leaves more room around the plates in which to circulate cooling air or refrigerant, so that cooling may be improved. - The heat-exchanging
module 147 also includes aPC board 226 for holding the electronic components of the module and anedge connector 224 for connecting themodule 147 to the instrument 140 (FIG. 10). The heating elements and temperature sensors on theplates 190, as well as theoptical boards PC board 226 by flex cables (not shown in FIG. 28 for clarity of illustration). Themodule 147 may also include agrounding trace 228 for shielding the optical detection circuit. Themodule 147 may optionally include an indicator, such as anLED 214, for indicating to a user the current status of the module such as “heating,” “cooling,” “finished,” or “fault”. - The
housing 208 may be molded from a rigid, high-performance plastic, or other conventional material. The primary functions of thehousing 208 are to provide a frame for holding theplates 190,optics assemblies fan 212, andPC board 226. Thehousing 208 also preferably provides flow channels and ports for directing cooling air from thefan 212 across the surfaces of theplates 190 and out of the housing. In the preferred embodiment, thehousing 208 comprises complementary pieces (only one piece shown in the schematic side view of FIG. 28) that fit together to enclose the components of themodule 147 between them. - Referring again to FIG. 23, the
plates - Ceramic plates are presently preferred because their inside surfaces may be conveniently machined to very high smoothness for high wear resistance, high chemical resistance, and good thermal contact to the flexible walls of the reaction vessel. Ceramic plates can also be made very thin, preferably between about 0.6 and 1.3 mm, for low thermal mass to provide for extremely rapid temperature changes. A plate made from ceramic is also both a good thermal conductor and an electrical insulator, so that the temperature of the plate may be well controlled using a resistive heating element coupled to the plate.
- Various thermal elements may be employed to heat and/or cool the
plates chamber 42. In general, suitable heating elements for heating the plate include conductive heaters, convection heaters, or radiation heaters. Examples of conductive heaters include resistive or inductive heating elements coupled to the plates, e.g., resistors or thermoelectric devices. Suitable convection heaters include forced air heaters or fluid heat-exchangers for flowing fluids past the plates. Suitable radiation heaters include infrared or microwave heaters. Similarly, various cooling elements may be used to cool the plates. For example, various convection cooling elements may be employed such as a fan, peltier device, refrigeration device, or jet nozzle for flowing cooling fluids past the surfaces of the plates. Alternatively, various conductive cooling elements may be used, such as a heat sink, e.g. a cooled metal block, in direct contact with the plates. - Referring to FIG. 24, each
plate 190 preferably has aresistive heating element 206 disposed on its outer surface. Theresistive heating element 206 is preferably a thick or thin film and may be directly screen printed onto eachplate 190, particularly plates comprising a ceramic material, such as aluminum nitride or aluminum oxide. Screen-printing provides high reliability and low cross-section for efficient transfer of heat into the reaction chamber. Thick or thin film resistors of varying geometric patterns may be deposited on the outer surfaces of the plates to provide more uniform heating, for example by having denser resistors at the extremities and thinner resistors in the middle. Although it is presently preferred to deposit a heating element on the outer surface of each plate, a heating element may alternatively be baked inside of each plate, particularly if the plates are ceramic. Theheating element 206 may comprise metals, tungsten, polysilicon, or other materials that heat when a voltage difference is applied across the material. Theheating element 206 has two ends which are connected torespective contacts 204 which are in turn connected to a voltage source (not shown in FIG. 24) to cause a current to flow through the heating element. Eachplate 190 also preferably includes atemperature sensor 192, such as a thermocouple, thermistor, or RTD, which is connected by twotraces 202 to respective ones of thecontacts 204. Thetemperature sensor 192 is be used to monitor the temperature of theplate 190 in a controlled feedback loop. - The plates have a low thermal mass to enable rapid heating and cooling of the plates. In particular, it is presently preferred that each of the plates has a thermal mass less than about 5 J/° C., more preferably less than 3 J/° C., and most preferably less than 1 J/° C. As used herein, the term thermal mass of a plate is defined as the specific heat of the plate multiplied by the mass of the plate. In addition, each plate should be large enough to cover a respective major wall of the reaction chamber. In the presently preferred embodiment, for example, each of the plates has a width X in the range of 2 to 22 mm, a length Y in the range of 2 to 22 mm, and a thickness in the range of 0.5 to 5 mm. The width X and length Y of each plate is selected to be slightly larger than the width and length of the reaction chamber. Moreover, each plate preferably has an angled bottom portion matching the geometry of the bottom portion of the reaction chamber, as previously described with reference to FIG. 34. Also in the preferred embodiment, each of the plates is made of aluminum nitride having a specific heat of about 0.75 J/g ° C. The mass of each plate is preferably in the range of 0.005 to 5.0 g so that each plate has a thermal mass in the range of 0.00375 to 3.75 J/° C.
- The opposing
plates 190 are positioned to receive the chamber of thevessel 40 between them such that the flexible major walls of the chamber contact and conform to the inner surfaces of the plates. It is presently preferred that theplates 190 be held in an opposing relationship to each other using, e.g., brackets, supports, or retainers. Alternatively, theplates 190 may be spring-biased towards each other as described in International Publication Number WO 98/38487, the disclosure of which is incorporated by reference herein. In another embodiment of the invention, one of the plates is held in a fixed position, and the second plate is spring-biased towards the first plate. If one or more springs are used to bias the plates towards each other, the springs should be sufficiently stiff to ensure that the plates are pressed against the flexible walls of the vessel with sufficient force to cause the walls to conform to the inner surfaces of the plates. - FIGS.29-30 illustrate a
preferred support structure 209 for holding theplates support structure 209 andplates support structure 209 includes a mountingplate 210 having theslot 148 formed therein. Theslot 148 is sufficiently large to enable the chamber of the vessel to be inserted through it. Spacing posts 230A, 230B extend from the mountingplate 210 on opposite sides of theslot 148. Spacing post 230A hasindentations 232 formed on opposite sides thereof (only one side visible in the isometric view of FIG. 29), and spacingpost 230B hasindentations 234 formed on opposite sides thereof (only one side visible in the isometric view of FIG. 29). Theindentations plates plates indentations retention clips plates 190A, 190E, may be retained by adhesive bonds, screws, bolts, clamps, or any other suitable means. - The mounting
plate 210 andspacing posts 230A, 230 are preferably integrally formed as a single molded piece of plastic. The plastic should be a high temperature plastic, such as polyetherimide, which will not deform of melt when theplates plate 210 may optionally includeindentations flex cables plates PC board 226 of the heat-exchanging module 147 (FIG. 28). The portion of theflex cables 238A adjacent theplate 190A is held in theindentation 240A by a piece oftape 242A, and the portion of theflex cables 238B adjacent theplate 190B is held in theindentation 240B by a piece oftape 242B. - FIG. 31 is an isometric view of the assembled
support structure 209. The mountingplate 210 preferably includestabs 246 extending from opposite sides thereof for securing thestructure 209 to the housing of the heat-exchanging module. Referring again to FIG. 28, thehousing 208 preferably includes slots for receiving the tabs to hold the mountingplate 210 securely in place. Alternatively, the mountingplate 210 may be attached to thehousing 208 using, e.g., adhesive bonding, screws, bolts, clamps, or any other conventional means of attachment. - Referring again to FIG. 29, the
support structure 209 preferably holds theplates wall 244 that is slightly tapered so that when theplates plates chamber 42 is inserted. The amount by which the inner surfaces are angled towards each other is very slight, preferably about 1° from parallel. The surfaces are angled towards each other so that, prior to the insertion of thechamber 42 between theplates chamber 42 of the vessel to be inserted between the plates and withdrawn from the plates more easily. Alternatively, the inner surfaces of theplates vessel 40 would be more difficult. - In addition, the inner surfaces of the
