US20080038813A1 - Sample vessels - Google Patents
Sample vessels Download PDFInfo
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- US20080038813A1 US20080038813A1 US11/740,650 US74065007A US2008038813A1 US 20080038813 A1 US20080038813 A1 US 20080038813A1 US 74065007 A US74065007 A US 74065007A US 2008038813 A1 US2008038813 A1 US 2008038813A1
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- sample
- vessel
- tubule
- sample vessel
- flexible body
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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
- B01L3/505—Containers for the purpose of retaining a material to be analysed, e.g. test tubes flexible containers not provided for above
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B5/00—Measuring for diagnostic purposes; Identification of persons
- A61B5/15—Devices for taking samples of blood
- A61B5/150007—Details
- A61B5/150015—Source of blood
- A61B5/150022—Source of blood for capillary blood or interstitial fluid
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- A—HUMAN NECESSITIES
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- A61B5/15—Devices for taking samples of blood
- A61B5/150007—Details
- A61B5/150015—Source of blood
- A61B5/15003—Source of blood for venous or arterial blood
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- A—HUMAN NECESSITIES
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- A61B5/15—Devices for taking samples of blood
- A61B5/150007—Details
- A61B5/150343—Collection vessels for collecting blood samples from the skin surface, e.g. test tubes, cuvettes
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61B5/15—Devices for taking samples of blood
- A61B5/150007—Details
- A61B5/150351—Caps, stoppers or lids for sealing or closing a blood collection vessel or container, e.g. a test-tube or syringe barrel
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61B5/150007—Details
- A61B5/150755—Blood sample preparation for further analysis, e.g. by separating blood components or by mixing
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61B5/15—Devices for taking samples of blood
- A61B5/150007—Details
- A61B5/150763—Details with identification means
- A61B5/150786—Optical identification systems, e.g. bar codes, colour codes
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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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- 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
- B01L7/525—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 with physical movement of samples between temperature zones
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N35/00—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor
- G01N35/00009—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor provided with a sample supporting tape, e.g. with absorbent zones
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N35/00—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor
- G01N35/10—Devices for transferring samples or any liquids to, in, or from, the analysis apparatus, e.g. suction devices, injection devices
- G01N35/1002—Reagent dispensers
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- A—HUMAN NECESSITIES
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- A61B5/15—Devices for taking samples of blood
- A61B5/150007—Details
- A61B5/150206—Construction or design features not otherwise provided for; manufacturing or production; packages; sterilisation of piercing element, piercing device or sampling device
- A61B5/150221—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
- B01L2300/00—Additional constructional details
- B01L2300/04—Closures and closing means
- B01L2300/041—Connecting closures to device or container
- B01L2300/044—Connecting closures to device or container pierceable, e.g. films, membranes
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- B—PERFORMING OPERATIONS; TRANSPORTING
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- B01L2300/06—Auxiliary integrated devices, integrated components
- B01L2300/0627—Sensor or part of a sensor is integrated
- B01L2300/0636—Integrated biosensor, microarrays
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- B—PERFORMING OPERATIONS; TRANSPORTING
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- B01L2300/08—Geometry, shape and general structure
- B01L2300/0809—Geometry, shape and general structure rectangular shaped
- B01L2300/0816—Cards, e.g. flat sample carriers usually with flow in two horizontal directions
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- B—PERFORMING OPERATIONS; TRANSPORTING
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- B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
- B01L2300/00—Additional constructional details
- B01L2300/08—Geometry, shape and general structure
- B01L2300/0832—Geometry, shape and general structure cylindrical, tube shaped
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- B—PERFORMING OPERATIONS; TRANSPORTING
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- B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
- B01L2300/00—Additional constructional details
- B01L2300/18—Means for temperature control
- B01L2300/1805—Conductive heating, heat from thermostatted solids is conducted to receptacles, e.g. heating plates, blocks
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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
- B01L2400/0481—Moving fluids with specific forces or mechanical means specific mechanical means and fluid pressure squeezing of channels or 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
- B01L2400/06—Valves, specific forms thereof
- B01L2400/0633—Valves, specific forms thereof with moving parts
- B01L2400/0655—Valves, specific forms thereof with moving parts pinch 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
- B01L2400/0677—Valves, specific forms thereof phase change valves; Meltable, freezing, dissolvable plugs; Destructible barriers
- B01L2400/0683—Valves, specific forms thereof phase change valves; Meltable, freezing, dissolvable plugs; Destructible barriers mechanically breaking a wall or membrane within a channel or chamber
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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
- B01L3/5027—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip
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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
- B01L3/508—Containers for the purpose of retaining a material to be analysed, e.g. test tubes rigid containers not provided for above
- B01L3/5082—Test tubes per se
- B01L3/50825—Closing or opening means, corks, bungs
Abstract
A device for processing a biological sample includes a processing unit having at least one opening to receive a sample vessel and a plurality of processing stations positioned along the opening. The processing stations each have a compression member adapted to compress the sample vessel within the opening and thereby move a substance within the sample vessel among the processing stations. An energy transfer element can be coupled to one or more of the processing stations for transferring thermal energy to the content at a processing station.
Description
- This application is a continuation of U.S. application Ser. No. 10/241,816, filed Sep. 11, 2001, which is a continuation-in-part of U.S. patent application Ser. No. 09/782,732, filed Feb. 13, 2001, now U.S. Pat. No. 6,780,617, which claims the benefit of U.S. Provisional Patent Application Ser. No. 60/259,025, filed Dec. 29, 2000. application Ser. No. 10/241,816 is also a continuation-in-part of U.S. patent application Ser. No. 09/910,233, filed Jul. 20, 2001, now U.S. Pat. No. 6,748,332, which is a continuation of U.S. patent application Ser. No. 09/339,056, filed Jun. 23, 1999, now U.S. Pat. No. 6,318,191, which claims the benefit of U.S. Provisional Patent Application Ser. No. 60/090,471, filed Jun. 24, 1998. application Ser. No. 10/241,816 further claims the benefit of U.S. Provisional Patent Application Ser. No. 60/318,768, filed Sep. 11, 2001. Each of the aforementioned patent applications and patents is incorporated herein by reference.
- Portions of the disclosed subject matter were made with government support under grant numbers 1R43HL65768, 1R43HL65867 and 1R43HL67568 awarded by the National Institutes of Health. The government has certain rights in those portions.
- As result of the Human Genome Project and other genetic research, a tremendous amount of genomic and biomarker information is presently available to healthcare providers. Using molecular diagnostic testing, genomic and biomarker information can provide a resource to healthcare providers to assist in the rapid and accurate diagnosis of illness. However, the development of diagnostic testing systems allowing the use of such genetic information, particularly in the clinical setting, has failed to match pace with the genetic research providing the information. Current diagnostic testing systems are mainly limited to large medical testing centers or research labs due to the high costs associated with acquiring and operating the systems and the complexity of the molecular diagnostic assays being employed. These current systems require a large initial capital investment and incur high costs for reagents, disposables, operation, maintenance, service and training.
- Sample preparation and handling generally includes sample collection and any preprocessing required for subsequent biological and chemical assays. Sample collection and handling is an important part of in vitro diagnostic (IVD) testing, and is an important factor in determining the feasibility of test automation. With the advancement of medicine, the number of possible assays available to perform is continually increasing. In parallel, sample collection methods have evolved over the last several decades. In the case of blood sample collection, for example, disposable plastic syringes first replaced glass syringes to improve safety. Later developments had vacuum tubes replacing the traditional syringes to simplify the blood collection process. However, a vacuum tube is generally not suitable for use as an IVD test reaction chamber. Thus, a re-sampling process is necessary for delivery of the sample to distinct assay containers for each of a variety of IVD tests. Automation of these processes is a daunting task. Indeed, in large clinical testing centers giant automation testing systems costing several million dollars are currently used. The major automated task in these machines is liquid handling, which entails the pipetting of the sample from sample tubes to 96-well plates, the addition of the reagent(s) to the wells, as well as moving reaction mixtures from well to well.
- Recently, nanotechnology has emerged to revolutionize automation and testing formats. In this direction, by using silicone micro-fabrication and etching technology, the lab-on-a-chip platform was developed in an attempt to integrate and miniaturize certain parts of the automation process into a chip with dimensions less than 2 mm by 2 mm. Liquid processing rates for certain lab-on-a-chip platforms can be on the scale of nanoliters per second. However, it is often difficult for users to interface with this type of platform to, for example, deliver the sample to the chip.
- Another concern of current sample handling devices is the large sample volume routinely drawn from a patient for IVD testing. In the case of blood sample collection, for example, a small vacuum tube may take close to 5 ml whole blood. When multiple samples are required in the testing of various assays, several tubes of blood are frequently ordered. However, only a small amount is needed for each assay. The drawing of a large volume of blood for multiple tests is a concern for pediatric patients as it can lead to iron deficiency anemia. It is even more critical for patients with pre-existing anemia or a bleeding disorder.
- The present invention provides sample processing devices and methods that facilitate the rapid analysis of biological samples, such as blood, saliva, or urine, in an efficient and cost effective manner with minimal, if any, exposure to biohazards. The sample processing devices and methods of the present invention are particularly suited to the clinical setting, allowing the clinician to readily proceed from acquisition of a test sample to analysis of the test results, with minimal human intervention. The sample processing devices of the present invention may be implemented as a hand-held system suitable for the processing of a single sample or as a larger, bench top unit suitable for the simultaneous processing of multiple samples. The present invention may be valuable in all diagnostic and therapeutic monitoring areas, including in the point-of-care or clinical setting, in high-throughput screening, and in biological warfare detection. In addition, the present invention provides a sample vessel for holding a biological sample throughout the processing of the sample.
- In accordance with one embodiment of the present invention, a device for processing a sample includes a processing unit having an opening to receive a sample vessel and at least one processing station positioned along the opening. The processing station includes a compression member adapted to compress the sample vessel within the opening and thereby displace a content of the sample vessel within the sample vessel. The content displaced by the compression member can be, for example, the sample, a reagent, or a mixture of the content and a reagent
- In accordance with another aspect, the processing station may include an energy transfer element for transferring energy to or from the content within the sample vessel and a control system coupled to the energy transfer element to control the energy transferred to or from the content. The energy transfer element can be, for example, an electronic heat element, a microwave source, a light source, an ultrasonic source or a cooling element.
- In accordance with a further aspect, the energy transfer element transfers thermal energy to or from the content within the sample vessel. An energy insulator may be positioned adjacent the processing station. The energy insulator can be, for example, an energy shielding layer, an energy absorption layer, an energy refraction layer, or a thermal insulator, depending on the type of energy transfer element employed. A temperature sensor may be coupled to the control system to monitor temperature at the processing station. Alternatively, the processing station may include a heat sink to dissipate thermal energy from the processing station.
- In accordance with another aspect, the processing station may include a stationary member opposing the compression member across the opening. The compression member can operate to compress the sample vessel against the stationary member within the opening.
- In accordance with a further aspect, a driver may be coupled to the compression member to selectively move the compression member and thereby compress the sample vessel within the opening. The driver can be, for example, a motor coupled to the compression member by a cam. Alternatively, the driver can be an electromagnetic actuating mechanism.
- In accordance with another aspect, the processing device can include a sensor for detecting a signal from the content within the sample vessel. An energy source can optionally be provided for applying energy to the content within the sample vessel to generate a signal from the content. In one embodiment, the processing device can include an electrophoresis system comprising a pair of electrodes adapted to have a predetermined voltage difference and an electrode actuator for inserting the electrodes into the sample vessel.
- In accordance with a further aspect, the processing device may include a reagent injector cartridge actuator adapted to receive a reagent injector cartridge having at least one needle in fluid communication with a reagent reservoir. The reagent injector cartridge actuator can be operable to move the reagent injector cartridge to inject a quantity of reagent into the sample vessel.
- In accordance with another embodiment of the invention, a sample vessel for holding a sample includes a sample containing portion for holding the sample and a handling portion for handling the sample vessel. The sample containing portion can have a wall constructed of a flexible material permitting substantial flattening of a selected segment of the sample containing portion. The handling portion can be coupled to the sample containing portion and preferably has a generally rigid construction to facilitate handling of the sample vessel.
- In accordance with another aspect, the sample containing portion of the sample vessel can be a tubule.
- In accordance with a further aspect, the sample vessel can include at least one pressure gate disposed within the sample containing portion to divide the sample containing portion into a plurality of segments. At least one of the segments of the sample vessel can have a filter contained therein that is structured to separate selected components of a sample material from other components of the sample material. Additionally, at least one of the segments of the sample vessel can contain a reagent. The reagent can be, for example, an anticoagulant, a cell lyses reagent, a nucleotide, an enzyme, a DNA polymerase, a template DNA, an oligonucleotide, a primer, an antigen, an antibody, a dye, a marker, a molecular probe, a buffer, or a detection material. The sample containing portion also can include an electrophoresis segment containing a gel for electrophoresis. The electrophoresis segment can include a pair of electrodes adapted to maintain a predetermined voltage difference therebetween. Additionally, one of the segments can contain multilayer membranes or a micro-array bio-chip for analyzing the sample.
- In accordance with another aspect, the sample containing portion can include a self-sealing injection channel formed therein. The self sealing injection channel is preferably normally substantially free of sample material and capable of fluid communication with the sample material in the sample containing portion.
- In accordance with another aspect, the sample vessel can include an instrument for obtaining a sample coupled to the sample vessel.
- In accordance with a further aspect, the handling portion of the sample vessel includes an opening for receiving a sample. The sample vessel also can include a closure for selective closing the opening. Preferably, the closure seats against the handling portion to close the opening. In addition, the instrument for obtaining a sample can be coupled to the closure of the sample vessel.
- In accordance with another aspect, the handling portion has a wall thickness greater than a thickness of the wall of the sample containing portion. Preferably, the thickness of the wall of the sample containing portion is less than or equal to 0.3 mm. In one embodiment, the handling portion can include a cylindrical sleeve sized and shaped to fit over a portion of the sample containing portion. The handling portion is preferably positioned longitudinally adjacent the sample containing portion.
- In accordance with another embodiment, a sample vessel for holding a sample includes a sample containing portion having at least one pressure gate disposed within the sample containing portion to divide the sample containing portion into a plurality of segments. Preferably, at least one segment of the sample containing portion has a wall constructed of a flexible material permitting substantial flattening of the segment of the sample containing portion.
- In accordance with another embodiment, a method of processing a sample within a sample vessel includes the steps of introducing the sample vessel into a device for processing the sample and compressing the sample vessel to move the sample within the sample vessel from a first segment to a second segment of the sample vessel.
- In accordance with another aspect, the method of processing a sample can include the step of introducing a reagent to the sample within a segment of the sample vessel.
- In accordance with a further aspect, the method of processing a sample can include the step of heating the sample in the first segment to a first temperature. The method can also include the step of heating the sample to a second temperature in the second segment. In one embodiment, the first temperature can be effective to denature the sample and the second temperature is one at which nucleic acid annealing and nucleic acid synthesis can occur. The method of processing a sample can further include the steps of compressing the sample vessel to move the sample within the sample vessel from the second segment to the first segment of the sample vessel and heating the sample to the first temperature in the first segment.
- In accordance with another aspect, the method of processing the sample can include the step of analyzing the sample by detecting a signal from the sample within a segment of the sample vessel and analyzing the detected signal to determine a condition of the sample. The analyzing step can include applying an excitation energy to the sample within the segment of the sample vessel. Additionally, the analyzing step can include conducting electrophoresis analysis of the sample by applying a selective voltage to the sample within a segment of the sample vessel, detecting light emitted from the sample, and analyzing the detected light to determine a condition of the sample.
- Alternatively, the analyzing step can include applying an excitation energy to a bio-array member contained within a segment of the sample vessel, detecting light emitted from the bio-array member, and analyzing the detected light to determine a condition of the sample. The bio-array member can be, for example, a multi-layer membrane or a micro-array bio-chip.
- In accordance with a further aspect, the method of processing a sample can include the step of agitating the sample within a segment of the sample vessel.