plates frame 46. In embodiments in which the inner surfaces are angled towards each other, the centers of the inner surfaces are preferably spaced a distance equal to the thickness of theframe 46 and the bottoms of the plates are initially spaced a distance that is slightly less than the thickness of theframe 46. When thechamber 42 is inserted between theplates rigid frame 46 forces the bottom portions of the plates apart so that thechamber 42 is firmly sandwiched between the plates. The distance that theplates frame 46 is usually very small, e.g., about 0.035 mm if the thickness of the frame is 1 mm and the inner surfaces are angled towards each other by 1°. - Referring again to FIG. 30, the retention clips236A, 236B should be sufficiently flexible to accommodate this slight outward movement of the
plates plates - Referring again to FIG. 28, to limit the amount that the
plates 190 can spread apart due to the pressurization of thevessel 40, stops may be molded into the housings ofoptics assemblies housing 249 of theoptics assembly 218 includes claw-like stops housing 249 is positioned such that the bottom edges of theplates stops stops plates plates frame 46. Preferably, the maximum spacing of the inner surfaces of theplates frame 46 to accommodate tolerance variations in thevessel 40 andplates frame 46. - FIG. 35 is a schematic, block diagram of the electronic components of the heat-exchanging
module 147. The module includes aconnector 224 or flex cable for connection to the main logic board of the instrument. The module also includesheater plates plates power input 253 from the instrument. Theplates temperature sensors 192A, 192B that output analog temperature signals to an analog-to-digital converter 264. Theconverter 264 converts the analog signals to digital signals and routes them to the microcontroller in the instrument through theconnector 224. - The heat-exchanging module also includes a cooling system, such as a
fan 212, for cooling theplates fan 212 is activated by switching apower switch 272, which is in turn controlled by acontrol logic block 270 that receives control signals from the microcontroller. The module further includes four light sources, such asLEDs 200, for excitation of labeled analytes in the reaction mixture and fourdetectors 198, preferably photodiodes, for detecting fluorescent emissions from the reaction mixture. The module also includes an adjustablecurrent source 255 for supplying a variable amount of current (e.g., in the range of 0 to 30 mA) to each LED to vary the brightness of the LED. A digital-to-analog converter 260 is connected between the adjustablecurrent source 255 and the microcontroller to permit the microcontroller to adjust the current source digitally. - The adjustable
current source 255 is preferably used to ensure that each LED has about the same brightness when activated. Due to manufacturing variances, many LEDs have different brightnesses when provided with the same amount of current. Therefore, it is presently preferred to test the brightness of each LED during manufacture of the heat-exchanging module and to store calibration data in amemory 268 of the module. The calibration data indicates the correct amount of current to provide to each LED. The microcontroller reads the calibration data from thememory 268 and controls thecurrent source 255 accordingly. - The module additionally includes a signal conditioning/gain select/offset adjust
block 262 comprised of amplifiers, switches, electronic filters, and a digital-to-analog converter. Theblock 262 adjusts the signals from thedetectors 198 to increase gain, offset, and reduce noise. The microcontroller controls block 262 through adigital output register 266. Theoutput register 266 receives data from the microcontroller and outputs control voltages to theblock 262. Theblock 262 outputs the adjusted detector signals to the microcontroller through the analog-to-digital converter 264 and theconnector 224. The module also includes thememory 268, preferably a serial EEPROM, for storing data specific to the module, such as calibration data for theLEDs 200,thermal plates temperature sensors 192A, 192B. - The operation of the cartridge and instrument will now be described. As shown in FIG. 3, a fluid sample to be analyzed is added to the
sample chamber 65 through thesample port 64 and thecap 30 screwed into theport 64 to seal the port shut. Referring to FIG. 10, thecartridge 20 is then placed into thecartridge nest 141 of theinstrument 140 for processing. All valves in thecartridge 20 are initially closed when the cartridge is placed into theinstrument 140. When the cartridge is placed in the instrument, thetransducer 92 contacts an external surface of theflexible gasket 63 forming the bottom wall of the lysingchamber 86, as shown in FIG. 5. - Referring again to FIG. 10, the
instrument 140 is preferably computer-controlled to perform the functions described in the following section, e.g., opening and closing valves in the cartridge usingvalve actuators 142, providing pressure to the cartridge throughnozzles 145, activating thetransducer 92, sensing liquid presence or liquid levels usingoptical sensors optical detection module 147. A programmer having ordinary skill in the art will be able to program a microcontroller and/or computer to perform these functions based upon the following description. - Referring to FIG. 9, liquids are preferably forced to flow through the cartridge using differential pressure. Although2o positive pressure is described herein, negative pressure (vacuum) may also be used to control fluid flow in the cartridge. The maximum amount of positive pressure that can be applied is usually limited by the hydrophobic membranes which may reach liquid break-through pressure above 30 psi. The lower limit of pressure is limited by the need to move sample and other fluids through the cartridge sufficiently quickly to meet assay goals. Below 1 psi, for example, sample may not flow efficiently through the
filter stack 87. Pressure in the range of 6 to 20 psi is generally adequate. The sample flow rate through the cartridge is preferably in the range of 10 to 30 ml/minute. The wash flow rate may be slower, e.g. 6 to 18 ml/minute so that the wash effectively washes the lysingchamber 86. - A specific protocol will now be described with reference to FIG. 9 to illustrate the operation of the cartridge. It is to be understood that this is merely an example of one possible protocol and is not intended to limit the scope of the invention. To begin, the cartridge is preferably primed with wash solution from the
wash chamber 66 before the fluid sample is forced to flow from thesample chamber 65. To prime the cartridge,valves chamber 66 through thepressure port 116 for about two seconds. A small portion of the wash solution flows through thechannels chamber 86, through thechannels U-shaped channel 122, and all the way to the hydrophobic membrane below thepressure port 128. - Following priming,
valve 115 andpressure port 116 are closed andvalves sample chamber 65 through thepressure port 105 for about 15 seconds to force the sample to flow through thechannel 106, through thefilter stack 87 in thechamber 87, through thechannels waste chamber 68. As the sample passes thedetection region 136 in thechannel 106, the reflective optical sensor 144 (FIG. 13) may be used to determine when thesample chamber 65 has been emptied. As the sample liquid flows through thefilter stack 87, target cells or viruses in the sample are captured. When a predetermined volume of sample reaches thewaste chamber 68, some of the liquid spills over into thesensor chamber 120, triggering the next step in the protocol. Alternatively, instead of using feedback from optical sensors to trigger events, the steps in a predetermined protocol may simply be timed, e.g., applying predetermined pressures for predetermined durations of time to move known volumes of fluid at known flow rates. - The flow-through design of the lysing
chamber 86 permits target cells or viruses from a relatively large sample volume to be concentrated into a much smaller volume for amplification and detection. This is important for the detection of low concentration analyte in the sample, such as nucleic acid. In particular, the ratio of the volume of the sample forced to flow through the lysingchamber 86 to the volume capacity of thechamber 86 is preferably at least 2:1, and more preferably at least 5:1. The volume of sample forced to flow through thechamber 86 is preferably at least 100 μ, and more preferably at least 1 ml. In the presently preferred embodiment, a sample volume of 5 ml is forced to flow through the lysingchamber 86, and thechamber 86 has a volume capacity of about 0.5 ml, so that the ratio is 10:1. In addition, the lysingchamber 86 may be sonicated (e.g., using an ultrasonic horn coupled to a wall of the chamber) as the sample is forced to flow through the chamber. Sonicating thechamber 86 helps to prevent clogging of thefilter stack 87, providing for more uniform flow through thechamber 86. In particular, the sound waves help keep particulate matter or So the beads in the filter stack from clogging one or more filters. - In the next step,