- In accordance with another embodiment, a method of treating a sample within a sample vessel can include the steps of introducing the sample vessel into a device for processing the sample within the sample vessel and compressing one of the segments to mix the reagent with the sample within the sample vessel. Preferably, the sample vessel has a plurality of segments including a segment for containing a reagent and a segment for containing the sample.
- In accordance with another aspect, the method of processing the sample can include the step of introducing the reagent into a reagent segment of the sample after the step of introducing the sample vessel into the device for processing the sample.
- In accordance with another embodiment, a thermal cycler includes a processing unit having an opening to receive a sample vessel containing a sample. The processing unit can have a first processing station, a second processing station, and a third processing station positioned along the opening. The first processing station can include a first compression member adapted to compress the sample vessel within the opening and a first energy transfer element for transferring energy to the sample at the first processing station. The second processing station can include a second compression member adapted to compress the sample vessel within the opening and a second energy transfer element for transferring energy to the sample at the second processing station. The third processing station can include a third compression member adapted to compress the sample vessel within the opening and a third energy transfer element for transferring energy to the sample at the third processing station. Compression of the sample vessel by of one of the compression members can displace the sample within the sample vessel between the processing stations.
- The present disclosure is also directed to sample vessels that can permit the collection and the processing of biological and chemical samples, such as, for example, blood, saliva, tissue, or urine, in a closed system. Sample devices disclosed herein may provide a uniform sample handling system that simplifies the sample collection process and reduces exposure to biohazards. One or more of the sample vessels disclosed herein can accommodate multiple fluid samples and a plurality of assays of different types, while concomitantly reducing the volume of sample necessary for testing.
- In accordance with one exemplary embodiment, a sample vessel may comprise a tubule having an opening for receiving a sample material and at least one compressible section, a generally rigid container receiving at least a portion of the tubule, and an interface in fluid communication with the opening in the tubule. The at least one compressible section may have a wall constructed at least partially from a material having sufficient flexibility to permit compression of opposed sections of the wall into contact. The interface may facilitate delivery of a sample material to the tubule through the opening.
- In accordance with another exemplary embodiment, a sample vessel may comprise a tubule having a plurality of lumens and a wall constructed at least partially from a material having sufficient flexibility to permit compression of opposed sections of the wall into contact with one another, and a pressure gate connecting at least two lumens of the plurality of lumens. The pressure gate may permit selective fluid flow between the at least two lumens.
- In accordance with another exemplary embodiment, a sample vessel may comprise a tubule having a wall that forms a lumen when the tubule is in an open configuration. The wall may have a plurality of sections including at least a first section of the wall having sufficient flexibility to permit compression of a portion of the tubule and at least a second section of the wall having sufficient rigidity to support a flow channel within the tubule during compression of the tubule.
- In accordance with another exemplary embodiment, an apparatus for drawing a sample into a sample vessel may comprise a cylindrical housing having an opening for receiving the sample vessel, first means for compressing a first portion of the sample vessel, and second means for compressing a second portion of the sample vessel. The first compression means may be positioned at a proximal end of the housing and the second compression means may be positioned at a distal end of the housing.
- These and other features and advantages of the sample vessels and processing devices and methods disclosed herein will be more fully understood by reference to the following detailed description in conjunction with the attached drawings in which like reference numerals refer to like elements through the different views. The drawings illustrate principles of the sample vessels and methods disclosed herein and, although not to scale, show relative dimensions.
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FIG. 1 is a schematic diagram of a device for processing a sample according to the present invention; -
FIG. 2 is a schematic diagram of the device ofFIG. 1 , illustrating a compression member of a processing station of the device compressing the sample vessel; -
FIG. 3 is a schematic diagram of an alternative embodiment of a device for processing a sample according to the present invention; -
FIG. 4 is a schematic diagram of an alternative embodiment of a device for processing a sample according to the present invention; -
FIG. 5 is a perspective view of an embodiment of a hand held device for processing a sample according to the present invention; -
FIG. 6 is a perspective view of an embodiment of a bench top device for processing a sample according to the present invention; -
FIG. 7 is a perspective view of the device ofFIG. 6 , illustrating the device with the top cover removed; -
FIG. 8 is a perspective view of an embodiment of a thermal cycling processing unit according to the present invention; -
FIG. 9 is a perspective view of the processing unit ofFIG. 8 ; -
FIG. 10 is a partially exploded, perspective view of a processing station of the processing unit ofFIG. 8 , illustrating a heat block unit and an insulator block unit of the processing station; -
FIG. 11 is a partially exploded, perspective view of the processing unit ofFIG. 8 , illustrating a plurality of heating block units and insulator block units; -
FIG. 12 is a partially exploded, perspective view of a processing station of an alternative embodiment of a processing unit according to the present invention; -
FIGS. 13A-13G are side elevational views, in cross-section, of a processing unit of the present invention, illustrating the operation of the processing unit; -
FIG. 14 is a side elevational view, in cross section, of a gel electrophoresis analysis unit of the present invention; -
FIGS. 15A-15B are side elevational views, in cross-section, of embodiments of a sample vessel according to the present invention; -
FIG. 16 is a side elevation view, in cross section, of a portion of a sample vessel according to the present invention, illustrating an injection channel formed in the sample vessel; -
FIG. 17 is a side elevational view of a reagent cartridge according to the present invention; -
FIG. 18 is a side elevational view, in cross-section, of a sample vessel according to the present invention; -
FIGS. 19A-19C illustrate an alternative embodiment of a processing unit of the present invention. -
FIG. 20A is a perspective view of an exemplary embodiment of a sample vessel; -
FIG. 20B is a side-elevational view in cross-section of the sample vessel ofFIG. 20A ; -
FIG. 20C is an exploded view of the sample vessel ofFIG. 20A , illustrating the tubule and collar removed from the container; -
FIG. 21A is a perspective view of an exemplary embodiment of a sample vessel; -
FIG. 21B is a side-elevational view in cross-section of the sample vessel ofFIG. 21A ; -
FIG. 21C is an exploded view of the sample vessel ofFIG. 21A , illustrating the tubule and collar removed from the container; -
FIGS. 22A-22B are side-elevational views in cross-section of an exemplary embodiment of a sample vessel having a pair of lumens separated by a pressure gate; -
FIG. 23 is a side-elevational view in cross-section of an exemplary embodiment of a sample vessel having three lumens separated by a pair of pressure gates; -
FIG. 24 is a side-elevational view in cross-section of another exemplary embodiment of a sample vessel having three lumens separated by a pair of pressure gates, illustrating a self-sealing, reinforced wall section for facilitating injection by a needle; -
FIG. 25A is a perspective view of an exemplary embodiment of a sample vessel having a pair of lumens connected by a micro-fluidic channel; -
FIGS. 25B-25C are digital photographs of the sample vessel ofFIG. 25A illustrating fluid flow through the lumens of the sample vessel; -
FIG. 26A is a perspective view of an exemplary embodiment of a segmented sample vessel having a plurality of lumens; -
FIGS. 26B and 26C are cross-sectional views of the sample vessel ofFIG. 26A ; -
FIG. 27 a perspective view of another exemplary embodiment of a segmented sample vessel having a plurality of lumens, illustrating a hinged cover for the sample vessel; -
FIG. 28 a perspective view of an exemplary embodiment of a segmented sample vessel having a plurality of lumens, illustrating alternative interfaces for the sample vessel; -
FIG. 29A is a side elevational view in partial cross-section of an exemplary embodiment of a sample vessel, illustrating the compression of the sample vessel; -
FIG. 29B is a cross-sectional view of the sample vessel ofFIG. 29A taken along a line transverse to the longitudinal axis of thetubule 1200; -
FIGS. 30A-30C are side elevational views in cross-section of an exemplary embodiment of a sample vessel, illustrating compression of the sample vessel into a plurality of configurations; -
FIG. 31 is a side elevational view in cross-section of an exemplary embodiment of a sample vessel having a composite cross-section and a micro-fluidic flow channel; -
FIGS. 32A-32B are side elevational views in cross-section of another exemplary embodiment of a sample vessel having a composite cross-section and a micro-fluidic flow channel, illustrating the sample vessel in a open configuration (FIG. 32A ) and a compressed configuration (FIG. 32B ); -
FIG. 33A is a side elevational view in cross-section of an exemplary embodiment of a sample vessel having a plurality micro-fluidic flow channels interconnecting a plurality of depressions formed on an interior wall surface of the sample vessel; -
FIG. 33B is a top view of an interior wall surface of the sample vessel ofFIG. 33A ; -
FIGS. 34A and 34B are side elevational views in cross-section of an exemplary embodiment of a sample vessel having a composite cross-section including opposed planar wall sections, illustrating the sample vessel in an open configuration (FIG. 34A ) and a compressed configuration (FIG. 34B ); -
FIG. 35A is a perspective view of an exemplary embodiment of a sample vessel having an adapter for facilitating handling of the sample vessel and/or connecting of the sample vessel to an external device; -
FIGS. 35B-35E are side elevational views in cross-section of a plurality of exemplary embodiments of an adapter connected to the sample vessel illustrated inFIG. 35A ; -
FIGS. 36A-36E are perspective views of an apparatus for drawing a sample into a sample vessel, illustrating the operation of the apparatus; and -
FIG. 37 is a perspective view of another exemplary embodiment of a sample vessel, illustrating the sample vessel with a portion of the wall removed to show a microarray on an interior surface of the wall of the sample vessel. - To provide an overall understanding, certain exemplary embodiments will now be described; however, it will be understood by one of ordinary skill in the art that the sample vessels and methods described herein can be adapted and modified to provide devices and methods for other suitable applications and that other additions and modifications can be made without departing from the scope of the present disclosure.
- Unless otherwise specified, the exemplary embodiments described below can be understood as providing exemplary features of varying detail of certain embodiments, and therefore, unless otherwise specified, features, components, modules, and/or aspects of the exemplary embodiments can be otherwise combined, separated, interchanged, and/or rearranged without departing from the scope of the present disclosure. Additionally, the shapes and sizes of components are also exemplary and unless otherwise specified, can be altered without affecting the disclosed devices or methods.
- The present disclosure provides devices and methods for processing a sample. The term “processing” as used herein generally refers to the preparation, treatment, analysis, and/or the performance of other testing protocols or assays on a content of the sample vessel in one or more steps. Exemplary processing steps include, for example: displacing a content, e.g., the sample or a reagent, of the sample vessel within the sample vessel to, for example, adjust the volume of the content, separate content components, mix contents within the sample vessel; effecting a chemical or biological reaction within a segment of the sample vessel by, for example, introducing a reagent to the sample, agitating the sample, transferring thermal energy to or from the sample, incubating the sample at a specified temperature, amplifying components of the sample, separating and/or isolating components of the sample; or analyzing the sample to determine a characteristic of the sample, such as, for example, the quantity, volume, mass, concentration, sequence, or nucleic acid size or other analyte size, of the sample. One skilled in the art will appreciate that the forgoing exemplary processing steps are described herein for illustrative purposes only. Other processing steps may be employed without departing from the scope of the present invention.
- A device for processing a sample according to the present invention can integrate one or more processing units into a single system depending on the process being employed. The processing units can include one or more processing stations at which one or more processing steps can be performed on the sample within the sample vessel. Sample materials that can be processed according to the present invention are generally biological samples or samples containing biological substance and include, for example, blood, urine, saliva, cell suspensions, biofluids, a piece of tissue, soil or other samples. A sample processing device of the present invention is particularly suited for nucleic acid amplification, such as polymerase chain reaction (PCR) or ligase chain reaction (LCR) amplification, and can include, for example, a sample pretreatment unit for extracting nucleic acid from sample, a thermal cycling reaction unit for amplification of the nucleic acid or signal, and (optionally) an analysis or detection unit for analyzing the amplified product. The sample processing device of the present invention can also be used for isothermal reaction of nucleic acid or signal amplifications, such as strand displacement amplification (SDA), rolling circle amplification (RCA), and transcription-mediated amplification (TMA). Other exemplary processes to be performed on samples can include clinical diagnosis, therapeutic monitoring, and screening of chemical compounds for discovery of new drugs. The following description primarily focuses on PCR amplification for illustration. However, one skilled in the art will appreciate that the devices and methods of the present invention are not limited to PCR amplification, as the devices and methods described below can be employed in other sample processing.
- An exemplary embodiment of a device for processing a sample is illustrated in
FIG. 1 . Theprocessing device 10 illustrated inFIG. 1 includes aprocessing unit 12 having anopening 14 to receive asample vessel 16. Theopening 14 can be a tubular shaped opening, an open-faced slot or other structure for receiving thesample vessel 16 in a removable and replaceable manner. Theprocessing unit 12 includes afirst processing station 18 and asecond processing station 20, each positioned along the length of theopening 14. Thefirst processing station 18 includes acompression member 22 adapted to compress thesample vessel 16 within theopening 14 and thereby displace a content of the sample vessel within thesample vessel 16. The content of the sample vessel can be, for example, the sample, a reagent contained within the sample vessel, or a mixture of the sample and the reagent. Adriver 24 is coupled to thecompression member 22 to selectively move thecompression member 22 and thereby compress thesample vessel 16 within theopening 14. Thedriver 24 can be, for example, an electromagnetic actuating mechanism, a motor, a solenoid, or any other device for imparting motion, preferably reciprocal motion, to thecompression member 22, as described in further detail below. - Preferably, the
compression member 22 is constructed from a rigid material such as a rigid plastic or a metal. The compression member can be constructed in any shape sufficient to impart a compressive force on the sample vessel. For example, thecompression member 22 can be a block having a rectilinear, planar surface for engaging thesample vessel 16, as illustrated inFIG. 1 . Alternatively, the compression member can have a curved, angular, or non-planar surface for engaging thesample vessel 16. - Moreover, the
compression member 22 alternatively can be an inflatable membrane that can be inflated by a fluid, e.g., air, nitrogen, saline, or water, to impart a compressive force on the sample vessel. In this embodiment, the amount of compression of the sample vessel may be controlled by the adjusting the inflation pressure of the membrane. - The
first processing station 18 can optionally include astationary member 26 positioned opposite thecompression member 22 across theopening 14. Thecompression member 22, thus, can compress a portion of thesample vessel 16 within theopening 14 against thestationary member 26, as illustrated inFIG. 2 . One skilled in the art will appreciate that thestationary member 26 may be replaced with a second compression member, such that the processing station includes two compression members that move together to compress the sample vessel therebetween. In addition, a stationary member or second compression member may be omitted by securing thesample vessel 16 within the opening on either side of the compression member. - In the illustrated embodiment, the
sample vessel 16 is a closed tubule flow-chamber for holding the sample. Preferably, one or more segments of thesample vessel 16 are constructed of a flexible, compressible material, such as, for example, polyethylene or polyurethane, to allow selective compression, and preferably flattening, of the sample vessel to move the sample, or other contents of the sample vessel, within the sample vessel, preferably while thesample vessel 16 remains in thedevice 10. In one preferred embodiment, thesample vessel 16 includes a plurality of segments separated by an integral, internal structure, such as a micro-fluidic pressure gate, as described in more detail below. Alternatively, thesample vessel 16 can be constructed without internal, integral structures to form segments and thedevice 10 can be utilized to segment the sample vessel by compressing selective portions of the sample vessel. One skilled in the art will appreciate that other types of sample vessels suitable for containing a sample may be used with thedevice 10 without departing from the scope of the present invention. - The
second processing station 20 can include asensor 28 for detecting a signal from the content, e.g., the sample or a reagent, of thesample vessel 16. For example, thesensor 28 can be an optical sensor for measuring light, for example fluorescent light, emitted from the sample or from fluorescent probes within the sample. In addition, multiple sensors or a spectrum sensor can be used when detection of multiple wavelength light is required. The detected signal can be sent to aCPU 30 to analyze the detected signal and determine a characteristic of the sample. - In operation, a sample can be introduced to a first segment A of the
sample vessel 16 by injecting the sample through the walls of thesample vessel 16 or by introducing the sample through an opening formed in thesample vessel 16, as described in more detail below. In the present exemplary embodiment illustrated inFIGS. 1 and 2 , thesample vessel 16 includes apressure gate 32 that divides thesample vessel 16 into a first segment A and a second segment B. Thesample vessel 14 can be inserted into theopening 14 of thedevice 10 such that the first segment A of thesample vessel 16 is aligned with thefirst processing station 18 and the second segment B is aligned with thesecond processing station 20, as illustrated inFIG. 1 . - The
driver 24 can operate to move thecompression member 22 into contact with thesample vessel 16 such that the first segment A of thesample vessel 16 is compressed within theopening 14 between thecompression member 22 and thestationary member 26. As the first segment A of thesample vessel 16 is compressed, a quantity of sample is displaced from the first segment A to the second segment B through thepressure gate 32. The volume of sample displaced is proportional to the amount of compression of the first segment A by thecompression member 22. Thus, thecompression member 22 of thefirst processing station 18 can be used to displace a specific quantity of sample into the second segment B of thesample vessel 16 for analysis at thesecond processing station 20. Substantially all of the sample can be displaced from the first segment A of thesample vessel 16 by completely flattening the first segment A of thesample vessel 16, as illustrated inFIG. 2 . The sample can be analyzed in the second segment B of thesample vessel 16 at thesecond processing station 20. - An alternative embodiment of a device for processing a sample is illustrated in
FIG. 3 . The device 38 includes aprocessing unit 40 having three processing stations positioned along theopening 14, namely, afirst process station 42, asecond processing station 44 adjacent thefirst processing station 42, and athird processing station 46 adjacent thesecond processing station 44. - The
first processing station 42 includes acompression member 22 coupled to adriver 24 and adapted to compress a segment of thesample vessel 16 against astationary member 26 within theopening 16. Thefirst processing station 42 can operate to displace a selective quantity of the sample from a first segment A of the sample vessel into other segments of the sample vessel. - The
second processing station 44 includes acompression member 22 coupled to adriver 24 and adapted to compress a second segment B of thesample vessel 16 against astationary member 26 within theopening 16. Thesecond processing station 44 includes anenergy transfer element 48 for transferring energy to or from the contents of thesample vessel 16. Theenergy transfer element 48 can be, for example, an electronic heat element, a microwave source, a light source, an ultrasonic source, a cooling element, or any other device for transferring energy. In one embodiment, theenergy transfer element 48 transfers thermal energy to or from the sample within the sample vessel. Theenergy transfer element 48 can be embedded in or otherwise coupled to thecompression member 22, as illustrated inFIG. 3 . Alternatively, theenergy transfer element 48 can be coupled to thestationary member 26 or can be positioned within the processing station independent of the compression member or the stationary member. Theenergy transfer element 48 can be coupled to a control system that controls the energy transferred to or from thesample vessel 16 by theenergy transfer element 48. The control system can be a component system of theCPU 30 or can be an independent system. The control system can also include atemperature sensor 50 to monitor the temperature of the energy transfer element. - The
second processing station 44 also can include asensor 52 for detecting a signal from the content of the sample vessel, particularly during processing in the second processing station. For example, thesensor 52 can be an optical sensor for measuring light, for example fluorescent light, emitted from the sample or from fluorescent probes within the sample. Thesensor 52 can be coupled to theCPU 30 for analysis of the detected signal to determine a characteristic of the sample. - The
third processing station 46 can include asensor 28 for detecting a signal from the content, e.g., the sample or a reagent, of thesample vessel 16. For example, thesensor 28 can be an optical sensor for measuring light, for example fluorescent light, emitted from the sample or from fluorescent probes within the sample. In addition, multiple sensors or a spectrum sensor can be used when detection of multiple wavelength light is required. The detected signal can be sent to aCPU 30 to analyze the detected signal and determine a characteristic of the sample. - In operation, a sample can be introduced into a first segment A of the
sample vessel 16 and thesample vessel 16 can be introduced into theopening 14 of thedevice 10. In the embodiment illustrated inFIG. 3 , thesample vessel 16 includes twopressure gates 32 that divide thesample vessel 16 into three segments, namely, the first segment A, a second segment B, and a third segment C. Thefirst processing station 42 can operate to displace a selective amount of the sample into the second segment B of thesample vessel 16 for processing at thesecond processing station 44. - At the
second processing station 44, energy can be transferred to or from the sample within the second segment B. In this manner, a biological or chemical reaction involving the sample may be carried out in the second segment B. Thesensor 52 can be used to monitor the reaction during the reaction process. - Upon completion of the reaction, the sample can be moved into the third segment C of the
sample vessel 16 by compressing thesample vessel 16 within the opening at thesecond processing station 44. Preferably, thecompression member 22 of thefirst processing station 42 substantially flattens the first segment A of thesample vessel 16 to inhibit the sample from entering the first segment A. The sample can be analyzed in the third segment C of thesample vessel 16 at thethird processing station 46. - A further embodiment of a device for processing a sample is illustrated in
FIG. 4 . Thedevice 56 includes aprocessing unit 58 having aprocessing station 60 positioned along theopening 14. Theprocessing station 60 includes acompression member 22 coupled to adriver 24 and adapted to compress a segment of thesample vessel 16 against astationary member 26 within theopening 16. In the embodiment illustrated inFIG. 4 , thesample vessel 16 includes apressure gate 32 that divides thesample vessel 16 into two segments, namely, a first segment A and a second segment B. Theprocessing station 60 can operate to displace a selective quantity of the content from the second segment B of the sample vessel into the first segment A of the sample vessel. For example, a reagent can be introduced into the second segment B of thesample vessel 16. A quantity of reagent can be displaced from the second segment B into the first segment A of thesample vessel 16 to mix with the sample in the first segment A. Alternatively, the reagent can be introduced into the first segment A of thesample vessel 16 and a quantity of the sample can be displaced from the second segment B into the first segment A by theprocessing station 60. Thus, the first segment A of thesample vessel 16 can act as a reaction mixture chamber for the sample and the reagent. The reagent can be pre-packaged in thesample vessel 16 or can be introduced to thesample vessel 16 after the sample is introduced to thesample vessel 16. For example, the reagent can be introduced using a reagent injector cartridge, described below, that is included with the device. - Referring to
FIG. 5 , another embodiment of device for processing a sample is illustrated. The illustrateddevice 100 is a hand held system for processing a nucleic acid sample, preferably in an “insert and test” format in which a sample vessel containing a nucleic acid sample is inserted into thedevice 100 and processing results are produced by the device with minimal human intervention. Thedevice 100 can include ahousing 112 having anopening 114 for receiving asample vessel 116 containing a sample for processing by thedevice 100. Theopening 114 can be a tubular shaped opening, as illustrated inFIG. 5 , or can be an open-faced slot or other structure for receiving the sample vessel in a removable and replaceable manner. A control panel 118 is located on the top of thehousing 112 for inputting information to thedevice 100 and amonitor 120 is provided for displaying operating information, such as the results of processing. Anexternal communication port 121 can be located on thehousing 112 for receiving information or outputting information, such as the results of processing and remote diagnosing of the system, to a remote system, such as a computer network. A battery 123 (FIG. 7 ) can be located within the housing to provide electrical power to the components of thedevice 100. - A
multi-sample device 200 for processing multiple samples is illustrated inFIG. 6 . Thedevice 200 is a bench top thermal cycling system for processing up to 96 nucleic acid samples simultaneously. Thesample processing device 200 operates on the same principals as thesample processing device 100 illustrated inFIG. 5 , except that themulti-sample device 200 provides increased capacity and throughput. Themulti-sample processing device 200 can include ahousing 202 having a plurality of wells oropenings 204, with each well being capable of receiving asample vessel 206 containing a sample for processing by the device. The exemplarymulti-sample device 200 illustrated inFIG. 6 has ninety-six wells for treating up to 96 samples simultaneously. One skilled in the art will appreciate that a multi-sample processing device according to the present invention may be designed with any number of wells, depending on the sample being tested and the processes being employed, without departing from the scope of the present invention. Acontrol panel 208 is located on the top of thehousing 202 for inputting information to themulti-sample processing device 200 and amonitor 210 is provided for displaying operating information, such as the results of testing. -
FIG. 7 illustrates the general components of thesample processing device 100 illustrated inFIG. 5 . The illustrateddevice 100 includes three primary processing units for processing a sample within the sample vessel, namely, apretreatment unit 122 for pretreating the sample, areaction unit 124 for amplifying certain components of the sample, and ananalysis unit 126 for analyzing the sample. The sample vessel can be loaded into thedevice 100 through theopening 114. The processing units of the device are preferably arranged along the axis of elongation of theopening 114. This arrangement allows the sample to be moved within the sample vessel between the processing units of thedevice 100 in a manner described in detail below. Preferably, the processing units are arranged linearly as illustrated inFIG. 7 , however, other arrangement are possible so long as the sample vessel can be positioned adjacent one or more of the processing units of thedevice 100. - Continuing to refer to
FIG. 7 , a pair of samplevessel loading wheels 128 is located at theentrance 130 of thesample vessel opening 114. Theentrance 130 is preferably tapered to facilitate loading of the sample vessel into theopening 114 of thedevice 100. Theloading wheels 128 further facilitate loading of the sample vessel by guiding the sample vessel into theopening 114. Asample collection unit 132 can be positioned proximate theentrance 130 of theopening 114 to allow a selective volume of the sample to dispense into the next processing unit or units within the sample vessel. Thesample collection unit 132 can include acompression member 22 opposed to astationary member 26 across the width of theopening 114. Alinear motor 138 is coupled to thecompression member 22. Thelinear motor 138 can operate to move thecompression member 22 toward or away from thestationary member 26 to selectively open and close theopening 114 therebetween. When the sample vessel is positioned within theopening 114, thelinear motor 138 can operate to compress the sample vessel between thecompression member 22 and thestationary member 26. As a result, a selective volume of the sample can be moved to the next processing unit within the sample vessel. Preferably, the sample vessel remains compressed between thecompression member 22 and thestationary member 26 of thesample collection unit 132 during processing of the sample by the other processing units to prevent the sample from exiting the processing unit area during processing. - The
pretreatment unit 122 is positioned adjacent the initialsample collection unit 132. Depending on the process being implemented, the sample may require pretreatment or preparation before proceeding with additional processing steps. Pretreatment can include, for example, adding a reagent or other material to the sample and incubating the mixture for certain time period. Thepretreatment unit 122 of thedevice 100 allows for any of such pretreatment steps to be implemented. For PCR testing, thesample pretreatment unit 122 can provide for nucleic acid extraction from a biological sample, such as blood. Any known methods for extracting nucleic acid can be utilized in the pretreatment unit, including using a cell lysis reagent, boiling the nucleic acid sample, GITC, or formamide for solubilization. Alternatively, filters can be used within the sample vessel to separate nucleic acid from unwanted cellular debris. - The
pretreatment unit 122 can include acompression member 22 and astationary member 26 opposed to thecompression member 26 across theopening 114. Thecompression member 22 and/or thestationary member 26 can optionally include an energy transfer element for transferring energy, e.g. thermal energy, to the sample within the sample vessel. The energy transfer element can be, for example, an electronic heat element (such as Kapton heater, a Nomex heater, a Mica heater, or a silicone rubber heater), a microwave generator, a light source, an electronic cooling element (such as Peltier element), an ultrasonic energy transfer element, or any another device suitable for transferring thermal energy. Adriver 24, for example an electromagnetic actuator such as linear stepper actuator, a relay actuator, or a solenoid, is coupled to thecompression member 22 and operates as a driver. During operation of thepretreatment unit 122, thedriver 24, moves thecompression member 22 to open theopening 114 between thecompression member 22 and thestationary member 26 of thepretreatment unit 122 to allow receipt of a sample vessel. After a sample vessel is loaded, thedriver 24 drives thecompression member 22 toward thestationary member 26, resulting in good surface contact between the sample vessel and the compression member and the stationary member and thus improved pretreatment. Once the pretreatment is completed, thedriver 24 moves thecompression member 22 of thepretreatment unit 122 to further compress the pretreatment segment of the sample vessel to move a selective amount of pretreated sample within the sample vessel to the next processing unit. - The
reaction unit 124 can include a plurality ofprocessing stations 150A-150C and is preferably positioned adjacent thepretreatment unit 122. Thereaction unit 124 can effect thermal cycling of the sample by selectively moving the sample, with the sample vessel, between theprocessing stations 150A-150C. The phrase “thermal cycling” as used herein refers to a process of heating and/or cooling a sample in two or more steps, with each step preferably occurring at a different temperature range from the previous step. Each of theprocessing stations 150A-150C can be maintained at a pre-selected temperature range controlled by atemperature control system 152 and aCPU 174. Although the exemplary embodiment includes three thermalcycling processing stations 150A-150C, thereaction unit 124 can include any number of processing stations 150, depending on the thermal cycling process employed. Alternatively, thereaction unit 124 can incubate a sample at a selective temperature for an isothermal reaction such as for TMA or SDA process. - In PCR based testing, thermal cycling can be used to denature, anneal, elongate and thereby amplify the nucleic acid sample. The PCR thermal cycling steps each occur at specified temperature ranges. Denaturing occurs at approximately 92° C.-96° C.; elongation occurs at approximately 70° C.-76° C.; and annealing occurs at approximately 48° C.-68° C. Each of the PCR thermal cycling steps, i.e. denaturing, annealing, and elongation, can be carried out independently at a separate processing station of the
reaction unit 124 by maintaining the processing stations at the temperature ranges effective for carrying out each of the PCR thermal cycling steps. For example, the denaturing step can be carried out atprocessing station 150A, the elongation step atprocessing station 150B, and the annealing step atprocessing station 150C. Alternatively, one or more of the PCR thermal cycling steps can be combined and carried out at the same processing station, thereby reducing the number of processing stations required. For example, denaturing can be carried out atprocessing station 150A and elongation and annealing can be carried out atprocessing station 150B, thus, eliminating the need for a third processing station. - Moreover, a processing station can be provided within the
reaction unit 122 for cooling of the sample by using a thermal energy element, a Peltier thermal electric element for example, to transfer thermal energy from the processing station. In PCR processing, for example, a processing station can be provided to preserve the nucleic acid sample between process steps by cooling the sample to a refrigeration temperature, e.g., 4° C. Additionally, a processing station can optionally be provided to cool the sample between thermal cycling steps to decrease the temperature down ramping time between successive thermal cycling steps. For example, as denaturing generally occurs at 92° C.-96° C. and annealing generally occurs at a significantly lower temperature, e.g., 48° C.-68° C., the sample can be cooled after denaturing in a cooling processing station, preferably at a temperature lower than the annealing temperature, to bring the sample temperature more quickly into the annealing temperature range. A thermal cycling processing station can optionally include aheat sink 166 coupled to either thecompression member 22 or thestationary member 26 to conduct heat away from the station and radiate the heat to the environment. - Each of the illustrated processing stations of the
reaction unit 124 includes acompression member 22 and astationary member 26. Thecompression member 22 of each thermal cycling processing unit can be coupled to adriver 24 for selectively moving thecompression member 22 toward and away from thestationary member 26. As discussed above, thedrivers 24 can be any device capable of imparting motion, preferably reciprocal motion, to the compression members. Adriver control system 160 is coupled to thedrivers 24 to control the operation of thedrivers 24. In one preferred embodiment illustrated inFIG. 7 , thedrivers 24 are electromagnetic actuators coupled to thedriver control system 160, which can be, for example, a control system for controlling the reciprocal motion of the actuators. Alternative drivers, compression members and stationary members are described below in connection withFIGS. 8-12 . Thedriver control system 160 is coupled to theCPU 174 such that the sample incubation time period, the pressure and the sample moving speed within the sample vessel can be controlled and coordinated by theCPU 174 to achieve the best reaction results. - Each of the thermal
cycling processing station 150A-150C can optionally include an energy transfer element for transferring energy, such as thermal energy, to the sample within the sample vessel. The energy transfer elements can be, for example, an electronic heat element, a microwave generator, a light source, an electronic cooling element, or any another device suitable for applying thermal energy. Each of the energy transfer elements is coupled to thetemperature control system 152 to maintain the associated processing station within a selected temperature range. One or more temperature sensors, coupled to thetemperature control system 152, can be positioned proximate theprocessing stations 150A-150C to monitor the temperature of the stations. - Between two adjacent processing units or two adjacent processing stations, at least one layer of
energy insulator 146 can optionally be provided to insulate the processing unit or the processing station from adjacent units or stations. An energy insulator layer can also be formed on the boundary of a processing station to prevent energy transfer to or from the environment. Theenergy insulator 146 can be, for example, an energy shielding layer, an energy absorption layer, an energy refraction layer, or a thermal insulator, depending on the type of energy transfer element employed. A thermal insulator can be constructed from a low thermal conductivity material such as certain ceramics or plastics. In one embodiment, the thermal insulator can be attached to the compression members and the stationary members. Alternatively, the thermal insulators can be separate from the compression members and stationary members and can be controlled independently by a driver to open and close theopening 114. In this embodiment, all the compression members and insulators can open initially to allow loading of the sample vessel, and then, the thermal insulators can compress the sample vessel within the opening to close the vessel and form separate segments within the sample vessel. Additionally, a spring element or other biasing mechanism can be optionally utilized to bias each thermal insulator. Through the spring element, a driver associated with one of the thermal insulators can apply sufficient pressure on the thermal insulator to minimize the quantity of sample remaining in the junction between adjacent processing stations during an incubation period, while still allowing sample flow through the thermal insulator when a higher pressure is applied to the sample in an adjacent processing station. This design simplifies the operation of multiple thermal insulators. - In an alternative embodiment, the processing stations can be spaced apart to inhibit conductive heat transfer between adjacent processing stations and, thereby, eliminate the need for insulators between the stations.