valves wash chamber 66 for about seven seconds to force the wash solution to flow through thechannels chamber 86. The washing solution washes away PCR inhibitors and contaminants from the lysingchamber 86 and carries then through thechannels waste chamber 68. A variety of suitable wash solutions of varying pH, solvent composition, and ionic strength may be used for this purpose and are well known in the art. For example, a suitable washing reagent is a solution of 80 mM potassium acetate, 8.3 mM Tris-HCl, pH 7.5, 40 uM EDTA, and 55% ethanol. The lysingchamber 86 may be sonicated (e.g., using an ultrasonic horn coupled to a wall of the chamber) while the wash solution is forced to flow through the chamber. Sonicating thechamber 86 helps to prevent clogging of thefilter stack 87, providing for more uniform flow through thechamber 86 as previously described. In addition, the sound waves may help loosen the material to be washed away. When the incremental volume of wash solution reaches thewaste chamber 68, some of the liquid spills over into thesensor chamber 121, triggering the next step in the protocol. - In the next step,
valve 115 is closed andvalve 119 is opened while a pressure of 15 psi is applied to thereagent chamber 67 through thepressure port 118 for about three seconds. The pressure forces lysing reagent to flow from thechamber 67 through thechannels chamber 86, and into thechannel 110. Thechamber 86 is thus filled with liquid. Suitable lysing reagents include, e.g., solutions containing a chaotropic salt, such as guanidine HC1, guanidine thiocyanate, guanidine isothiocyanate, sodium iodide, urea, sodium perchlorate, and potassium bromide. In the presently preferred embodiment, a lysing reagent that is not inhibitory to PCR is used. The lysing reagent comprises 10 mM tris, 5% tween-20, 1 mM tris (2-carboxyethyl phosphine hydrochloride), 0.1 mM Ethylene Glycol-bis (b-amino-ethyl ether)- N,N,N′, N′-tetracetic acid. After the lysingchamber 86 is filled with lysing reagent, thevalves Valve 119 remains open and a pressure of 20 psi is applied topressure port 118. The static pressure in thelysis chamber 86 is therefore increased to 20 psi in preparation for the lysis of the cells or viruses trapped in thefilter stack 87. - Referring again to FIG. 5, the pressurization of the lysing
chamber 86 is important because it ensures effective coupling between thetransducer 92 and theflexible wall 63 of the lysingchamber 86. To disrupt the cells or viruses in thechamber 86, thetransducer 92 is activated (i.e., set into vibratory motion). Theflexible wall 63 of the lysingchamber 86 transfers the vibratory motion of thetransducer 92 to the liquid in thechamber 86 by allowing slight deflections without creating high stresses in the wall. Thewall 63 may be formed by the elastomeric membrane as previously described. Alternatively, the wall may be a film or sheet of polymeric material (e.g., a polypropylene film) preferably having a thickness in the range of 0.025 to 0.1 mm. Thetransducer 92 is preferably an ultrasonic horn for sonicating thechamber 86. Thechamber 86 is preferably sonicated for 10 to 40 seconds at a frequency in the range of 20 to 60 kHz. In the exemplary protocol, the chamber is sonicated for 15 seconds at a frequency of 47 kHz. The amplitude of the horn tip is preferably in the range of 20 to 25 pm (measured peak to peak). - As the tip of the
transducer 92 vibrates, it repeatedly impacts theflexible wall 63. On its forward stroke (in the upward direction in FIG. 6), the tip of thetransducer 92 pushes thewall 63 and creates a pressure pulse or pressure wave in thechamber 86. On its retreating stroke (downward in FIG. 5), the tip of thetransducer 92 usually separates from theflexible wall 63 because theflexible wall 63 cannot move at the same frequency as the transducer. On its next forward stroke, the tip of thetransducer 92 once again impacts thewall 63 in a head-on collision as the tip and wall speed towards each other. Because thetransducer 92 and thewall 63 separate as thetransducer 92 vibrates, the effective forward stroke of the transducer is less than its peak-to-peak amplitude. The effective forward stroke determines the level of sonication in thechamber 86. It is therefore important to increase the static pressure in the lysingchamber 86 so that when the tip of thetransducer 92 retreats, theflexible wall 63 is forced outwardly to meet the tip on its return stroke. The static pressure in thechamber 86 should be sufficient to ensure that the effective forward stroke of thetransducer 92 generates pressure pulses or pressure waves in thechamber 86. It is presently preferred to increase the static pressure in thechamber 86 to at least 5 psi above the ambient pressure external to the cartridge, and more preferably to a pressure in the range of 15 to 25 psi above the ambient pressure. - On each forward stroke, the
transducer 92 imparts a velocity to the liquid in thechamber 86, thus creating a pressure wave that quickly sweeps across thechamber 86. The beads in the filter stack 87 (FIG. 6) are agitated by the pressure waves in thechamber 86. The pressure waves propel the beads into violent motion in thechamber 86, and the beads mechanically rupture the cells or viruses to release the material (e.g., nucleic acid) therefrom. It should be noted that some types of cells, such as blood cells, are relatively weak and may be disrupted using only pressure waves (e.g., ultrasonic waves) without the use of beads. Other types of cells (particularly spores) have highly resistant cell walls and beads are generally required for effective lysis. - Referring again to FIG. 9, following disruption of the cells or viruses,
valves reagent chamber 67 through thepressure port 118. The pressure forces the lysis reagent to elute the nucleic acid from thefilter stack 87 and to flow with the nucleic acid into theneutralization chamber 70. The lysingchamber 86 may be sonicated (e.g., using an ultrasonic horn coupled to a wall of the chamber) while the eluting the nucleic acid. Sonicating thechamber 86 may help prevent clogging of thefilter stack 87, as previously described. The chamber 420 is partially filled (e.g., half-filled) with neutralizer, such as detergent, for neutralizing the lysing reagent. If a lysing reagent non-inhibitory to PCR is used, the neutralizer is optional. - In the next step, the
valve 124 is closed to hold the lysing reagent, analyte, and neutralizer in thechamber 70. Thevalve 114 is opened and a pressure of 15 psi is applied for about three seconds through thepressure port 128 to force any liquid in theU-shaped channel 122 to flow into thewaste chamber 68. Next,valves pressure port 123 on top of theneutralizer chamber 70. The pressure forces the neutralized lysing reagent and nucleic acid in thechamber 70 to flow into thechannel 122 and into themaster mix chamber 71. Thevalve 126 to themaster mix chamber 71 is then closed. The master mix chamber contains PCR reagents and fluorescent probes that mix with the neutralized lysing reagent and nucleic acid to form a reaction mixture. - In the next step, the
channel 122 is cleared by openingvalve 114 to wastechamber 68 and applying a pressure of 15 psi for about one second to pressureport 128. In the next step, the reaction mixture formed in themaster mix chamber 71 is moved into thereaction vessel 40 as follows.Valves pressure port 125 on top of themaster mix chamber 71 to force the reaction mixture to flow through thechannel 122,valve 127, andchannel 80 into thereaction vessel 40 through theport 41. The reaction mixture fills thechamber 42 of the vessel, displacing air in the chamber which exits through theoutlet channel 52. The air escaping through theoutlet channel 52 travels inchannel 81past sensor region 130 and intochannel 131. Fromchannel 131, the air flows intochannel 132, throughvalve 133,channel 134, and exits the cartridge through thevent 36. When a volume of reaction mixture sufficient to fill thechamber 42 has flowed into the vessel, excess reaction mixture exits the vessel through theoutlet channel 52. The excess reaction mixture flows intochannel 81 and is optically detected in thesensor region 130. When the reaction mixture is detected,valve 133 is closed while pressure from thepressure port 125 is applied to pressurize thereaction chamber 42. - Referring again to FIG. 23, the pressurization of the
chamber 42 expands the flexiblemajor walls 48 of the vessel. In particular the pressure forces themajor walls 48 to contact and conform to the inner surfaces of theplates plates chamber 42. It is presently preferred to pressurize thechamber 42 to a pressure in the range of 2 to 30 psi above ambient pressure. This range is presently preferred because 2 psi is generally enough pressure to ensure conformity between thewalls 48 and the surfaces of theplates walls 48, deformation of theframe 46 orplates chamber 42 is pressurized to a pressure in the range of 8 to 15 psi above ambient pressure. This range is more preferred because it is safely within the practical limits described above. When thechamber 42 is pressurized, the reaction mixture in thevessel 40 is thermally processed and optically interrogated to determine the presence or absence of a target analyte in the mixture. - Referring again to FIG. 35, the reaction mixture is thermally processed between the
plates temperature sensors 192A, 192B. Proportioning may be accomplished either by varying the ratio of “on” time to “off” time, or, preferably with proportional analog outputs which decrease the average power being supplied either to the heating elements on theplates fan 212 as the actual temperature of theplates - As the reaction mixture is thermally cycled between the