- Operation of the thermal
cycling reaction unit 124 will be generally described with reference toFIGS. 13A-13G . The thermal cycling process begins by opening each of the processing stations, e.g.first processing station 150A,second processing station 150B, andthird processing station 150C, to receive the sample vessel within theopening 114, as illustrated inFIG. 13A . After the sample vessel is loaded with pretreated sample material, or the pretreated sample is dispensed frompretreatment unit 122 into thereaction unit 124, thesecond processing station 150B and thethird processing station 150C are closed by moving thecompression member 22B and thecompression member 22C of each station toward the respectivestationary member FIG. 13B . As thesecond processing station 150B and thethird processing station 150C are closed, the sample vessel is compressed between the compression member and the stationary member, displacing the sample within the sample vessel into a segment of the sample vessel adjacent thefirst processing station 150A. - Next, the
compression member 22A and theinsulator 146A can compress the sample vessel to adjust the sample volume contained within the segment of the sample vessel adjacent thefirst processing station 150A, as well as the surface area to volume ratio of the segment. Theinsulator 146A can then be closed to seal the sample in thefirst processing station 150A, as illustrated inFIG. 13C . Alternatively, if thedevice 100 is provided with a sample pretreatment unit, the sample pretreatment unit can function to close the sample vessel within thefirst processing station 150A. Other alternatives include pre-sealing the sample vessel after loading a sample, or providing the sample vessel with pressure gates, discussed below, formed between adjacent reaction zones. Once the sample is sealed within thefirst processing station 150A, the sample can be heated or cooled by thefirst processing station 150A. In PCR thermal cycling, for example, the sample can be heated to a temperature effective to denature the nucleic acid sample. Preferably, the sample vessel is pressed into contact with thecompression member 22A and thestationary member 26A by thecompression member 22A to flatten the sample vessel and to ensure good thermal contact between the sample vessel and thecompression member 22A and thestationary member 26A. Thecompression member 22A can also optionally periodically squeeze the sample vessel to agitate the sample and to generate sample flow in the segment of the sample vessel during the reaction period to speed up the reaction. - After a predetermined period, the
second processing station 150B can be opened to allow the sample to move into thesecond processing station 150B, as illustrated inFIG. 13D . Next, thefirst processing station 150A closes, compressing the sample vessel and moving the entire sample, within thevessel 16, into a segment of the sample vessel adjacent thesecond processing station 150B, as illustrated inFIG. 13E . Thethird processing station 150C can then open to allow the sample to move into the segment of the sample vessel adjacent thethird processing station 150C, as illustrated inFIG. 13F . Thesecond processing station 150B closes, compressing the sample vessel and moving the sample completely into the segment of the sample vessel adjacent thethird processing station 150C, as illustrated inFIG. 13G . The sample can then be heated or cooled by thethird processing station 150C for a set time period. In PCR thermal cycling for example, the sample can be heated to a temperature effective to anneal the nucleic acid sample in thethird processing station 150C. Theheat sink 166 can facilitate the temperature transition from the denaturing temperature of thefirst processing station 150A to the annealing temperature of thethird processing station 150C by dissipating excess heat to the environment. Thus, the sample can be moved from the denaturing step at the first processing station to the annealing step at the third processing station. - After a predetermined time period, the
second processing station 150B opens to allow the sample to move into the second processing station, as illustrated inFIG. 13F . Thethird processing station 150C then closes, compressing thesample vessel 16 and moving the sample entirely into the segment of the sample vessel adjacent thesecond processing station 150B, as illustrated inFIG. 13E . The sample can then be heated or cooled by thesecond processing station 150B for a set time period. In PCR thermal cycling for example, the sample can be heated to a temperature effective to elongate the nucleic acid sample. Upon conclusion of the elongation step, the sample can be returned to the segment of the sample vessel adjacent thefirst processing station 150A to repeat the cycle, i.e., denaturing and annealing and elongating or, the sample can be moved to a segment of the sample vessel adjacent thesample detection unit 126 if PCR thermal cycling is completed. - The illustrated thermal
cycling reaction unit 124 provides denaturing in thefirst processing station 150A, annealing in thethird processing station 150C, and elongation in thesecond processing station 150B, as this arrangement is deemed thermodynamically efficient. One skilled in the art will appreciate, however, that the PCR thermal cycling steps can occur in any of the processing stations without departing from the scope of the present invention. - Sample thermal cycling using the
reaction unit 124 of the present invention results in faster thermal cycling times and lower energy consumption compared to conventional thermal cycling devices. Sample vessel shape alteration, i.e. flattening, by thereaction unit 124 results in significant increases in the surface/volume ratio and sample vessel contact with the members of the reaction unit. This allows the processing stations of thereaction unit 124 to heat the sample more directly, increasing the sample temperature ramping rate and avoiding unnecessary temperature ramping of the members and thus decreasing the amount of energy consumed. Equally important is that sample vessel shape alteration provides for the uniform transfer of thermal energy to the sample, dramatically reducing reaction mixture temperature gradients. Thereaction unit 124 further allows the use of fluid flow to mix the sample as the sample is moved from one processing station to another. - Moreover, the
reaction unit 124 allows the use of a disposable, single-use sample vessel that minimizes contamination of the sample, contamination of the reaction unit and exposure of the operator to biohazards. Additionally, thereaction unit 124 does not require a fluid handling system, as the sample can be moved within the sample vessel during processing. - Referring again to
FIG. 7 , thereaction unit 124 can optionally include areaction sensor 168 for monitoring the reaction in real-time within thereaction unit 124 by analyzing the sample, including any reaction products from the reaction with the sample. Thereaction sensor 168 can include an integrallight source 169 for applying excitation energy to the sample within the sample vessel. Alternatively, a light source, or other source of excitation energy, can be provided separate from thereaction sensor 168. Thereaction sensor 168 can be an optical sensor for measuring light, for example fluorescent light, emitted from the sample or from fluorescent probes within the sample. In the case of PCR, any known real-time PCR detection system can be employed, including, for example, using fluorescent dyes, such as ethidium bromide, intercalating into the DNA molecule, using a dual labeled probe tagged with a reported dye and a quenching dye, or using hybridization probes, which will result in Fluorescence Resonance Energy Transfer (FRET) only when the two probes are hybridized and in close proximity. In each of these approaches, the fluorescence signal is substantially proportional to the amount of specific DNA product amplified. Thereaction detection sensor 168 is placed to monitor the fluorescence from the sample, preferably in the annealing processing station, or other processing stations of the reaction unit, dependent on the assay selected. Multiple sensors or a spectrum sensor can be used when detection of multiple wavelength light is required. The detected signal is then sent to theCPU 174 for further analyzing the amount of product. - Continuing to refer to
FIG. 7 , the sample detection oranalysis unit 126 of thedevice 100 is provided to analyze the sample after processing by thereaction unit 124. Theanalysis unit 126 is preferably positioned proximate thereaction unit 124. In one embodiment of the invention, a source of excitation energy, for example a light source, can apply excitation energy to the sample and a signal detector, for example an optical sensor, can detect light emitted from the sample in response to illumination by the excitation light. Specific illustrative practices, include detecting the transmission of light through the sample, detecting reflected light, detecting scattering light, and detecting emitted light. The detected light, in the form of the signal output from the sensor, can be analyzed by aCPU 174 provided in the device through known signal processing algorithms. Suitable sample analysis systems, employing a light source and an optical sensor or sensors, detects signals including light intensity at a given wavelength, phase or spectrum of the light, as well as location of the signal. For example, the flow induced testing system described in U.S. Pat. No. 6,318,191 and the multi-layer testing system described in U.S. Pat. App. Pub. No. US 2004/0105782 A1, both of which are incorporated herein by reference, describe suitable sample analysis systems. - In the case of a PCR based assay, gel electrophoresis or capillary electrophoresis can be employed to analyze the nucleic acid sample, as illustrated in
FIGS. 7 and 14 . Suitable nucleic acid sizing gels include agarose and polyacrylamide. Thegel 184 can be introduced to thesample vessel 16 during processing or, preferably, is pre-loaded into ananalysis segment 210 of the sample vessel, as discussed in more detail below. Theexemplary analysis unit 126 includes alight source 170 for illuminating the nucleic acid sample and the gel and anoptical sensor 172 in the form of linear charge coupled device (CCD).Electrode activators 176 operate to insert apositive electrode 180 and anegative electrode 182 into thesample vessel 16. Thepositive electrode 180 and thenegative electrode 182 are electrically connected to a voltage source, which creates a voltage difference between the electrodes. As nucleic acid products are negatively charged, the nucleic acid products within the sample will move through thegel 184 toward thepositive electrode 180. The gel separates the sample components by size, allowing smaller components, such as nucleic acid products, to travel faster, and thus, further, than larger components. A suitable dye or fluorescent tag can be introduced to gel to identify the nucleic acid products. Light from thelight source 170 can illuminate the dyed or tagged nucleic acid products in the gel and theoptical sensor 172 can then identify the illuminated nucleic acid products. The output signal of theoptical sensor 172 can be analyzed byCPU 174 according to known signal processing method to determine the presence, absence, quantity or other condition of the nucleic acid sample. - Alternatively, the nucleic acid sample can be analyzed in accordance with conventional nucleic acid analysis methods, such as, for example, chemiluminescence, fluorescently labeled primers, antibody capture, DNA chip, and/or magnetic bead detection methods.
- One skilled in the art will appreciate that the processing units and the processing stations of the above-described exemplary embodiments of the sample processing device of the present invention can be arranged in any order depending on the sample being processed and the process being utilized. The sample processing device of the present invention may include any combination of the processing units and processing stations described herein, as well as additional processing units and processing stations that will be apparent to those skilled in the art upon reading this disclosure. Moreover, the sample processing device may include only a single processing unit, such as, for example, a reaction unit for thermal cycling a sample, or may include a only a single processing station, such as, for example, a processing station for displacing a specified volume of reagent or sample.
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FIGS. 8-12 illustrate alternative embodiments of areaction unit 250 for thermal cycling a sample according to the present invention. Thereaction unit 250 can include one ormore openings 252 for receiving one ormore sample vessels 16. The embodiments illustrated inFIGS. 8-12 have threeopenings 252, permitting the simultaneous thermal cycling of up to three samples. Thereaction unit 250 comprises three processing stations: afirst processing station 254, asecond processing station 256, and athird processing station 258.Thermal insulators 260A-260D are positioned between the processing stations and at the top of thefirst processing station 254 and the bottom of thethird processing station 258. - Referring specifically to
FIGS. 8 and 10 , thefirst processing station 254, as well as the second andthird processing stations heat element 262 for transferring thermal energy to the sample vessel when the sample vessel is positioned within anopening 252. Theheat element 262 can be a Kapton heater, a Nomex heater, a Mica heater, a silicone rubber heater or any other thermal energy transfer element suitable for delivering thermal energy. Theheat element 262 can be seated in arecess 264 formed in theprocessing station 254 and secured to the processing station by an adhesive or other attachment means. Theheat element 262 of each of the processing stations is preferably coupled to atemperature controller 266 for controlling the temperature of the heat element. One ormore temperature sensors 268 can be positioned in theprocessing station 254 to measure the temperature of theprocessing station 254. Thetemperature sensor 268 can be coupled to thethermal controller 266 such that thetemperature controller 266 can monitor and adjust the temperature of the processing station in a feedback control manner. - Referring to
FIGS. 10 and 11 , each processing station comprises astationary member 270 and acompression member 272 adapted to compress the sample vessel selectively within one or more of theopenings 252 and thereby move the sample within the sample vessel. Thecompression member 272 is preferably complimentary in shape to thestationary member 270 and includes a plurality of finger-like closure elements orshutters 274 sized and shaped to slide within theopenings 252.Guide rails 276 are positioned on either side of the compression member. The guide rails 276 are preferably sized and shaped to fit withingrooves 278 formed in the side walls of thestationary member 270. The combination of theguide rails 276 and thegrooves 280 allow thecompression member 272 to reciprocate relative to thestationary member 270 to selectively open and close theopenings 252. - Each thermal insulator 260 can be configured in a manner analogous to the processing stations. For example, the
thermal insulator 260B comprises an insulatorstationary member 280 and aninsulator compression member 282 adapted to compress a sample vessel within one or more of theopenings 252. Theinsulator compression member 282 includes a plurality of finger-like closure elements orshutters 284 sized and shape to slide within theopenings 252 to selectively open and close theopenings 252. - Each
compression member 272 andinsulator compression member 282 is coupled to a driver, such as an electromagnetic driver mechanism, as described above, or any other mechanism for imparting motion, preferably reciprocating motion, to the compression members. Each compression member can be coupled to anarm 286 for providing a connection between the compression member and the driver, as best illustrated inFIGS. 9-11 . In one embodiment, illustrated inFIG. 10 , thearms 286 are hollow tubes that receivecoiled springs 288 and dowels 290. Thesprings 288 operate to bias thecompression members stationary member 270 and the insulatorstationary member 280, respectively. An elastic element, such as the coiled spring used here, provides a simple mechanism for assisting the driver to regulate the compressing pressure applied to the sample vessel. The driver can be amotor 292 for driving a rotating shaft, as best illustrated inFIG. 8 . The rotary motion of the shaft can be translated to reciprocating motion throughcams 294 provided for each of thecompression members cams 294 are coupled to thearms 286. Thecams 294 can be configured to selectively open and close thecompression members - In one alternative embodiment of the reaction unit, the
compression members holes 296 for receiving acam 294 and alinear spring element 298.Spring elements 298 each operate to bias a respective compression member in a direction away from the corresponding stationary member. Thecams 294, in combination with thesprings 298, act to impart reciprocating motion to the actuators and regulate the compressing pressure on the sample vessel. -
FIGS. 19A-19C illustrate a further embodiment of the reaction unit of the present invention. Thereaction unit 350 includes nineopenings 352 for receiving up to nine sample vessels simultaneously. Thereaction unit 350 includes three processing stations: afirst processing station 354, a second processing station 356, and athird processing station 358.Thermal insulators 360A-360D are positioned adjacent each of the processing stations and at the top of thefirst processing station 354 and the bottom of the third processing station. Topthermal insulator 360A and bottomthermal insulator 360D are movable independent of thefirst processing station 354 and thethird processing station 358, respectively. Intermediatethermal insulators first processing station 354 and the second processing station 356, respectively. - Each processing station comprises a
stationary member 370 and acomplementary compression member 372 adapted to compress the sample vessel selectively within one or more of theopenings 352 and thereby move the sample within the sample vessel. Eachstationary member 370 has aprojection 374 aligned with one of theopenings 352. Thecompression members 372 are each provided with aprojection 376, positioned on an opposite side of theopening 352. When acompression member 372 is slid on the correspondingstationary member 370, theprojections openings 352 therebetween. - Each
compression member 372, as well as intermediatethermal insulators arm 380 coupled by acam 384 to arotary shaft 382. Astationary insulator member 362 is coupled, and aligned with an edge of each opening 352 on eachstationary member 370. Eachstationary insulator member 362 is inserted in each of the openings of a movableinsulator compression member 360 to react to compression and open or close the opening. Theshaft 382 is rotated by a stepper motor or aservo motor 386. Thecams 384 translate the rotation of theshaft 382 into linear reciprocal motion, which is imparted to thearms 380 to effect selective opening and closing of theopenings 352 and compression of the sample vessels therein. - Each
arm 380 includes aninner shaft 390 received within anouter sleeve 392. Aspring 394 is interposed between theinner shaft 390 and the respective compression member or thermal insulator. Asecond spring 396 is positioned on an opposite side of the respective compression member or thermal insulator. Thespring 394 cooperates with thesecond spring 396 to allow the compression member or thermal insulator to “float” along the axis of thearm 380. In this manner, thearm 380 can apply sufficient force to the compression member or thermal insulator to compress the sample vessel within anopening 352 and, thereby, displace substantially all of the sample from the compressed portion of the sample vessel. An increase of pressure within the sample vessel, for example, from the compression of an adjacent portion of the sample vessel, however, can cause the sample to displace within the sample vessel through the compressed portion of the sample vessel, as thesprings - Each
stationary member 370 andcompression member 372 can be provided with an embedded thermalenergy transfer device 398 for eachopening 352 to apply thermal energy to the sample vessel within theopening 352. In addition, thestationary member 370 andcompression member 372 can includetemperature sensors 399 associated with eachenergy transfer device 398 to monitor the temperature of the sample vessel. -
FIGS. 15A and 15B illustrate embodiments of asample vessel 16 according to the present invention. The illustratedsample vessel 16 is a closed tubule system that provides a disposable, single use container and reaction vessel for the sample. Thesample vessel 16 can be constructed of a resiliently compressible, flexible, and ultra-high strength material, such as polyethylene or polyurethane. Thesample vessel 16 can have a seamless, flattenable cross-sectional profile and thin-walled construction that is optimized for fast and uniform heat transfer, for maximum surface contact with the sample, and for high pressure resistance. Preferably, the walls are constructed to converge when the sample vessel is compressed in a direction perpendicular to the longitudinal axis of the sample vessel such that the volume of the compressed portion of the sample vessel decreases and the ratio of the surface area to the volume of the compressed portion increases, without fracturing of the sample vessel. In one illustrative preferred practice, the walls of thesample vessel 16 have a wall thickness of approximately 0.01 mm to 0.5 mm. Experimental results indicate that constructing a sample vessel having a wall thickness within this preferred range significantly increases the efficiency of heat transfer to the sample. In an alternative embodiment, a two-layer wall structure can be used, with the inner layer providing bio-compatibility, using material such as polyethylene or polyurethane, and the outer layer providing lower permeability, using material such as high density polyethylene or aluminum foil. In addition, the material selected to construct the portions of the wall of the sample vessel, such as a detection segment of thesample vessel 16, can be optically transmissive over a selected wavelength range to facilitate optical analysis of the sample within the sample vessel. - The
sample vessel 16 can be divided into multiple segments by one ormore pressure gates 32. In the case of PCR testing, for example, the sample vessel can be divided into asample collection segment 205, asample pretreatment segment 206, asample reaction segment 208, and asample analysis segment 210. The illustratedpressure gates 32 are internal to the tubule structure of thevessel 16 and provide a fluid tight seal between the segments of thesample vessel 16, under normal operating conditions. Preferably, thepressure gates 32 open upon the application of pressure greater than a certain value, for example, approximately 3 atmospheres. When external pressure is provided to one segment, thepressure gate 32 can open, allowing the sample to flow from the high pressure compartment to the low pressure compartment. - The
sample vessel 16 can include a handling portion having a generally rigid construction to facilitate handling of the sample vessel. The handling portion can be coupled to one or more of the segments of the sample vessels used to contain the sample. For example, the handling portion can be a cylindrical sleeve constructed of a generally rigid material, such as a plastic or a metal, that is sized and shaped to fit over one or more of the segment of the sample vessel. In one embodiment, the cylindrical sleeve can be removable and replaceable. Alternatively, the handling portion can be a rigid segment, such as a rigid ring, positioned at an end of the sample vessel or between two segments of the sample vessel. In the embodiments illustratedFIGS. 15A and 15B , the handling portion is a segment of the sample vessel having an increased wall thickness. For example, thesample collection segment 205 and thesample pretreatment segment 206 have a wall thickness greater than the wall thickness of thereaction segment 208. The increased wall thickness provides sufficient rigidity to thesample collection segment 205 and thesample pretreatment segment 206 to facilitate handling of thesample vessel 16. In one embodiment, the wall thickness of the handling portion is greater than 0.3 mm. - The
sample vessel 16 can include an instrument, such as a sampling pipette or a needle 107, for direct collection of the sample to be treated and analyzed within thesample vessel 16, as illustrated inFIG. 15A . Theneedle 207 can be positioned at one end of thesample vessel 16 and can be connected to thesample collection chamber 205 through aconduit 209 formed in the wall of thesample vessel 16. Aneedle cover 211 can be provided to secure theneedle 207 prior to and after use. Theneedle cover 211 can be, for example, a penetrable rubber cover or a removable plastic cover. - In another embodiment, illustrated in
FIG. 15B , asampling instrument 214, such as a pipette, a stick, or a tweezer, can be coupled to acover 212 that selectively closes the conduit or opening 209 formed in the wall of the sample vessel. Thecover 212 can include areservoir 216 for containing a reagent and a sample during sampling. For sampling, thecover 212 can be removed from the sample vessel to expose thesampling instrument 214. Thesampling instrument 214 can be used to collect the sample, by pipetting, swabbing, or gathering the sample, for example, and then thesampling instrument 214 can be inserted into thesample collection segment 205 through theconduit 209. The sample can then be introduced to thesample collection segment 205 by compressing thecover 216 to displace the sample from thereservoir 216. Alternatively, the sample can be introduced to thesample collection segment 205 or to another segment of the sample vessel, depending of the segments present in the sample vessel, after collection by a separate instrument. -
Sample vessel 16 can be particularly suited for PCR testing using the sample processing device of the present invention, as described above. For example, nucleic acid extraction can be performed within thesample pretreatment segment 206 of such asample vessel 16. A cell lyses reagent, for example, GENERELEASER® from Bioventures, Release-IT™ from CPG Biotech, or Lyse-N-Go™ from Pierce, or other extraction reagents can be introduced to thepretreatment segment 206 to extract nucleic acid from the initial sample. Extraction reagents can be stored within thepretreatment segment 206 or can be delivered to the segment. Additionally, one or more filters can be positioned within thepretreatment segment 206 of the sample vessel to separate nucleic acid from unwanted cellular debris. - After incubation of the sample for certain time period, a portion of pretreated sample can be moved into the
reaction segment 208. For a reaction sample volume of approximately 5 μl-25 μl, aPCR reaction segment 208 of thesample vessel 16 according to one illustrative practice of the invention has a wall thickness, indicated by reference character t inFIG. 15A , of approximately 0.01 mm-0.3 mm, a diameter of less than approximately 6 mm, and a length of less than approximately 30 mm. PCR reagents, such as nucleotides, oligonucleotides, primers and enzymes, can be pre-packaged in the reaction segment orreaction segments 206, or can be delivered, for example, through the walls of the sample vessel using a needle, using for example, a reagent injector cartridge described below, before moving the sample into the segment. - A pre-packaged
reagent storage segment 214 can be used to stored a pre-packaged reagent. Such a reagent storage segment can be formed between any two adjacent processing segments and may store any reagent needed for a reaction. For example, thereagent storage section 214 can store PCR reagents, whilereagent storage sections reagent storage segment 214 is utilized, thesample vessel 16 can be compressed at thereagent storage segment 214 to displace the reagent into thepretreatment segment 206. Alternatively, the sample can be moved from thepretreatment segment 206, through thereagent storage segment 214 where mixing with the reagent, to thereaction segment 208. - A self-sealing
injection channel 218 can be formed in the sample vessel to facilitate delivery of reagent or other materials to the sample vessel, as illustrated inFIG. 16 . The illustrated self sealinginjection channel 218 is normally substantially free of fluidic material and is capable of fluid communication with the adjacent segment in the vessel. An injection of reagent through an injection channel occurs preferably prior to moving any sample into the segment to avoid contamination. In addition, the sample treatment devices of the invention can utilize areaction cartridge 220 with a single ormultiple needles 222 in fluid communication with one or more reservoirs, as illustrated inFIG. 17 . Thereaction cartridge 220 can be used to inject or deposit reagent or other materials, simultaneously, or sequentially into multiple segments of the sample vessel. Suitable self-sealing injection channels and reagent cartridges are described in U.S. Pat. No. 6,318,191, incorporated herein by reference. - One skilled in the art will appreciate that while it may be preferable for the wall of the sample vessel to be uniform along the circumference and the longitudinal axis of the vessel, only a portion of the wall along the circumference and/or the longitudinal axis of the vessel need be resilient and compressible and have the preferred thickness to affect flattening of the sample vessel. Thus, the sample vessel need not have a uniform axial or circumferential cross-section.
- PCR thermal cycling can be performed in the
reaction segment 208 of thesample vessel 16. The thin walled, compressible construction of thesample vessel 16 greatly improves the rate and efficiency of thermal cycling. The construction of the sample vessel allows the vessel to deform or flatten readily, increasing thermal contact with the reaction unit of thedevice 10 and increasing surface/volume ratio of the sample within the sample vessel. As a result, the reaction mixture ramping rate is increased and thermal energy is more uniformly transferred to the sample. - PCR analysis can be performed in the
sample vessel 16. For example, real-time detection methods can be used within thereaction segment 208; gel electrophoresis or other nucleic acid detection methods can be used within theanalysis segment 210 to analyze the sample. In the case of gel electrophoresis, a gel can be introduced to theanalysis segment 210 to facilitate gel electrophoresis, as described above in connection withFIG. 14 . - In one preferred embodiment, illustrated in
FIG. 15A , theanalysis segment 210 is divided into two electrophoresis capillaries, namely, asample capillary 230 and acontrol capillary 232, by a diametrically-central divider 234.Pressure gates 32 at either end of the capillaries control the movement of the sample and the reagents into both capillaries. Each capillary is filled with an electrophoresis gel such that gel electrophoresis can be performed simultaneously in both capillaries. A pair ofelectrodes 240, for both capillary 230 and 232, can be positioned within the walls of the sample vessel. Areagent storage segment 236 can be provided at the proximal end of thesample capillary 230 for storing reagent within the sample vessel prior to the sample entering thesample capillary 230. A control material can be stored in acontrol storage segment 242 positioned at the proximal end of thecontrol capillary 232. A reagent can be stored in areagent segment 244 positioned at the distal end of the capillaries and in communication with both thesample capillary 230 and thecontrol capillary 232 for detection or display signal. The presence of thecontrol capillary 232 facilitates detection and analysis of the sample by providing a basis of comparison for the sample analysis. - One skilled in the art will appreciate that the number of segments within the sample vessel is dependent upon the sample being processed and the processing methods being employed. For example, in the case of PCR testing, the number of segments within the sample vessel can be three or more. Alternatively, thermal cycling and analysis may be performed in one segment, reducing the number of segments to two. In certain cases, an isothermal nucleic acid amplification method, for example, only one segment may be necessary.
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FIG. 18 illustrates asample vessel 416 particularly suited for use in a multi-opening sample processing device such as, for example, the sample processing device illustrated inFIG. 6 . Thesample vessel 416 includes anopening 420 for receiving the sample, a cap orclosure 424 for selectively closing and sealing theopening 420, and asample containing portion 426 within which the sample can be treated. Theopening 420 is formed in ahandling portion 428 that is preferably constructed of a generally rigid or semi-rigid material, such as plastic or metal, to facilitate handling of thesample vessel 416. The handlingportion 428 includes acollar 430 against which thecap 424 seats. Sample material can be introduced into thesample containing portion 426 of thesample vessel 416 through theopening 420. Thecollar 428 preferable tapers from a larger diameter to the smaller diameter of thesample containing portion 426. Thesample containing portion 426 is preferable constructed of a resiliently compressible, flexible, and ultra-high strength material, such as polyethylene or polyurethane. Thesample containing portion 426 can have a seamless, flattenable cross-section profile and thin-walled construction that is optimized for fast and uniform heat transfer, for maximum surface contact with the sample, and for high pressure resistance. In accordance with one embodiment, thesample containing portion 426 has a wall thickness of approximately 0.01 mm-0.3 mm. Preferably, thesample containing portion 426 of thesample vessel 416 is in a flattened state prior to introduction of the sample. Introduction of the sample to thesample containing portion 426 will cause the walls of the sample containing portion to separate and the volume of the sample containing portion to increase. Compression of a selected portion of thesample containing portion 426 can cause the sample to displace to another portion within the sample containing portion along the length of the sample vessel. The surface of the sample vessel can be chemically treated to reduce a surface effect on the reaction. - The embodiments of the sample vessel described herein in connection with
FIGS. 14-16 and 18, are not limited to use with the embodiments of the sample processing device described herein. The sample vessel of the present invention may be used with any sample testing or processing system. Likewise, the sample processing device of the present invention is not limited to use with the sample vessels described herein. Other sample vessels may be used without departing from the scope of the present invention. - Certain changes may be made in the above constructions without departing from the scope of the invention. It is intended that all matter contained in the above description or shown in the accompanying drawings be interpreted as illustrative and not in a limiting sense.
- The present disclosure is also directed to sample vessels that may be utilized to collect and process one or more samples in a closed system. Exemplary samples that may be collected, processed, or otherwise contained by the sample vessels disclosed herein include biological samples, such as blood, urine, saliva, tissue, cell suspensions, microbial organisms, viruses, nucleic acids, and oligonucleotides samples; soil; water; and any other sample materials that may be assayed using known assays. The term “collection” as used herein generally refers to the extraction or gathering of the sample from a sample source, the subsequent transfer of the sample into the sample vessel, or the combination of extraction and subsequent transferring of the sample into the sample vessel. Exemplary sample gathering may include pipetting, biopsying, swabbing, drawing a fluid sample or other methods for extracting a sample from a sample source. Exemplary sample sources may include humans or other animals, plants, water sources, cell cultures, food, other sample vessels, and chemical and biological assays. Sample sources may also include interim storage media, for example, test tubes, syringes, absorbent applicators and other interim storage media for containing a sample of interest. The term “processing” as used herein generally refers to the preparation, treatment, analysis, and/or the performance of other testing protocols or assays on a content of the sample vessel in one or more steps. Exemplary processing steps include, for example: displacing a content, e.g., the sample or a reagent, of the sample vessel within the sample vessel to, for example, adjust the volume of the content, separate content components, mix contents within the sample vessel; effecting a chemical or biological reaction within a segment of the sample vessel by, for example, introducing a reagent to the sample, agitating the sample, transferring thermal energy to or from the sample, incubating the sample at a specified temperature, amplifying components of the sample, extracting, separating and/or isolating components of the sample; or analyzing the sample to determine a characteristic of the sample, such as, for example, the quantity, count, volume, mass, concentration, or expression level of a molecule, a target, a content, a marker or an analyte, binding activity, nucleic acid sequence, or nucleic acid size or other analyte size, of the sample. One skilled in the art will appreciate that the forgoing exemplary processing steps are described herein for illustrative purposes only. Other processing steps may be employed without departing from the scope of the present disclosure.