heater plates LEDs 200 to excite different fluorescently-labeled analytes in the mixture and by detecting light emitted (fluorescent output) from thechamber 42 using detectors the 198. Referring again to FIG. 22, excitation beams are preferably transmitted to thechamber 42 through the opticallytransmissive side wall 57A, while fluorescent emission is detected through theside wall 57B. - One advantage of the cartridge of the present invention is that it allows the intracellular material from a relatively large volume of fluid sample, e.g. several milliliters or more, to be separated from the sample and concentrated into a much smaller volume of reaction fluid, e.g., 100 μL or less. The cartridge permits extraordinary concentration factors by efficiently extracting material from milliliter quantities of fluid sample. In particular, the
sample chamber 65 preferably has a volume capacity in the range of 100 μl to 12 ml. More preferably, thesample chamber 65 has a volume capacity of at least 1 ml. The lower limit of 1 ml is preferred because at least 1 ml of sample should be analyzed to detect low concentration analytes such as nucleic acid. The upper limit of 12 ml is preferred because a sample volume greater than 12 ml would require a much larger cartridge and likely clog the filter stack. In the presently preferred embodiment, the sample chamber has a volume capacity of 5.5 ml for holding 5 ml of sample. - The
wash chamber 66 has a volume capacity proportional to the volume of the lysingchamber 86. In particular, thewash chamber 66 preferably holds a volume of wash that is at least one to two times the volume of the lysingchamber 86 to ensure that there is enough wash solution to wash out PCR inhibitors and debris from thechamber 86. In the presently preferred embodiment, the volume of the lysingchamber 86 is about 0.5 ml and the volume of thewash chamber 66 is 2.5 ml for holding 2 ml of wash solution. The lysing chamber volume of 0.5 ml is a compromise between a size large enough to avoid clogging of thefilter stack 87 and a size small enough to concentrate analyte into a small volume for improved amplification and detection. - The
reagent chamber 67 preferably holds a volume of lysing reagent that is at least one to two times the volume of the lysingchamber 86 so that there is sufficient lysing reagent to pressurize the chamber and to elute nucleic acid from the chamber. In the presently preferred embodiment, thechamber 67 has a volume capacity of 1.5 ml for holding about 1 to 1.5 ml of lysing reagent. Thewaste chamber 68 has a volume capacity sufficient to hold the sample, wash solution, and unused lysing reagent. Thewaste chamber 68 is sized at 9.5 ml volume capacity in the preferred embodiment. - The size of the
neutralization chamber 70 is dependent upon the volume of the lysingchamber 86 since the neutralizer in thechamber 70 neutralizes the volume of lysing reagent that fills lo the lysingchamber 86. It is currently preferred that the lysing chamber have a volume if 0.5 ml, so thechamber 70 has a volume capacity of 1.0 ml for holding about 0.5 ml of neutralizer that is mixed with 0.5 ml of the lysing reagent and eluted analyte. The volume capacity of themaster mix chamber 71 should be sufficient to produce a reaction mixture to fill thevessel 40 and thechannels - The flow channels in the cartridge are generally D-shaped in cross section (with the
gasket 63 forming the flat side of the channel) and preferably have a width or diameter in the range of {fraction (1/64)} to ⅛ of an inch (0.4 to 3.2 mm), and more preferably a width of {fraction (1/32)} to {fraction (1/16)} of an inch (0.8 to 1.6 mm). These ranges are presently preferred to avoid having channels to narrow (which creates flow restriction) and to avoid having channels too wide (which yields unused volumes of liquid sitting in the flow path). - Many modifications to the structure and operation of the cartridge and instrument are possible in alternative embodiments. For example, although amplification by PCR is presently preferred, the cartridge and instrument may be used to amplify nucleic acid sequences using any amplification method, including both thermal cycling amplification methods and isothermal amplification methods. Suitable thermal cycling methods include, but are not limited to, the Polymerase Chain Reaction (PCR; U.S Pat. Nos. 4,683,202, 4,683,195 and 4,965,188); Reverse Transcriptase PCR (RT-PCR); DNA Ligase Chain Reaction (LCR; International Patent Application No. WO 89/09835); and transcription-based amplification (D. Y. Kwoh et al. 1989, Proc. Natl.
Acad. Sci. USA 86, 1173-1177). Suitable isothermal amplification methods useful in the practice of the present invention include, but are not limited to, Rolling Circle Amplification; Strand Displacement Amplification (SDA; Walker et al. 1992, Proc. Nati.Acad. Sci. USA 89, 392-396); Q-.beta. replicase (Lizardi et al. 1988, Bio/Technology 6, 1197-1202); Nucleic Acid-Based Sequence Amplification (NASBA; R. Sooknanan and L. Malek 1995, Bio/Technology 13, 563-65); and Self-Sustained Sequence Replication (3SR; Guatelli et al. 1990, Proc. Nati.Acad. Sci. USA 87, 1874-1878). - Moreover, the cartridge and instrument may be used to conduct chemical reactions other than nucleic acid amplification. Further, although fluorescence excitation and emission detection is preferred, optical detection methods such as those used in direct absorption and/or transmission with on-axis geometries may also be used to detect analyte in the cartridge. Another possible detection method is time decay fluorescence. Additionally, the cartridge is not limited to detection based upon fluorescent labels. For example, detection may be based upon phosphorescent labels, chemiluminescent labels, or electrochemiluminescent labels.
- A fluid sample may be introduced into the cartridge by a variety of means, manual or automated. For manual addition, a measured volume of material may be placed into a receiving area of the cartridge through an input port and a cap is then placed over the port. Alternatively, a greater amount of sample material than required for the analysis can be added to the cartridge and mechanisms within the cartridge can effect the precise measuring and aliquoting of the sample needed for the specified protocol. It may be desirable to place certain samples, such as tissue biopsy material, soil, feces, exudates, and other complex lo material into another device or accessory and then place the secondary device or accessory into the cartridge. For example, a piece of tissue may be placed into the lumen of a secondary device that serves as the cap to the input port of the cartridge. When the cap is pressed into the port, the tissue is forced through a mesh that slices or otherwise divides the tissue.
- For automated sample introduction, additional design features of the cartridge are employed and, in many cases, impart specimen accession functionality directly into the cartridge. With certain samples, such as those presenting a risk of hazard to the operator or the environment, such as human retrovirus pathogens, the transfer of the sample to the cartridge may pose a risk. Thus, in one embodiment, a syringe may be integrated into a device to provide a means for moving external fluidic samples directly into the cartridge. Alternatively, a venous puncture needle and an evacuated blood tube can be attached to the cartridge forming an assembly that can be used to acquire a sample of blood. After collection, the tube and needle are removed and discarded, and the cartridge is then placed in an instrument to effect processing. The advantage of such an approach is that the operator or the environment is not exposed to pathogens.
- The input port can be designed with a consideration of appropriate human factors as a function of the nature of the intended specimen. For example, respiratory specimens may be acquired from the lower respiratory tract as expectorants from coughing, or as swab or brush samples from the back of the throat or the nares. In the former case, the input port can be designed to allow the patient to cough directly into the cartridge or to otherwise facilitate spitting of the expectorated sample into the cartridge. For brush or swab specimens, the specimen is placed into the input port where features of the port and closure facilitate the breaking off and retaining of the end of the swab or brush in the cartridge receiving area.
- In another embodiment, the cartridge includes input and output tubes that may be positioned in a sample pool of very large volume, such as a flowing stream of water, so that the sample material flows through the cartridge. Alternatively, a hydrophilic wicking material can serve as an interactive region so that the entire cartridge can be immersed directly into the specimen, and a sufficient amount of specimen is absorbed into the wicking material. The cartridge is then removed, and can be transported to the laboratory or analyzed directly using a portable instrument. In another embodiment, tubing can be utilized so that one end of the tube is in direct communication with the cartridge to provide a fluidic interface with at least one interactive region and the other end is accessible to the external environment to serve as a receiver for sample. The tube can then be placed into a specimen and serve as a sipper. The cartridge itself may also serve as the actual specimen collection device, thereby reducing handling and inconvenience. In the case of specimens involved in legal disputes or criminal investigations, the direct accessing of the test material into the fluidic cartridge is advantageous because the chain of custody is conveniently and reliably preserved.
- Referring again to FIG. 9, reagents may be exogenously introduced into the cartridge before use, e.g., through sealable openings in the
reagent chamber 67,neutralizer chamber 70, andmaster mix chamber 71. Alternatively, the reagents may be placed in the cartridge during manufacture, e.g., as aqueous solutions or dried reagents requiring reconstitution. The particular format is selected based on a variety of parameters, including whether the interaction is solution-phase or solid-phase, the inherent thermal stability of the reagent, speed of reconstitution, and reaction kinetics. Reagents containing compounds that are thermally unstable when in solution can be stabilized by drying using techniques such as lyophilization. Additives, such as simple alcohol sugars, methylcelluloses, and bulking proteins may be added to the reagent before drying to increase stability or reconstitutability. - Referring again to FIG. 21, the
reaction vessel 40 does not require two flexible sheets forming opposingmajor walls 48 of thereaction chamber 42. For example, in one alternative embodiment, thevessel 40 has only one flexible sheet forming a major wall of the chamber. Therigid frame 46 defines the other major wall of the chamber, as well as the side walls of the chamber. In this embodiment, the major wall formed by theframe 46 should have a minimum thickness of about 0.05 inches (1.25 mm) which is typically the practical minimum thickness for injection molding, while the flexible sheet may be as thin as 0.0005 inches (0.0125 mm). The advantage to this embodiment is that the manufacturing of thereaction vessel 40 is simplified, and hence less expensive, since only one flexible sheet need be attached to theframe 46. The disadvantage is that the heating and cooling rates of the reaction mixture are likely to be slower since the major wall formed by theframe 46 will probably not permit as high a rate of heat transfer as the thin, flexible sheet. - Referring to FIG. 28, the heat-exchanging
module 147 only requires one thermal surface for contacting a flexible wall of thereaction vessel 40 and one thermal element for heating and/or cooling the thermal surface. The advantage to using one thermal surface and one thermal element is that the apparatus may be manufactured less expensively. The disadvantage is that the heating and cooling rates are likely to be about twice as slow. Further, although it is presently preferred that the thermal surfaces be formed by the thermallyconductive plates 190, each thermal surface may be provided by any rigid structure having a contact area for contacting a wall of thevessel 40. The thermal surface preferably comprises a material having a high thermal conductivity, such as ceramic or metal. Moreover, the thermal surface may comprise the surface of the thermal element itself. For example, the thermal surface may be the surface of a thermoelectric device that contacts the wall to heat and/or cool so the chamber. - It is presently preferred to build the transducer into the
instrument 140. In another embodiment, however, the transducer may be built into the cartridge. For example, a piezoelectric disk may be built into the cartridge for sonicating the lysing chamber. Alternatively, a speaker or electromagnetic coil device may be built into the cartridge. In these embodiments, the cartridge includes suitable electrical connectors for connecting the transducer to a power supply. In embodiments in which the transducer is built into the cartridge, the transducer should be prevented from contacting the fluid sample directly, e.g., the transducer should be laminated or separated from the sample by a chamber wall. Further, lysis of the cells or viruses may be performed using a heater in place of or in combination with a transducer. The heater may be a resistive heating element that is part of cartridge, or the heater could be built into the instrument that receives the cartridge. In this embodiment, the cells or viruses are disrupted by heating the lysis chamber to a high temperature (e.g., 95° C.) to disrupt the cell walls. - FIGS.36-46 show another
apparatus 350 for disrupting cells or viruses according to the present invention. FIG. 36 shows an isometric view of theapparatus 350, and FIG. 37 shows a cross sectional view of theapparatus 350. As shown in FIGS. 36-37, theapparatus 350 includes a cartridge orcontainer 358 having achamber 367 for holding the cells or viruses. The container includes aflexible wall 440 defining thechamber 367. In this embodiment, theflexible wall 440 is the bottom wall of thechamber 367. Theflexible wall 440 is preferably a sheet or film of polymeric material (e.g., a polypropylene film) and thewall 440 preferably has a thickness in the range of 0.025 to 0.1 mm. Theapparatus 350 also includes atransducer 314, such as an ultrasonic horn, for contacting an external surface of the flexible wall 440 (i.e., a surface of thewall 440 that is external to the chamber 367). Thetransducer 314 should be capable of vibratory motion sufficient to create pressure pulses in thechamber 367. Suitable transducers include ultrasonic, piezoelectric, magnetostrictive, or electrostatic transducers. The transducer may also be an electromagnetic device having a wound coil, such as a voice coil motor or a solenoid device. - The
apparatus 350 further includes asupport structure 352 for holding thecontainer 358 and thetransducer 314 against each other such that thetransducer 314 contacts thewall 440 of thechamber 367 and for applying a substantially constant force to thecontainer 358 or to thetransducer 314 to press together thetransducer 314 and thewall 440 of the chamber. Thesupport structure 352 includes abase structure 354 having astand 356. Thetransducer 314 is slidably mounted to thebase structure 354 by aguide 364. Theguide 364 is either integrally formed with thebase structure 354 or fixedly attached to the base structure. Thesupport structure 352 also includes aholder 360 attached to thebase structure 354 for holding thecontainer 358. Theholder 360 has a U-shaped bottom portion providing access to theflexible wall 440 of thechamber 367. Theguide 364 and theholder 360 are arranged to hold thetransducer 314 and thecontainer 358, respectively, such that the external surface of thewall 440 contacts thetransducer 314. Thesupport structure 352 also includes atop retainer 362 for thecontainer 358. Theretainer 362 is U-shaped to allow access to anexit port 444 formed in thecontainer 358. - The
support structure 352 further includes an elastic body, such as aspring 366, for applying a force to thetransducer 314 to press thetransducer 314 against thewall 440. When thetransducer 314 is in contact with thewall 440, the force provided by thespring 366 is constant, providing for consistent coupling between thetransducer 314 and thewall 440. Thespring 366 is positioned between aspring guide 372 and the base of acoupler 368 that supports the bottom of thetransducer 314. As shown in FIG. 36, thecoupler 370 preferably has awindow 370 through which the power cord (not shown) of thetransducer 314 may be placed. Bolts or screws 376 hold thespring guide 372 inadjustment grooves 374 formed in thebase structure 354. The magnitude of the force provided by thespring 366 may be adjusted by changing the preload on the spring. To adjust the preload on thespring 366, the bolts 376 holding thespring guide 372 are loosened, theguide 372 is moved to a new position, and the bolts 376 are retightened to hold theguide 372 in the new position. - Once the preload on the
spring 366 is adjusted to provide a suitable coupling force between thetransducer 314 and thewall 440, it is desirable to keep the preload constant from one use of theapparatus 350 to the next so that valid comparisons can be made between different samples disrupted by the apparatus. - The magnitude of the force provided by the
spring 366 to press together thetransducer 314 and thewall 440 is important for achieving a consistent transfer of energy between thetransducer 314 and thechamber 367. If the force is too light, thetransducer 314 will only be held lightly against thewall 440, leading to poor translation of vibratory movement from thetransducer 314 to thewall 440. If the force is too strong, thecontainer 358 orwall 440 may be damaged during sonication. An intermediate force results in the most consistent and repeatable transfer of vibratory motion from thetransducer 314 to thewall 440. It is presently preferred that thespring 366 provide a force in the range of 1 to 5 lbs., with a force of about 2 lbs. being the most preferred. - FIG. 38 shows an exploded view of the
container 358, and FIG. 39 shows an assembled view of thecontainer 358. As shown in FIGS. 38-39, thecontainer 358 has a body comprising atop piece 448, amiddle piece 450, and abottom piece 452. Themiddle piece 450 defines aninlet port 442 to thechamber 367, and thetop piece 448 defines anoutlet port 444 to the chamber. Theports chamber 367. Theflexible wall 440 is held between the middle andbottom pieces gaskets flexible wall 440 may simply be heat sealed to themiddle piece 450 so that thebottom piece 452 andgaskets - The
container 358 also includes afilter stack 446 in thechamber 367 for capturing sample components (e.g., target cells or viruses) as the sample flows through thechamber 367. The filter stack comprises (from bottom to top in FIGS. 38-39) agasket 456, afirst filter 458, agasket 460, asecond filter 464 having a smaller average pore size than thefirst filter 458, and agasket 466. The filter stack is held between the top andmiddle pieces container 358. The filter stack also includesbeads 462 disposed between the first andsecond filters gasket 460 spaces thefirst filter 458 from thesecond filter 464. Thegasket 460 should be thick enough to permit the beads to move freely in the space between thefilters chamber 367 first flows through thefilter 458 and then through thefilter 466. After flowing through the filter stack, the sample flows along flow ribs 468 (FIG. 38) formed in the portion of thetop piece 448 that defines the top of the chamber and through the outlet port 444 (FIG. 39). - The filter stack is effective for capturing cells or viruses as a fluid sample flows through the