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FIGS. 20A-20C illustrate an exemplary embodiment of asample vessel 1000 for collecting and processing one or more samples. The illustratedsample vessel 1000 comprises atubule 1200 that provides a disposable, single use container and collection and processing vessel for the sample. Thetubule 1200 may be constructed from any biocompatible material and may be manufactured by injection molding, insert molding, dip molding, blow-molding, extrusion, co-extrusion, lamination, assembling from a sheet material, or other processes generally used to manufacture medical devices and implants. Thetubule 1200 may receive sample in solid or liquid form and, in certain embodiments, may be sized to collect and/or process sample volumes in the range of 2 microliters to 2000 microliters. - The
tubule 1200 may be used with any known sample testing or processing system, including, for example, the systems described in U.S. Pat. No. 6,318,191, U.S. patent application Ser. No. 10/605,459, filed Sep. 30, 2003, which is a continuation of U.S. patent application Ser. No. 09/339,055, abandoned, and U.S. Pat. No. 6,780,617. Each of the aforementioned patents and patents applications is incorporated herein by reference. - In the exemplary embodiment illustrated in
FIGS. 20 and 21 , thetubule 1200 may include anopening 1400 for receiving a volume of sample material. Thetubule 1200 may include acompressible segment 1600 having awall 1800 constructed at least partially from a material having sufficient flexibility to permit compression of the opposed segments of thewall 1800 into contact. For example, thewall 1800 may be constructed to converge when thecompressible segment 1600 of thetubule 1200 is compressed in a direction perpendicular to the longitudinal axis of the tubule such that the volume of thecompressed segment 1600 of thetubule 1200 decreases, without fracturing of the sample vessel. Thewalls 1800 of thecompressible segment 1600 may be constructed of a resiliently compressible, flexible, and ultra-high strength material, such as polyethylene, polyurethane, polyvinyl chloride, polypropylene, or any other plastic material suitable for biomedical or chemical assaying applications. In one illustrative embodiment, thewalls 1800 of thecompressible segment 1600 have a wall thickness of approximately 0.01 mm to 0.5 mm. Experimental results indicate that constructing a compressible segment of a tubule having a wall thickness within this range significantly increases the efficiency of sample processing, such as heat transfer to the sample and sample transfer between the segments, and detection. In the illustrated embodiment, thecompressible segment 1600 oftubule 1200 extends the entire length of thetubule 1200. Alternatively, as discussed below, thetubule 1200 may include one or more discretecompressible segment 1600 spaced apart from one or more segments having different (e.g., non-flexible) properties. - In other exemplary embodiments, the
tubule 1200 may comprise a multi-layer wall structure. For example, thetubule 1200 may include an inner layer providing bio-compatibility, using material such as polyethylene or polyurethane, and an outer layer providing lower permeability, using material such as high density polyethylene or a metal foil, such as aluminum foil or a metal deposition. One skilled in the art will appreciate that one or more additional layers may also be employed, depending on, for example, the sample type, the reagent(s) employed, and the assay(s) being performed. - The material selected to construct portions of the wall of the
tubule 1200, for example an optional detection segment of thetubule 1200, can be optically transmissive over a selected wavelength range to facilitate optical analysis of the sample within thetubule 1200. - The
sample vessel 1000 of the exemplary embodiment illustrated inFIGS. 20A-20C may comprise a generalrigid container 2000 for receiving all or at least a portion of thetubule 1200. In the illustrated embodiment, thecontainer 2000 is sized to receive the complete length of thetubule 1200. Thecontainer 2000 may be constructed of a material having increased rigidity compared to the material of thetubule 1200 to facilitate handling of thetubule 1200. In certain embodiments, thecontainer 2000 may be constructed of a material having a lower permeability than the material of thetubule 1200. In the illustrated embodiment, thecontainer 2000 is a glass vacuum tube. Suitable glass vacuum tubes are available under the trademark VACUTAINER® from Becton-Dickenson. Thesample vessel 1000 can be used in a manner similar to a glass vacuum tube to collect a sample, such as a blood sample. Acontainer 2000 may be optionally used with any of the tubule embodiments disclosed herein. - The
sample vessel 1000 may comprise aninterface 3000 that is in fluid communication with theopening 1400 in thetubule 1200. Theinterface 3000 may permit collection of the sample within thetubule 1200 by facilitating delivery of the sample material to thetubule 1200 through theopening 1400. In certain exemplary embodiments, theinterface 3000 may include an instrument for collecting the sample form a sample source. In the exemplary embodiment illustrated inFIGS. 20A and 20B , theinterface 3000 is astopper 3200 that may be coupled to thetubule 1200 and may selectively seal theopening 1400 in thetubule 1200 to facilitate collection of the sample from a separate instrument. In the exemplary embodiment, thestopper 3200 is removably and replaceably connected to therigid container 2000 and seals anopening 2200 in thecontainer 2000. Thestopper 3200 may include a first annular portion 3400 having anopening 3600 sized and shaped to receive thetubule 1200 in a fluid tight relationship. The first annular portion 3400 is further sized and shaped to engage the walls of the container in a fluid tight relationship. Thestopper 3200 may include a secondannular portion 3800 that has a diameter greater than the diameter of both the first annular portion 3400 and thecontainer 2000. Theopening 3600 extends through the second annular portion 38 to form aninterface channel 3700. A penetrable, self-sealingportion 4000, such as a self-sealing membrane, may be provided to selectively seal theopening 3600 and, thus, permit selective transfer of the sample (from, for example, the sample collection instrument) through theinterface channel 3700 into thetubule 1200. The self-sealingportion 4000 may be constructed of any biocompatible, resilient, self-sealing material that can be penetrated by a needle or other sample collection instrument. Suitable materials may include rubber and silicon. In certain embodiments, thestopper 3200 may be constructed completely from a biocompatible, resilient, self-sealing material such as rubber or an elastomeric polymer. Theinterface channel 3700 may taper or otherwise narrow through the cross-section of thestopper 3200 to provide a guide for a needle or other instrument transferring the sample to thetubule 1200. - Alternatively, the
interface 3000 may include other mechanisms for selectively sealing theopening 1400 in thetubule 1200. For example, the interface may include a self-sealing elastomeric duckbill closure. Alternatively, theinterface 3000 may include a valve for selectively closing and opening theinterface channel 3700. - The
sample vessel 1000 may include aclamp 5000 for compressing thecompressible segment 1800 of the tubule to adjust the volume of thetubule 1200. Theclamp 5000 may be configured to compress opposing wall portions of thecompressible section 1600 into contact thereby dividing thetubule 1200 into two segments, 1600A and 1600B, as best illustrated inFIG. 20B . When theclamp 5000 is employed, thesegment 1600A remains in fluid communication with theinterface channel 3700 andsegment 1600B is sealed fromsegment 1600A by theclamp 5000. Once the sample is delivered to thesegment 1600A of thetubule 1200, theclamp 5000 may be removed, providing additional volume in thetubule 1200 that may permit future segmentation of the tubule and displacement of the sample within thetubule 1200 by compression of thetubule 1200. - The
clamp 5000 may be positioned at any location along the longitudinal axis of thetubule 1200. Additional clamps may also be employed to divide the tubule into additional segments. In illustrated exemplary embodiment, theclamp 5000 is disk-shaped and includes aradial slot 5200 that is sized to receive thetubule 1800 in a compressed state. One skilled in the art will appreciate that other devices may used to compress and, thereby, divide thetubule 1200. - In certain exemplary embodiments, the
tubule 1200 may be wholly or partially evacuated to place thelumen 4200 of thetubule 1200 under negative pressure, e.g., at a pressure less than atmospheric pressure, to facilitate fluid flow into thetubule 1200. Negative pressure can be generated by, for example, compressing thetubule 1200 to collapse thelumen 4200. An apparatus suitable for compressing the tubule is illustrated inFIGS. 36A-36C , described below. Alternatively thetubule 1200 may be compressed by hand. Thetubule 1200 may also be manufactured to include a negative pressure. - In certain embodiments, the
container 2000 may be wholly or partially evacuated to a negative pressure. For example, thecontainer 2000 may be evacuated to inhibit loss of negative pressure within thetubule 1200 and to hold the shape of thetubule 1200 during storage. - A reagent may be pre-packaged in the
tubule 1200 or can be introduced to thetubule 1200 after the sample is introduced to thetubule 1200. For example, a reagent can be introduced using a reagent injector cartridge associated with the sample processing system, by a needle, or by another device capable of fluid communication with thetubule 1200. The reagent can be, for example, an anticoagulant, a cell lyses reagent, a nucleotide, an enzyme, a DNA polymerase, a template DNA, an oligonucleotide, a primer, an antigen, an antibody, a dye, a marker, a molecular probe, a buffer, or a detection material. The reagent can be in liquid or solid form. In the case of a solid reagent, the reagent may be coated onto the walls of thetubule 1200. - In certain exemplary embodiments, the
interface 3000 may include one ormore chambers 44 that are in fluid communication with thetubule 1200 to selectively receive a volume of fluid, such as the sample material or a reagent, from thetubule 1200. In certain exemplary embodiments, thechamber 4400 may be evacuated or constructed to have a substantially small initial volume and may be expendable when receiving fluid. Thechamber 4400 can be used as a waste container to receive and store overflow sample, wash buffer, or reaction mixture during the sample processing. For example, compressing a segment of thetubule 1200 may move a portion of the sample to thechamber 4400. - In the exemplary embodiment illustrated in
FIGS. 21A-21C , for example, thestopper 3200 includes anannular chamber 4400 that is in fluid communication with theinterface channel 3700 in thestopper 3200, and, thus, thetubule 1200, through apressure gate 4800. In certain embodiments described herein, one or more pressure gates may be employed to selectively control the flow of fluid between segments, lumens, and other portions of the tubule, as well as between the tubule and external devices. For example, the illustratedpressure gate 4800 provides a fluid tight seal between thechamber 4400 and theinterface channel 3700 under normal operating conditions. Thepressure gate 4800 may open upon the application of a fluid pressure greater than a certain threshold pressure, for example, approximately 3 atmospheres. When a fluid pressure equal to or greater than the threshold pressure is applied to thepressure gate 4800, thepressure gate 4800 can open, allowing the sample or a reagent to flow from the high-pressure compartment, e.g., from thetubule 1200 or from thechamber 4400, to the low-pressure compartment. In certain embodiments, the pressure gate may be reversible, i.e., the pressure gate may be configured to re-close if the fluid pressure is reduced to value less than the threshold pressure. In other embodiments, the pressure gate may be irreversible, i.e., the pressure gate may be initially closed and may remain open once opened. For example, once a threshold pressure is exceeded the irreversible pressure gate remains open, even if the pressure applied to the pressure gate is reduced to below the threshold pressure. One example of an irreversible pressure gate is the pressure gate described below in connection withFIGS. 22A-22B . - In the illustrated embodiment of
FIGS. 21A and 21B , thepressure gate 4800 is a slit formed in thestopper 3200 between theinterface channel 3700 and thechamber 4400. The material forming thestopper 3200 may be selected to be sufficiently flexible and resilient to allow the slit to open at the threshold pressure and to close at pressures lower than the threshold pressure. - A
label 6000 identifying the sample within thesample vessel 1200 may be attached to theinterface 3000, thecontainer 2000, or thetubule 1200. Thelabel 6000 can be a bar code or other indicia for identifying the sample. -
FIGS. 22A and 22B illustrate another exemplary embodiment of asample vessel 10000. Thesample vessel 10000 comprises atubule 11200, which can be analogous in construction to thetubule 1200, having a plurality oflumens lumens lumens FIG. 22A illustrates thepressure gate 14800 in a closed position andFIG. 22B illustrates the pressure gate in an open position that permits fluid flow between the lumens. - In the exemplary embodiment, the
lumens tubule 1200. One skilled in the art will appreciate that other lumen orientations are possible. Thelumens lumens lumen 14200B has a smaller diameter than thelumen 14200A. Although two lumens are illustrated in the exemplary embodiment, one skilled in the art will appreciate that thetubule 1200 may be constructed of any number of lumens. - The
pressure gate 14800 in the present embodiment is coextensive with thelumens pressure gate 14800 extends along the entire length of the lumens. Alternatively, thepressure gate 14800 may extend along only a portion or portions of the lumens, particularly in embodiments in which thetubule 1200 is segmented into discrete longitudinally extending segments, as in the case of the embodiment illustrated inFIGS. 26A-26C . In such embodiments, one or more pressure gates may be provided between adjacent lumens. - In the exemplary embodiment, the opposed portions of the
wall 11800 of thetubule 11200 are compressed into contact to form alongitudinally extending seam 17000 that divides thetubule 11200 into two lumens,lumens tubule 11200 into multiple lumens, theseam 17000 may further provide an irreversible pressure gate,pressure gate 14800, between thelumens seam 17000 may be formed by mechanically clamping or otherwise compressing a cylindrical tubule or by applying vacuum pressure to the interior of a cylindrical tubule. Alternatively, theseam 17000 may be formed during manufacturing of the tubule by, for example, extrusion, molding, or lamination processes. The opposed wall portions that are compressed into contact to form theseam 17000, and thepressure gate 14800, may be bonded together by mechanical or chemical bonding, by heating sealing, for example, by bringing hot surfaces into contact with the tubule wall immediately after extrusion, by ultrasonic welding, by mechanical interlocking, or both other connection mechanisms, to create theirreversible pressure gate 14800. - The
pressure gate 14800 is initially in a closed configuration that inhibits fluid flow between thelumens pressure gate 14800 may open by separating the compressed opposed walls forming thepressure gate 14800. Applying a threshold pressure to thepressure gate 14800, as described above, may open thepressure gate 14800. Alternatively, energy may be applied to thepressure gate 14800 to weaken the bond between the compressed opposed walls. For example, thermal energy or light, e.g., ultra-violet light, may be applied to thepressure gate 14800 or to selected portions or all of thetubule 11200. The threshold pressure and/or the amount energy to open thepressure gate 14800 may vary depending on the type and strength of the bond. Alternatively, the bond between the compressed opposed wall portions may be weakened or broken by chemical reaction with reagent or the sample. - In certain exemplary embodiments, one or more of the lumens may include one or more reagents. Reagents may be provided to one or more lumens prior to sample collection, e.g., one or more reagents pre-packaged with the tubule, or after sample collection. In the exemplary embodiment illustrated in
FIGS. 22A and 22B , for example, a reagent may be provided inlumen 14200B.Lumen 14200A may be utilized for sample collection and processing. Sample collection may occur with thepressure gate 14800 in a closed configuration, as illustrated inFIG. 22A . Upon transfer of the sample to lumen 14200A, thepressure gate 14800 may be opened automatically due to release of pressure within thelumen 14200A, or selectively by applying energy to the pressure gate and/or a threshold fluid pressure. In other embodiments, thelumen pressure gate 14800, the reagent(s) can mix with and interact with the sample in thelumen 14200A, as illustrated inFIG. 22B . Automatic release of thepressure gate 14800 and mixing of the reagent with the sample may be beneficial in certain applications, such as the mixing of an anticoagulant with a blood sample. -
FIG. 23 illustrates another embodiment of amulti-lumen tubule 11200 that includes three lumens, namely afirst lumen 14200A, asecond lumen 14200B, and athird lumen 14200C. Each lumen may be separated apressure gate 14800, for example, an irreversible pressure gate, as described above. Each of thelumens second lumen 14200B may be provided with one or more prepackaged reagents andfirst lumen 14200A may be used for sample collection and processing. Upon sample collection infirst lumen 14200A,pressure gate 14800A may be opened allowing fluid communication between thesecond lumen 14200B and thefirst lumen 14200B.FIG. 23 illustrates thepressure gate 14800A in an open configuration.Lumen 14200C may be utilized as an injection channel for receiving one or more reagents, typically, but not necessarily, after sample collection infirst lumen 14200A. Thelumen 14200C may be free of sample material untilpressure gate 14800A is transitioned to an open configuration.FIG. 23 illustratespressure gate 14800B in a closed configuration that inhibits fluid communication betweenthird lumen 14200C andfirst lumen 14200A. Reagent may be delivered to thethird lumen 14200C by aneedle 19000, such as a needle from a reagent injection cartridge, or by other instruments that can penetrate the lumen or otherwise provide fluid communication between a reagent source and thelumen 14200C. Thelumen 14200C may be free of sample and reagent material until reagent is injected to avoid cross contamination of theinjection needle 19000. The portion of the wall 11800C proximal thethird lumen 14200C may be constructed of a resilient, self-sealing material to facilitate re-sealing of thewall 11800 after penetration to deliver reagent. - One or more lumens of the