chamber 367 without clogging of the. The first filter 458 (having the largest pore size) filters out coarse material such as salt crystals, cellular debris, hair, tissue, etc. The second filter 464 (having a smaller pore size) captures target cells or viruses in the fluid sample. The average pore size of thefirst filter 458 is selected to be small enough to filter coarse material from the fluid sample (e.g., salt crystals, cellular debris, hair, tissue) yet large enough to allow the passage of the target cells or viruses. In general, the average pore size of thefirst filter 458 should be in the range of about 2 to 25 μm, with a presently preferred pore size of about 5 μm. The average pore size of thesecond filter 464 is selected to be slightly smaller than the average size of the target cells or viruses to be captured (typically in the range of 0.2 to 5 μm). - The
beads 462 are useful for disrupting the captured cells or viruses to release the intracellular material (e.g., nucleic acid) therefrom. Movement of thebeads 462 ruptures the cells or viruses captured on thefilter 464. Suitable beads for rupturing cells or viruses include borosilicate glass, lime glass, silica, and polystyrene beads. The beads may be porous or non-porous and preferably have an average diameter in the range of 1 to 200 pm. In the presently preferred embodiment, thebeads 462 are polystyrene beads having an average diameter of about 100 μm. - The
beads 462 may have a binding affinity for target cells or viruses in the fluid sample to facilitate capture of the target cells or viruses. For example, antibodies or certain receptors may be coated onto the surface of thebeads 462 to bind target cells in the sample. Moreover, thechamber 367 may contain two different types of beads for interacting with target cells or viruses. For example, the chamber may contain a first set of beads coated with antibodies or receptors for binding target cells or viruses and a second set of beads (intermixed with the first set) for rupturing the captured cells or viruses. The beads in the chamber may also have a binding affinity for the intracellular material (e.g., nucleic acid) released from the ruptured cells or viruses. Such beads may be useful for isolating target nucleic acid for subsequent elution and analysis. For example, thechamber 367 may contain silica beads to isolate DNA or cellulose beads with oligo dT to isolate messenger RNA for RT-PCR. Thechamber 367 may also contain beads for removing unwanted material (e.g., proteins, peptides) or chemicals (e.g., salts, metal ions, or detergents) from the sample that might inhibit PCR. - To ensure that the air bubbles can escape from the
chamber 367, it is desirable to use thecontainer 358 in an orientation in which liquid flows up (relative to gravity) through thefilters chamber 367. The upward flow through the chamber 5 367 aids the flow of air bubbles out of the chamber. Thus, theinlet port 442 for entry of fluids into thechamber 367 should generally be at a lower elevation than theoutlet port 444. The volume capacity of thechamber 367 is usually in the range of 50 to 500 μl. The volume capacity of thechamber 367 is selected to provide for concentration of analyte separated from a fluid sample without the chamber being so small that thefilters - The
pieces container 358 are preferably molded polymeric parts (e.g., polypropylene, polycarbonate, acrylic, etc.). Although molding is preferred for mass production, it also possible to machine the top, middle, andbottom pieces pieces container 358. Another method for fabricating thecontainer 358 is to mold the body as a single piece and heat seal theflexible wall 440 and thefilters - FIG. 40 shows a fluidic system for use with the apparatus. The system includes a
bottle 470 for holding lysis buffer, abottle 472 containing wash solution, and asample container 474 for holding a fluid sample. Thebottles sample container 474 are connected via tubing to the valve ports of asyringe pump 476. The inlet port of thecontainer 358 is also connected to thesyringe pump 476. The outlet port of thecontainer 358 is connected to the common port of adistribution valve 478. The system also includes acollection tube 480 for receiving intracellular material removed from the sample, awaste container 482 for receiving waste, and a pressure source, such as apump 484. Thecollection tube 480,waste container 482, and pump 484 are connected to respective peripheral ports of thedistribution valve 478. Apressure regulator 486 regulates the pressure supplied by thepump 484. - A specific protocol will now be described with reference to FIGS.39-40 to illustrate the operation of the
container 358. It is to be understood that this is merely an example of one possible protocol and is not intended to limit the scope of the invention. Thesyringe pump 476 pumps a fluid sample from thesample container 474 through thecontainer 358 and into thewaste container 482. As the fluid sample is forced to flow through the filters in thechamber 367, coarse material is filtered by thefilter 458 and target cells or viruses in the sample are captured by thefilter 464. Thechamber 367 may be sonicated as the sample is forced to flow through the chamber to help prevent clogging of the filters. Next, thesyringe pump 476 pumps wash solution from thebottle 472 through thecontainer 358 and into thewaste container 482. The washing solution washes away PCR inhibitors and contaminants from thechamber 367. - In the next step, the
syringe pump 476 pumps lysis buffer from thebottle 470 into thecontainer 358 so that thechamber 367 is filled with liquid. The lysis buffer should be a medium through which pressure waves can be transmitted. For example, the lysis buffer may comprise deionized water for holding the cells or viruses in suspension or solution. Alternatively, the lysis buffer may include one or more lysing agents to aid in the disruption of the cells or viruses. One of the advantages of the present invention, however, is that harsh lysing agents are not required for successful disruption of the cells or viruses. Next, the distribution valve of thesyringe pump 476 is closed upstream of thecontainer 358, and thedistribution valve 478 is opened. Thepump 484 then pressurized thechamber 367 through theoutlet port 444, preferably to about 20 psi above the ambient pressure. Thedistribution valve 478 downstream of thecontainer 358 is then closed. The static pressure in thechamber 367 is therefore increased to about 20 psi in preparation for the disruption of the cells or viruses trapped on thefilter 464. - Referring again to FIG. 37, the pressurization of the
chamber 367 is important because it ensures effective coupling between thetransducer 314 and theflexible wall 440. To disrupt the cells or viruses in thechamber 367, thetransducer 314 is activated (i.e., set into vibratory motion). Theflexible wall 440 transfers the vibrational motion of thetransducer 314 to the liquid in thechamber 367 by allowing slight deflections without creating high stresses in the wall. Thetransducer 314 is preferably an ultrasonic horn for sonicating thechamber 367. Thechamber 367 is preferably sonicated for 10 to 40 seconds at a frequency in the range of 20 to 60 kHz. In the exemplary protocol, the chamber is sonicated for 15 seconds at a frequency of 40 kHz. The amplitude of the horn tip is preferably in the range of 20 to 25 μm (measured peak to peak). - As the tip of the
transducer 314 vibrates, it repeatedly impacts theflexible wall 440. On its forward stroke (in the upward direction in FIG. 37), the tip of thetransducer 314 pushes thewall 440 and creates a pressure pulse or pressure wave in thechamber 367. On its retreating stroke (downward in FIG. 37), the tip of thetransducer 314 usually separates from theflexible wall 440 because theflexible wall 440 cannot move at the same frequency as the transducer. On its next forward stroke, the tip of thetransducer 314 once again impacts thewall 440 in a head-on collision as the tip and wall speed towards each other. - Because the
transducer 314 and thewall 440 separate as thetransducer 314 vibrates, the effective forward stroke of the transducer is less than its peak-to-peak amplitude. The effective forward stroke determines the level of sonication in thechamber 367. It is therefore important to increase the static pressure in thechamber 367 so that when the tip of thetransducer 314 retreats, theflexible wall 440 is forced outwardly to meet the tip on its return stroke. The static pressure in thechamber 367 should be sufficient to ensure that the effective forward stroke of thetransducer 314 generates the necessary pressure pulses or pressure waves in the chamber to effect cell disruption. It is presently preferred to increase the static pressure in thechamber 367 to at least 5 psi above the ambient pressure, and more preferably to a pressure in the range of 15 to 25 psi above the ambient pressure. - On each forward stroke, the
transducer 314 imparts a velocity to the liquid in thechamber 367, thus creating a pressure wave that quickly sweeps across the chamber. Thebeads 462 in the filter stack 446 (FIG. 38) are agitated by the pressure waves in thechamber 367. The pressure waves propel the beads into violent motion, and the beads mechanically rupture the cells or viruses to release the analyte (e.g., nucleic acid) therefrom. Referring again to FIG. 40, following disruption of the cells or viruses, thesyringe pump 476 pumps the released intracellular material from thecontainer 358 into thecollection tube 480. - FIG. 41 shows another embodiment of the invention in which the
container 358 has asolid wall 488 for contacting thetransducer 314. Thesolid wall 488 differs from theflexible wall 440 previously described with reference to FIG. 37. Whereas the flexible wall is typically a thin film that bends under its own weight and does not hold its shape unless held on its edges, thesolid wall 488 holds it shape when unsupported. The advantage of using a solid wall to contact thetransducer 314 is that there is no need to pressurize thechamber 367 to ensure effective coupling between thewall 488 and thetransducer 314. The elastic restoring force of thesolid wall 488 provides the necessary coupling between the wall and thetransducer 314. However, the proper design of thesolid wall 488 is necessary so that the wall is not damaged (e.g., melted) by the vibratory movements of thetransducer 314. - In particular, the
solid wall 488 should have a natural frequency that is higher than the vibrating frequency at which thetransducer 314 is operated. Preferably, the ratio of the natural frequency of thewall 488 to the vibrating frequency is at least 2:1, and more preferably the ratio is at least 4:1. In addition, thewall 488 should not be so rigid that it cannot transfer the vibratory motion of the transducer to the liquid in thechamber 367. It is preferred that thewall 488 be capable of deflecting a distance in the range of 5 to 40 μm, and more preferably about 20 μm peak to peak when thetransducer 314 applies a force in the range of 1 to 10 lbs. to the external surface of thewall 488. It is more preferable that thewall 488 be capable of deflecting a distance in the range of 5 to 40 μm, and more preferably about 20 μm peak to peak when thetransducer 314 applies a force in the range of 2 to 5 lbs. To achieve these criteria, thewall 488 is dome-shaped and convex with respect to the transducer 314(i.e., thewall 488 curves outwardly towards the transducer). The advantage to the dome-shaped design of thewall 488 is that the dome shape increases the natural frequency of the wall (compared to a flat wall) without causing the wall to be so stiff that it cannot transfer the vibratory movements of thetransducer 314 to thechamber 367. - FIG. 42 shows a cross sectional view of the
wall 488. The dome-shapedportion 495 of the wall preferably has a radius of curvature R in the range of 6.3 to 12.7 mm when the diameter D of the dome-shaped portion is about 11.1 mm. More preferably, the dome-shapedportion 495 of the wall preferably has a radius of curvature R of about 9.5 mm when the diameter D of the dome-shaped portion is about 11.1 mm. Thewall 488 also includes a flatouter rim 497 for clamping thewall 488 in thecontainer 358. Alternatively, thewall 488 may be integrally molded with either ofpieces 450, 452 (FIG. 41). The thickness T of the wall is preferably in the range of 0.25 to 1 mm. If it is less than 0.25 mm thick, thewall 488 may be too weak. If the wall has a thickness greater than 1 mm, the wall may be too stiff to deflect properly in response to the vibratory movements of the transducer. In the presently preferred embodiment, thewall 488 has a thickness T of about 0.5 mm. Thewall 488 is preferably a molded plastic part. Suitable materials for thewall 488 include Delrin® (acetal resins or polymethylene oxide), polypropylene, or polycarbonate. - The interaction of the
transducer 314 with thesolid wall 488 will now be described with reference to FIG. 41. Prior to activating the transducer, target cells or viruses are captured on thefilter 490 by forcing a fluid sample to flow though the chamber 367 (e.g., using the fluidic system previously described with reference to FIG. 40). In addition, thechamber 367 is filled with a liquid (e.g., lysis buffer) as previously described. Unlike the previously described embodiments, however, thechamber 367 does not require pressurization. Instead, it is preferred that ambient pressure is maintained in the chamber. Thetransducer 314 is placed in contact with the external surface of thewall 488, preferably using a support structure as previously described with reference to FIG. 37. In particular, a spring preferably pushes the transducer against thewall 488 with a force in the range of 1 to 10 lbs., and more preferably in the range of 2 to 5 lbs. - To disrupt the cells or viruses in the
chamber 367, thetransducer 314 is activated (i.e., induced into vibratory motion). As the tip of thetransducer 314 vibrates, it deflects thewall 488. On its forward stroke (in the upward direction in FIG. 41), the tip of thetransducer 314 pushes thewall 488 and creates a pressure pulse or pressure wave in thechamber 367. On its retreating stroke (downward in FIG. 41), thewall 488 remains in contact with the tip of thetransducer 314 because thewall 488 has a natural frequency higher than the vibrating frequency of the transducer. In embodiments in which the transducer is an ultrasonic horn for sonicating thechamber 367, thechamber 367 is preferably sonicated for 10 to 40 seconds at a frequency in the range of 20 to 40 kHz. In the exemplary protocol, the chamber is sonicated for 15 seconds at a frequency of 40 kHz. The amplitude of the horn tip is preferably in the range of 20 to 25 μm (measured peak to peak), and the natural frequency of thewall 488 should be greater than 40 kHz, preferably at least 80 kHz, and more preferably at least 160 kHz. - One advantage to using the
solid interface wall 488 is that strong pressure drops can be achieved in thechamber 367 as long as the static pressure in the chamber is low. For example, at atmospheric pressure, cavitation (the making and breaking of microscopic bubbles) can occur in thechamber 367. As these bubbles or cavities grow to resonant size, they collapse violently, producing very high local pressure changes. The pressure changes provide a mechanical shock to the cells or viruses, resulting in their disruption. The disruption of the cells or viruses may also be caused by sharp pressure rises resulting from the vibratory movement of thetransducer 314. In addition, the disruption of the cells or viruses may be caused by the violent motion of thebeads 462 in thechamber 367. The beads are agitated by the dynamic pressure pulses in the chamber and rupture the cells or viruses. In experimental testing, the applicants have found that it is usually necessary to use beads to disrupt certain types of cells (particularly spores) having highly resistant cell walls. Other types of cells, such as blood cells, are easier to disrupt and may often be disrupted without the use of thebeads 462. - Although the use of an ultrasonic transducer has been described as a preferred embodiment, it is to be understood that different types of transducers may be employed in the practice of the present invention. The transducer should be capable of creating pressure pulses or pressure waves in the
chamber 367. In addition, the transducer should be capable of providing high velocity impacts to the liquid in the chamber. Suitable transducers include ultrasonic, piezoelectric, magnetostrictive, or electrostatic transducer. The transducer may also be an electromagnetic device having a wound coil, such as a voice coil motor or a solenoid device. The vibrating frequency of the transducer may be ultrasonic (i.e., above 20 kHz) or below ultrasonic (e.g., in the range of 60 to 20,000 Hz). The advantage to using higher frequencies is that cell disruption is very rapid and can often be completed in 10 to 20 seconds. The disadvantage is that ultrasonic transducers are often more expensive than a simple mechanical vibrator, e.g., a speaker or electromagnetic coil device. In one alternative embodiment, for example, thesolid wall 488 is used in combination with a speaker or electromagnetic coil device that vibrates at an operating frequency in the range of 5 to 10 kHz. - FIGS.43A-43B illustrate another
solid wall 500 for contacting a transducer according to the present invention. As shown in FIG. 43A, one side of thewall 500 has acentral portion 502 and a plurality of stiffeningribs 504 extending radially from thecentral portion 502. The wall also hasrecesses 506 formed between theribs 504. As shown in FIG. 43B, the other side of thewall 500 has aflat surface 508. FIG. 44 shows a partially-cut away isometric view of thecontainer 358 with thewall 500. Thewall 500 is preferably positioned so that the side of the wall having the flat surface is internal to thechamber 367 and such that the side of the wall having theribs 504 is external to the chamber. Theribs 504 are advantageous because they increase the natural frequency of the wall without causing the wall to be so stiff that it cannot transfer the vibratory movements of the transducer to thechamber 367. - FIG. 45 shows a bottom plan view of the
container 358 having thewall 500. Thecentral portion 502 provides the external surface of thewall 500 for contacting a transducer. The interaction of thewall 500 with the transducer is analogous to the interaction of thewall 488 with the transducer previously described with reference to FIG. 41. In particular, thewall 500 remains in contact with the tip of the transducer because thewall 500 has a natural frequency higher than the vibrating frequency of the transducer. Consequently, pressurization is not required, and cavitation may be achieved. Thesolid walls container 358 or thewalls - Although the above description contains many specificities, these should not be construed as limitations on the scope of the invention, but merely as illustrations of some of the presently preferred embodiments. Many possible variations and modifications to the invention will be apparent to one skilled in the art upon consideration of this disclosure.