tubule 11200 may include a reinforced wall portion 17100, as illustrated inFIG. 24 . The reinforced wall portion 17100 may have an increased wall thickness compared with the remainder of thetubule wall 11800 to facilitate needle penetration and re-sealing. For example, the reinforced portion may have a wall thickness of approximately 1 mm to 5 mm greater than other portions of the wall. The reinforced portion 17100 may be constructed from a different material, having increased strength and/or resiliency, for example, than the remainder of thetubule wall 11800. Needle guides 17200 may be provided to direct needle penetration and inhibit tearing of thetubule wall 11800. -
FIGS. 25A-25E illustrate another exemplary embodiment of amulti-lumen tubule 11200 that includes a pair of parallel lumens, namelyfirst lumen lumens layer fluid channel 17600 in the form of a slit opening that extends the length of thetubule 11200. Although one fluid channel is illustrated, additional fluid channels may be provided. Thefluid channel 17600 permits the sample to be moved between thefirst lumen 14200A and thesecond lumen 14200B and to occupy both lumens simultaneously. For example, during sample collection, portions of the sample, or the entire sample, can be transferred from theopening 11400 along the length of thefirst lumen 14200A, through thefluid channel 17600, and along the length of thesecond lumen 14200B.FIGS. 25B-25E illustrate the flow of a sample, in fluid form, through the first lumen to the end of the first lumen due to relatively low flow resistance of the lumen relative to the fluid channel 17600 (FIG. 25B ), through a portion 17400 of thefluid channel 17600 distal to the opening in thefirst lumen 14200A (FIG. 25C ), along thefluid channel 17600 and through thesecond lumen 14200B (FIG. 25D ) to fill both lumens (FIG. 25D ). In embodiments in which a solid reagent is packed into thelumens 14200A and/or 14200B of thetubule 11200, flow of the sample through the lumens via thefluid channel 17600 can facilitate mixing of the solid reagent with the sample. For example, in the case of blood samples, the inventors have determined that by allowing the blood sample to flow through thefirst lumen 14200A and thesecond lumen 14200B via thefluid channel 17600 can improve mixing of the sample with an anticoagulant coated on the inner walls of the two lumens. -
FIGS. 26A-26C illustrate another exemplary embodiment of amulti-lumen tubule 11200 having three parallel lumens, namely afirst lumen 14200A, asecond lumen 14200B, and athird lumen 14200C. In the exemplary embodiment, each lumen of thetubule 11200 is divided into a plurality of longitudinally extendingsegments 18000. For example, thethird lumen 14200C, illustrated in cross-section inFIG. 26B , includes fivesegments 18000A-E. Each of thesegments 18000 can be used for one or more sample collection and/or sample processing steps, including the processing steps described above. In PCR (polymer chain reaction) testing, for example, one segment may used for sample collection, one segment may be used for sample pretreatment, e.g., nucleic acid extraction, one or more segments may used for sample processing, e.g., thermocycling, and one or more segments may be used for sample analysis. Any number of segments may be provided. In addition, one or more segments may be used to store reagent or as an injection channel for the delivery of reagent. The number of segments may be varied depending of the sample being processed and the processing steps selected. - Each of the
segments 18000 may be separated by a seal 18200 that provides a temporary or permanent fluid seal betweenadjacent segments 18000. A seal 18200 may be a pressure gate, such as the reversible and irreversible pressure gates described above. Alternatively, a seal 18200 may be formed by bonding or fusing of compressed opposed wall sections of the tubule. The seal 18200 may be formed by applying energy, such as thermal energy or RF energy, by ultrasonic welding, or by using a bonding agent. A clamp may also be applied to the exterior of the tubule to compress the wall of the tubule and form a seal separating the segments in the tubule. For example, the clamp may be an electro-mechanical clamping mechanism as described below in connection withFIG. 29 . Any other mechanism for provided an external compressive force on the tubule may be employed as the clamping mechanism. One or more clamps may be provided as part of the sample processing system used to process the sample within thetubule 11200. The segments may be connected by one or more micro-fluidic flow channels that provide selective fluid connection between the segments, as described below. A seal 18200 may be a filter disposed within the tubule to separate selected components of a fluid within the tubule from other segment or components of the fluid within the tubule. - In the illustrated exemplary embodiment, the
interface 3000 for facilitating delivery of the sample to thetubule 11200 includes aneedle 18400 for direct collection of the sample to be processed with thesample vessel 10000. Theneedle 18400 is positioned a proximal end of the tubule and is fluid communication with an opening in thetubule 11200. In the illustrated exemplary embodiment, theneedle 18400 is in fluid communication with an opening in thefirst lumen 14200A, however, theneedle 18400 may be connected to any one or all of thelumens 14200 of thetubule 11200. A removable andreplaceable needle cover 18600 may be provided to secure theneedle 18400 prior to and after use. Alternatively, theneedle cover 18600 may be connected by a hinge, as shown inFIG. 27 , or by another mechanism that allows to thecover 18600 to be moved into and out of position about theneedle 18400. A needle safety mechanism may be coupled to the needle and the sample vessel. -
FIG. 28 illustrates another embodiment of thecover 18600 in which the sample collection instrument, e.g., theneedle 18400, is connected to thecover 18600. In the illustrated exemplary embodiment, theproximal end 18400A of theneedle 18400 may be used for sample collection from a sample source and thedistal end 18400B of theneedle 18400 may be used to provide a fluid connection with an opening in thetubule 11200 throughinterface 3000. For example, thedistal end 18400B may be used to penetrate a self-sealingmembrane 4000 provided in theinterface 3000. In another embodiment, acover 19000 may include a sample instrument in the form of aneedle 18400 and may have a compressible portion in fluid communication with the needle to facilitate drawing a fluid sample into theneedle 18400 and transferring the sample to thesample vessel 11000.Cover 19000 may be particularly useful as a finger prick for collection a blood sample. -
FIG. 29 illustrates a processing station 30000 of an exemplary sample processing device, such as a sample processing device described in U.S. Pat. No. 6,318,191 and U.S. patent application Ser. No. 09/782,732, filed Feb. 13, 2001. The exemplary processing station 30000 includes multiple compression members, namelyfirst compression member 30200A,second compression member 30200B, andthird compression member 30200C. Each compression member 30200 is adapted to compress a sample vessel, for example, thetubule 1200 ofsample vessel 1000 described above, and thereby displace the contents of the sample vessel, e.g. reagent or sample, within the sample vessel. Although the exemplary processing station 30000 is illustrated in connection withsample vessel 1000, one skilled in the art will appreciate that any of the sample vessels disclosed herein may be used in with the exemplary processing station 30000. A plurality of compression members 30200 may be oriented parallel to the longitudinal axis of thetubule 1200, as illustrated inFIG. 29A . Alternatively, a plurality of compression members 30200 may be oriented transverse to the longitudinal axis of the tubule, i.e., oriented latitudinally, as illustrated inFIG. 34B described below, or in other orientations depending on the compression configuration desired. A driver may be coupled to one or more of the compression members 30200 to selectively move the compression member into contact with the sample vessel. The driver can be, for example, an electromagnetic actuating mechanism, a motor, a solenoid, or any other device for imparting motion on the compression members 30200. Astationary member 30400 or another compression member may be provided opposite compression member 30200. - A compression member 30200 may be employed to compress a portion of the
wall 1800 of thetubule 1200 into contact with another portion of thewall 11800 of thetubule 1200 to form a seal in thetubule 1200 and thereby divide thetubule 1200 into multiple segments. In alternative embodiments, a compression member 30200 may compress a portion of thewall 1800 of thetubule 1200 into proximity with another portion of thewall 1800 of thetubule 1200 to form amicro-fluidic channel 30600 between segments of thetubule 1200. For example, in the embodiment illustrated inFIG. 29 ,compression member 30200B compresses a portion ofwall 1800 into proximity with another portion of the wall to create amicro-fluidic channel 30600 that connects afirst segment 18000A and asecond segment 18000B of thetubule 1200. The width of themicro-fluid channel 30600 may be adjusted by displacing thecompression member 30200B towards or away from thetubule 1200. Micro-fluid channels may be formed having a gap less than 200 microns, preferably 10 to 30 microns. - The compression members 30200 may be arranged in a variety of orientations to compress the
tubule 1200 into a variety of configurations. For example, inFIG. 29B , the width of themicro-fluidic channel 30600 extends across the entire width of thetubule 1200. Such a compressed configuration may be formed by acompression member 30200B having a planar compression surface 30800 for engaging thetubule 1200 that is sized to engage the entire compressed wall surface of the tubule. In other embodiments, the size or shape of the compression surface 30800 may be varied and the number and orientation ofcompression members 30200B may be varied. For example,FIG. 30A illustrates acompressed tubule 1200 having a centrally locatedflow channel 30600 that may be formed by a compression member 30200 having a groove formed on the bottom surface thereof or by three compression members 30200 aligned transverse to the longitudinal axis of thetubule 1200. A centrally positioned compression member may compresswall portion 1800A into proximity with an opposed wall portion, while a pair of compression members, one on either side of the central compression member, may compressside wall portions 1800B and 1800C, respectively.FIG. 30B illustrates acompressed tubule 1200 having a centrally locatedlumen 30600 formed by compressing thetubule 1200 into a non-planar configuration. In this illustrated embodiment, a triangular profile flow channel is formed, which inherently forces a cell or particle to flow through the central line of the channel, thus reducing the need to regulate the tolerance in forming the flow channel.FIG. 30C illustrates acompressed tubule 1200 having aflow channel 30600 formed off-set from the center of thetubule 1200. In the illustrated embodiment, the flow channel is formed on a lateral edge of thetubule 1200. - At least a portion of the wall of the
tubule 1200 may be optically transparent to allow monitoring or detection of the sample or reaction. The transparent portion of the wall may be located in the flow channel section, thus allowing the monitoring of sample or reaction under flow or through a thin layer of liquid, for processes such as counting cells, reaction hybridization, or detection, for example, microarray spots. - One skilled in the art will appreciate that while it may be desirable in certain applications for the wall of the tubules disclosed herein to be uniform along the circumference and the longitudinal axis of the tubule, only a portion of the wall along the circumference and/or longitudinal axis of the tubule need be resilient and compressible. Thus, the tubule need not have a uniform cross-section, either along the longitudinal axis or transverse to the longitudinal axis. In certain exemplary embodiments, for example, a section of the wall of the tubule may be formed of a material selected to provide a property distinct from a property of another section of the wall. Exemplary properties that may be varied include permeability, flexibility, hardness, resiliency, optical transparency, biocompatibility, surface smoothness of the inner wall, and surface chemistry of the inner wall, for example the hydrophobic or hydrophilic properties of the inner wall surface. Surface properties may be rendered by coating with a layer of material, such as a thermoset urethane aired by UV energy or other cross linking methods.
-
FIGS. 34A and 34B illustrate an exemplary embodiment of asample vessel 1000 in the form of atubule 1200 havingwall sections 1800A that are formed of a material selected to provide a property distinct from a property of a plurality ofother wall sections 1800B of thetubule 1200.Wall sections 1800A may be opposed to one another, as illustrated, or positioned at other positions in the cross section of thetubule 1200.Wall sections 1800A may similar in size, shape and material properties, as illustrated, or may vary in size, shape, and material properties from one another. In the illustrated embodiment,wall sections 1800A are selected from a material having sufficient flexibility to permit compression of thetubule 1200, as illustrated inFIG. 34B .Wall sections 1800B are formed of a material having increased rigidity compared to the material ofwall sections 1800A. In the illustrated embodiment,wall sections 1800B preferably have sufficient rigidity to resist flexing during compression and thereby maintain a planar configuration.Wall sections 1800B may be opposed to one another, as illustrated, or positioned at other positions in the cross section of thetubule 1200.Wall sections 1800B may be similar in size, shape and material properties, as illustrated, or may vary in size, shape, and material properties from one another. In the illustrated embodiment, thewall sections tubule 1200 and transverse to the longitudinal axis.Wall sections tubule 1200.Wall sections wall sections 1800A may be formed of a relatively low durometer polyurethane, for example, in the range of from 40 A to 90 A depending on thickness, andwall sections 1800B may be formed of a polyurethane having a relatively higher durometer, for example, in the range of from 40 D to 90D depending on thickness. A tubule having wall sections of varying properties may be manufactured by conventional extrusion, co-extrusion, injection molding, insert molding, dip molding, blow molding, transfer molding, or lamination processes. - During compression of the
tubule 1200 illustrated inFIGS. 34A and 34B , thewall sections 1800A flex allowing afirst wall section 1800B to be moved into proximity or contact withsecond wall section 1800B′.Wall sections 1800B may provide improved sealing surfaces due to the increased rigidity compared withwall sections 1800A. In addition,walls sections 1800B permit the formation of a precisely definedmicro-fluid flow channel 30600, as illustrated inFIG. 34B . The increased rigidity of thewall sections 1800B allows for the formation of a smaller and more uniform flow channel than more flexible wall sections.FIG. 34B illustrates the formation of amicro-fluidic flow channel 30600 betweensegments tubule 1200. In the illustrated embodiment, thecompression members 30200A-C are oriented transverse to the longitudinal axis of the tubule to form aflow channel 30600 that extends latitudinally, i.e., transverse to the longitudinal axis, betweenfirst segment 18000A andsecond segment 18000B. - In other exemplary embodiments, the number of wall sections of differing properties may be varied. For example, a
single wall section 1800B having increased rigidity may be provided or three or more wall sections having increased rigidity may be provided. - In certain exemplary embodiments, a
flow channel 30600 may be pre-formed in a section of thewall 1800 of the tubule as illustrated inFIGS. 31 and 32 A-B. Thepre-formed flow channel 30600 may be agroove 31600 formed in a wall section of thetubule 1200. Thegroove 31600 may be formed by scoring or etching thewall 1800 of thetubule 1200 or may be formed during the extrusion or molding of thetubule 1200. Thegroove 31600 in the illustrated embodiments extends longitudinally, however, thegroove 31600 may be formed in any direction, including latitudinally. More than onegroove 31600 may be provided. Thegroove 31600 may have a variety of cross-section shapes and sizes. In the embodiment illustrated inFIG. 31 , thegroove 31600 has a triangular cross-section. In the embodiment illustrated inFIGS. 32A-32B , the groove 31006 has a rectangular cross-section. The cross-sectional size of thegroove 31600 can be selected based on desired shear rate profile of theflow channel 30600. - The
groove 31600 may be formed in any section of thewall 1800 of thetubule 1200. For example, thegroove 31600 may be formed in awall section 1800B having increased rigidity compared to other wall sections of thetubule 1200, as is the case for the illustrated embodiments ofFIGS. 31 and 32 A-B. During compression of thetubule 1200, as illustrated inFIG. 32B , thewall section 1800Bcontacts wall section 1800B′ to provide a fluid tight seal.Groove 31600 provides aflow channel 30600 that extends longitudinally through the fluid tight seal. -
FIGS. 33A and 33B illustrate an exemplary embodiment of asample vessel 40000 comprising a tubule 41200 having a plurality offlow channels 30600 and one or a plurality ofdepressions 40800 formed on aninterior wall surface 41000 of thewall 41800 of the tubule 41200. Eachdepression 40800 can form a micro-cup during compression of the tubule 41200 that can hold a fixed volume of sample or reagent. The volume of a depression forming a micro-cup can be from 0.1 microliter to 10 microliter, preferably, from 0.5 microliter to 4 microliter. A pattern of one ormore grooves 31600 anddepressions 40800 may be formed on theinterior wall surface 41000 of the tubule 41200 and may interconnect to provide a network of micro-cups interconnected bymicro-fluidic flow channels 30600, as best illustrated inFIG. 33B . Such a network may be used to perform a variety of processing steps within one or more micro-cups and may permit the transport of small, precise volumes of sample and reagent between the micro-cups via micro-fluid flow channels by selectively compressing the tubule 41200. The network of grooves and depressions may be formed using semi-conductor processing techniques. For example, a mask pattern may be applied to an interior wall surface of thetubule 1200 using conventional photolithographic techniques. The grooves and depressions may then be formed by etching or otherwise removing portions of the interior wall surface based on the pattern imaged onto the interior wall surface. It may be desirable to form the network of grooves and depressions on aplanar substrate 41800A constructed of a material suitable for use in the tubule 41200, as illustrated inFIGS. 33A and 33B . A second layer 41800B of material can be attached to theplanar substrate 41800A to form thewall 41800 of the tubule 41200. - Referring to