- Therefore, the scope of the invention should be determined by the following claims and their legal equivalents.
Claims (20)
1. A device for use with a transducer to separate an analyte from a fluid sample, the device comprising a cartridge having:
a) a sample flow path;
b) a lysing chamber in the sample flow path for lysing cells or viruses to release the analyte therefrom, wherein the lysing chamber contains at least one filter for capturing the cells or viruses from the sample as the sample flows through the lysing chamber, the cartridge includes at least one wall defining the lysing chamber, and the wall has an external surface for contacting the transducer to sonicate the lysing chamber;
c) a waste chamber in fluid communication with the lysing chamber via the sample flow path for receiving the remaining sample fluid after the sample flows through the lysing chamber;
d) a third chamber connected to the lysing chamber via an analyte flow path for receiving the analyte separated from the sample; and
e) at least one flow controller for directing the sample into the waste chamber after the sample flows through the lysing chamber and for directing the analyte separated from the sample into the third chamber.
2. The device of claim 1 , wherein the third chamber comprises a mixing chamber for mixing the analyte with one or more reagents.
3. The device of claim 2 , wherein the cartridge further includes a reaction chamber in fluid communication with the mixing chamber for holding the analyte for chemical reaction or optical detection.
4. The device of claim 2 , wherein the cartridge further includes:
i) a reaction chamber in fluid communication with the mixing chamber for amplifying the analyte; and
ii) a capillary electrophoresis area in communication with the reaction chamber.
5. The device of claim 1 , wherein the third chamber comprises a reaction chamber for amplifying the analyte and holding the analyte for optical detection, and wherein the cartridge is in combination with an instrument having a heater for heating the reaction chamber and having at least one optical detector for detecting the analyte.
6. The device of claim 1 , wherein the third chamber comprises a reaction chamber for amplifying the analyte, and the cartridge further comprises a capillary electrophoresis area in communication with the reaction chamber.
7. The device of claim 1 , wherein the wall is dome-shaped and convex with respect to the transducer.
8. The device of claim 1 , wherein the wall comprises a sheet or film of polymeric material.
9. The device of claim 8 , wherein the wall has a thickness in the range 0.025 to 0.1 mm.
10. The device of claim 1 , wherein the wall has stiffening ribs.
11. The device of claim 10 , wherein the ribs extend radially from a central portion of the wall.
12. The device of claim 1 , further comprising beads disposed in the lysing chamber for rupturing the cells or viruses.
13. The device of claim 12 , wherein the beads further have a binding affinity for the cells or viruses to be disrupted.
14. The device of claim 12 , wherein the beads further have a binding affinity for the analyte.
15. The device of claim 1 , wherein the lysing chamber contains a first set of beads for binding the cells or viruses and a second set of beads for rupturing the cells or viruses.
16. The device of claim 1 , wherein the cartridge includes a first filter in the sample flow path for filtering coarse material from the sample and a second filter in the lysing chamber, the second filter having a smaller average pore size than the first filter
17. The device of claim 16 , wherein both the first and second filters are positioned in the lysing chamber, and wherein beads are disposed between the filters.
18. The device of claim 17 , further comprising a third filter in the lysing chamber, wherein the third filter is spaced from the second filter, and the third filter has a smaller average pore size than the second filter.
19. The device of claim 18 , wherein the cartridge includes a first set of beads disposed between the first and second filters and a second set of beads disposed between the second and third filters.
20. The device of claim 19 , wherein the average diameter of the beads in the first set differs from the average diameter of the beads in the second set.
Priority Applications (4)
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US09/970,434 US20020019060A1 (en) | 1999-05-28 | 2001-10-02 | Device for analyzing a fluid sample |
US11/977,697 US9789481B2 (en) | 1999-05-28 | 2007-10-24 | Device for extracting nucleic acid from a sample |
US11/977,615 US8580559B2 (en) | 1999-05-28 | 2007-10-24 | Device for extracting nucleic acid from a sample |
US13/081,060 US9156032B2 (en) | 1999-05-28 | 2011-04-06 | Apparatus and method for analyzing fluid sample |
Applications Claiming Priority (4)
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US09/331,911 US6440725B1 (en) | 1997-12-24 | 1998-12-24 | Integrated fluid manipulation cartridge |
US13670399P | 1999-05-28 | 1999-05-28 | |
US09/583,807 US6391541B1 (en) | 1999-05-28 | 2000-05-30 | Apparatus for analyzing a fluid sample |
US09/970,434 US20020019060A1 (en) | 1999-05-28 | 2001-10-02 | Device for analyzing a fluid sample |
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US09/583,807 Continuation US6391541B1 (en) | 1999-05-28 | 2000-05-30 | Apparatus for analyzing a fluid sample |
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US13/081,060 Continuation US9156032B2 (en) | 1999-05-28 | 2011-04-06 | Apparatus and method for analyzing fluid sample |
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US09/800,590 Expired - Lifetime US6881541B2 (en) | 1999-05-28 | 2001-03-06 | Method for analyzing a fluid sample |
US09/970,434 Abandoned US20020019060A1 (en) | 1999-05-28 | 2001-10-02 | Device for analyzing a fluid sample |
US11/977,697 Expired - Lifetime US9789481B2 (en) | 1999-05-28 | 2007-10-24 | Device for extracting nucleic acid from a sample |
US11/977,615 Expired - Lifetime US8580559B2 (en) | 1999-05-28 | 2007-10-24 | Device for extracting nucleic acid from a sample |
US13/081,060 Expired - Lifetime US9156032B2 (en) | 1999-05-28 | 2011-04-06 | Apparatus and method for analyzing fluid sample |
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US09/801,077 Expired - Lifetime US6783736B1 (en) | 1999-05-28 | 2001-03-06 | Cartridge for analyzing a fluid sample |
US09/800,590 Expired - Lifetime US6881541B2 (en) | 1999-05-28 | 2001-03-06 | Method for analyzing a fluid sample |
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US13/081,060 Expired - Lifetime US9156032B2 (en) | 1999-05-28 | 2011-04-06 | Apparatus and method for analyzing fluid sample |
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EP (2) | EP1208189B1 (en) |
JP (2) | JP4078073B2 (en) |
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