FIGS. 33A and 33B , one or more sample orreagent processing devices 41400 may be provided on theinterior wall surface 41000 of the tubule 41200. For example, a microarray device may be embedded on theinterior wall surface 41000 of the tubule 41200. Anexemplary microarray device 41400 may comprise a plurality of reagent coated zones for simultaneous analysis of a plurality of analytes within a sample. Theprocessing device 41400 may also be a micro-fluid device or a lab-on-a-chip device, or any other device for processing a sample. Theprocessing device 41400 may be interconnected with one ormore depressions 40800 or other processing devices viaflow channels 30600. Any number of processing devices of any type may be provided in the tubule 41200. - Referring to
FIG. 37 , asample vessel 70000 comprising atubule 71200 divided intomultiple segments 78000A-C. Segment 78000B may be constructed of a rigid, generally non-flexible material and may have a processing device, such as amicroarray 71400, embedded on the interior wall thereof. Thesegment 78000B may provide a pre-formed flow channel between twocompressible segments 78000A and 78000C. By alternately compressing the two flexible segments 70800A and 78000C, the sample may flow through theflow channel 70600 to facilitate high efficient hybridization or binding of analytes to the reagent spots of themicroarray 71400. A flow channel 706 having a small gap may also increase wash efficiency as a laminar flow is formed. -
FIGS. 35A-35E illustrates an exemplary embodiment of asample vessel 1000 comprising atubule 1200 and anadapter 50000 that is connected to thetubule 1200 of thesample vessel 1000. Theadapter 50000 may be provided to facilitate handling of thesample vessel 1000 and/or to facilitate connection of thetubule 1200 to an external device, such as a micro-fluid device, a lab-on-a-chip device, a microarray device, a reagent source, another sample vessel, or any other device suitable for containing or processing a sample. In the illustrated embodiments, theadapter 50000 is a generally planar tab that is coextensive with thetubule 1200. One skilled in the art will appreciate that theadapter 50000 need not be coextensive with the tubule and may be constructed of varying sizes and shapes depending upon the application. Moreover, more than one adapter may be provided. - The
adapter 50000 may be constructed of any material suitable for use in construction thetubule 1200. For example, the adapter may be constructed of polyurethane. Theadapter 50000 may be constructed of the same or a different material than thetubule 1200. To facilitate handling, theadapter 50000 may be constructed of a material having increased rigidity compared to the material of thetubule 1200, for example a high durometer polyurethane. In certain embodiments, theadapter 50000 may be manufactured with thetubule 1200 in, for example, a co-extrusion process or an injection molding process. Alternatively, theadapter 50000 may be manufactured independently and attached to thetubule 1200 in a post-forming process by, for example, bonding. - The exemplary embodiment of
FIGS. 35A-35E also includes acontainer 2000 and aninterface 3000, as described above. Thecontainer 2000 removably and replaceably encloses thetubule 1200 to protect thesample tubule 1200 and when removed, may allow direct manipulation oftubule 1200. A portion ofadapter 50000 may not be enclosed bycontainer 2000. The exposed portion of theadapter 50000 can be directly accessed by a user for labeling, handling and other processing. Theinterface 3000 includes aninterface channel 3700 that communicates with an opening in thetubule 1200 to facilitate delivery of a sample to thetubule 1200. In the illustrated embodiment, a removable and replaceable cover 58600 is provided to selectively open and close theinterface channel 3700. The exemplary cover 58600 includes a sample collection instrument in the form of a tissue swab 584 for collecting tissue samples from a sample source. - FIGS. 35A-B illustrate an embodiment of the
adapter 50000 that is constructed to facilitate handling of thesample vessel 1000. -
FIG. 35C illustrates an embodiment of the adapter 50000C that is designed to facilitate delivery of a reagent or a sample from an external device, such as aneedle 9000 from a reagent injector cartridge. The adapter 50000C includes a reversible orirreversible pressure gate 4800 that provides a fluid channel to permit selective displacement of a fluid, e.g., a sample or reagent, between thetubule 1200 and the external device, in the present embodiment,needle 9000. The adapter 50000C may include a self-sealingmembrane 54000, valve, or other sealing mechanism to facilitate selective communication with the external device. A reservoir 50200 may be provide to contain a fluid delivered from the external device or fluid from thetubule 1200. In use, theneedle 9000 may penetrate the self-sealingmembrane 54000 to deliver fluid to the reservoir 50200 or to withdraw fluid from the reservoir 50200.Pressure gate 4800 may be opened in the manner described above, e.g. by compressing thetubule 1200 or the reservoir 50200, to withdraw fluid from the reservoir 50200 or to deliver fluid to the reservoir 50200 from thetubule 1200. Theneedle 9000 may be coupled with a sensor, such as an electrode, a fiber optical sensor, for penetrating theself sealing membrane 54000 and measuring a sample property. -
FIG. 35D illustrates an embodiment of theadapter 50000D that comprises a compressible reservoir 50600 and a reversible orirreversible pressure gate 4800 that provides a fluid channel to permit selective displacement of a fluid, e.g., a sample or reagent, to thetubule 1200 from the compressible reservoir 50600. The compressible reservoir 50600 may contain a pre-packed reagent. In certain embodiments, the compressible reservoir 50600 may be a blister pack. Upon compression of the compressible reservoir 50600,pressure gate 4800 may open and fluid with the compressible reservoir 50600 can be displaced in to thetubule 1200. -
FIG. 35E illustrates an embodiment of the adapter 50000E that comprises a reservoir 50200, a first reversible or irreversible pressure gate 4800A that provides a fluid channel to permit selective displacement of a fluid, e.g., a sample or reagent, between thetubule 1200 and the reservoir 50200, and a second reversible orirreversible pressure gate 4800B that provides a fluid channel to permit selective displacement of a fluid, e.g., a sample or reagent, between anexternal device 50800 and the reservoir 50200. A connector 50900 may be provided to interface with theexternal device 50800. Such device may be an Access™ card for Micronics Inc., a LabChip® product from Caliper, Inc. or a GeneChip® from Affymetrix, Inc. - FIGS. 36A-E illustrate another exemplary embodiment of a
sample vessel 60000 that comprises atubule 1000 and an apparatus 60200 for drawing a sample into thetubule 1200 of thesample vessel 1000. The apparatus 60200 includes a cylindrical housing 60400 having an opening 60600 for receiving thetubule 1200. The opening 60200 extends from a proximal end 60800 to a distal end 61000 of the housing 60400. Both the housing 60400 and the opening 60600 can be sized and shaped to accommodate the size and shape of thetubule 1200 or other sample vessels. For example, the housing 60400 and opening 60600 are cylindrical in shape and have a circular cross-section analogous to that of thetubule 1200. Theadapter 60000 comprises first means 61200 for compressing a first portion of thetubule 1200 andsecond means 61400 for compressing a second portion of thetubule 1200. The first compression means 61200 may be spaced apart from the second compression means 61400. For example, the first compression means 61200 may be positioned at the proximal end 60800 of the housing 60200 and the second compression means 61400 may be positioned at the distal end 61000 of the housing 60200. The spacing between the first and second compression means may be selected based on the desired sample collection volume in thetubule 1200. - The first compression means 61200 may comprise a first pair of spaced apart rollers, 61600A and 61600B. At least one of the rollers 61600A-B may be selectively movable into contact with the other roller to compress the
tubule 1200 between the rollers 61600A-B. Afirst activator 62000 may be coupled to the rollers 61600A, 61600B to effect separation or compression of the rollers. The second compression means 61200 may comprise a second pair of spaced apart rollers, 61800A and 61800B. At least one of the rollers 61800A-B may be selectively movable into contact with the other roller to compress thetubule 1200 between the rollers 61800A-B. A second activator 62200 may be coupled to the rollers 61800A, 61800B to effect separation or compression of the rollers. In addition to rollers, or other compression mechanisms may be employed for the first and second compression means, including the compression members described above. Any structure suitable for selective compression of thetubule 1200 may be employed. The first and second compression means need not be the same structure. - In use, the
tubule 1200 is inserted into the opening 60600 at the proximal end 60800 of the housing 60400 and drawn completely through the opening 60600 to the distal end 61000 of the housing 60400. As thetubule 1200 is drawn through the housing 60400, thetubule 1200 is flatten and compressed, as illustrated inFIG. 36B , to evacuate thetubule 1200. At the time of sample collection, acover 68600 may be removed to expose a sample collection instrument, such as aneedle 68400, that is in fluid connection with thetubule 1200. Theneedle 68400 can be inserted into the sample source and the first compression means 61200 may be separated to draw the sample into thetubule 1200, as illustrated inFIG. 36C . Thesample vessel 1000 may then be inserted into a device 63000 for removing theneedle 68400, or other sample collection instrument, as illustrated inFIG. 36D . The device 63000 may also include a mechanism for sealing the proximal end of thetubule 1200 after theneedle 68400 is removed, by, for example, compressing and heating the wall of thetubule 1200 at the proximal end to bond or fuse the walls together. The second compression means 61400 may separate and theadapter 60000 may be removed from thetubule 1200, as illustrated inFIG. 36E . - While the sample vessels disclosed herein have been particularly shown and described with references to exemplary embodiments thereof, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the disclosure. Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation, many equivalents to the exemplary embodiments described specifically herein. Such equivalents are intended to be encompassed in the scope of the present disclosure.
Claims (28)
1. A flexible vessel for thermal cycling a sample, the flexible vessel comprising:
a soft-sided reaction vessel comprising:
a receptacle for receiving the sample, and
a flexible body coupled to the receptacle, the flexible body having first and second portions coupled together and in fluid communication with each other, wherein the flexible body is configured for insertion into a thermal cycler such that the first portion is received into a first temperature zone and the second portion is received into a second temperature zone of the thermal cycler.
2. The vessel of claim 1 , wherein the flexible body is formed from two faces of plastic sheeting that are sealed together to form sealed sides.
3. The vessel of claim 2 , further comprising a plurality of additional soft-sided reaction vessels, each having a receptacle and a flexible body coupled to the receptacle, wherein the plurality of additional bodies are formed from the two faces of plastic sheeting and each has sealed sides.
4. The vessel of claim 3 , wherein the two faces of plastic sheeting are sealed together such that each flexible body is separated from its adjacent flexible body by a sealed side.
5. The vessel of claim 1 , wherein the flexible body contains dried PCR reagents.
6. A flexible vessel for thermal cycling a sample, the flexible vessel comprising two faces of flexible material that are sealed together to form a plurality of flexible bodies, each flexible body separated from its adjacent flexible body by a sealed side, and each flexible body having a first portion and a second portion, the first and second portions coupled together and in fluid communication with each other, wherein the flexible bodies are configured for insertion into a thermal cycling apparatus such that the first portion of each flexible body is received into a first temperature zone and the second portion of each flexible body is received into a second temperature zone of the thermal cycler.
7. The vessel of claim 6 , further comprising a plurality of receptacles, each receptacle fluidly coupled to its respective flexible body.
8. The vessel of claim 6 , wherein the flexible material is a thin plastic film.
9. The vessel of claim 8 , wherein the thin plastic film comprises aluminum lamination.
10. The vessel of claim 8 , wherein the thin plastic film is selected from the group consisting of polyethylene, polyurethane and alloys thereof.
11. The vessel of claim 8 , wherein the thin plastic film transmits about 80% to about 90% of incident light.
12. The vessel of claim 6 , wherein the vessel body has a coefficient of heat transfer of about 0.02 to about 20 W/m*degK.
13. The vessel of claim 6 , wherein each flexible body contains dried PCR reagents.
14. A thermal cycling system comprising the reaction vessel of claim 6 received into the thermal cycler, wherein the first temperature zone of the thermal cycler is configured for receiving the first portion of the reaction vessel, the first temperature zone comprising a first heater, the first temperature zone movable between an open orientation in which the first heater affects the temperature of the reaction mixture contained within the first portion, and a closed orientation in which the reaction mixture is forced from the first portion and the first heater does not substantially affect the temperature of the reaction mixture, and the second temperature zone of the thermal cycler is configured for receiving the second portion of the reaction vessel, the second temperature zone comprising a second heater, the second temperature zone movable between an open orientation in which the second heater affects the temperature of the reaction mixture contained within the second portion, and a closed orientation in which the reaction mixture is forced from the second portion and the second heater does not substantially affect the temperature of reaction mixture.
15. The thermal cycling system of claim 14 , wherein each flexible body contains a PCR reaction mixture.
16. The thermal cycling system of claim 15 , wherein the PCR reaction mixture is sealed within each flexible body.
17. The thermal cycling system of claim 16 , wherein each flexible body is heat-sealed to seal the reaction mixture within each flexible body.
18. The thermal cycling system of claim 16 , wherein the first portion of each flexible body is coupled to a fitting, and closure of the fitting seals the reaction mixture within its respective flexible body.
19. The vessel of claim 1 , wherein the flexible body comprises a thin plastic film.
20. The vessel of claim 19 , wherein the flexible body further comprises aluminum lamination.
21. The vessel of claim 19 , wherein the thin plastic film is selected from the group consisting of polyethylene, polyolefin, polyurethane and alloys thereof.
22. The vessel of claim 19 , wherein the thin plastic film transmits about 80% to about 90% of incident light.
23. The vessel of claim 1 , wherein the vessel body has a coefficient of heat transfer of about 0.02 to about 20 W/m*degK.
24. The vessel of claim 1 , wherein the flexible body is formed from two walls of plastic and has a flattenable cross-sectional profile.
25. The vessel of claim 24 , further comprising a plurality of additional soft-sided reaction vessels, each having a receptacle and a flexible body coupled to the receptacle, wherein the plurality of additional bodies are each formed from two walls of plastic and has a flattenable cross-sectional profile.
26. A flexible vessel for thermal cycling a sample, the flexible vessel comprising a plurality of flexible bodies, each flexible body separated from its adjacent flexible body, and each flexible body having a first portion and a second portion, the first and second portions coupled together and in fluid communication with each other, wherein the flexible bodies are configured for insertion into a thermal cycling apparatus such that the first portion of each flexible body is received into a first temperature zone and the second portion of each flexible body is received into a second temperature zone of the thermal cycler.
27. A thermal cycling system comprising the reaction vessel of claim 26 received into the thermal cycler, wherein a first temperature zone of the thermal cycler is configured for receiving the first portions of the flexible bodies of the reaction vessel, the first temperature zone comprising a first heater, the first temperature zone movable between an open orientation in which the first heater affects the temperature of reaction mixtures contained within the respective first portions, and a closed orientation in which the reaction mixtures are forced from the respective first portions and the first heater does not substantially affect temperatures of the reaction mixtures, and a second temperature zone of the thermal cycler is configured for receiving the second portions of the flexible bodies of the reaction vessel, the second temperature zone comprising a second heater, the second temperature zone movable between an open orientation in which the second heater affects temperatures of the reaction mixtures contained within the respective second portion, and a closed orientation in which the reaction mixtures are forced from the respective second portions and the second heater does not substantially affect temperatures of the reaction mixtures.
28. The thermal cycling system of claim 27 , wherein each flexible body is sealed to seal the reaction mixture within each flexible body.
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US09/910,233 US6748332B2 (en) | 1998-06-24 | 2001-07-20 | Fluid sample testing system |
US31876801P | 2001-09-11 | 2001-09-11 | |
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