method and system for processing sample processing devices

专利摘要:
METHOD AND SYSTEM FOR SAMPLING PROCESSING DEVICES. The present invention relates to systems and methods for processing sample processing devices. The system may include a sample processing device (300) comprising a detection chamber (350), a motor (126) configured to rotate the sample processing device about an axis of rotation, and an optical module ( 16) operatively positioned relative to the sample processing device and configured to determine whether a selected volume of material is present in the detection chamber of the sample processing device. The method may include rotating the sample processing device about an axis of rotation, and determining whether a selected volume of material is present in the detection chamber, while rotating the sample processing device. In some embodiments, the determination of whether a selected volume of material is present can be performed by optically checking the detection chamber for an optical property of the material.
公开号:BR112013029181B1
申请号:R112013029181-8
申请日:2012-05-18
公开日:2020-11-03
发明作者:Peter D. Ludowise；David A. Whitman；Kyle C. Armantrout；Maurice Exner；Lucien A. E. Jacky；Michelle Tabb
申请人:Focus Diagnostics, Inc.；Diasorin S.P.A.；
IPC主号:

专利说明:

CONTINUATION OF PATENT APPLICATION DATA
[0001] The present patent application claims the benefit of U.S. Provisional Patent Application Serial No. 611487,618, filed on May 18, 2011, which is hereby incorporated by reference. CONCESSION INFORMATION
[0002] The present invention may have been obtained with support from the United States government under Grant No. HHS0100201000049C of the U.S. Department of Health & Human Services Biomedical Advanced Research & Development (BARDA). FIELD
[0003] The present invention relates generally to the processing, or testing, of samples, devices, systems and methods, in particular to systems and methods for determining whether a selected volume of material is present in a particular chamber of a sample processing device, and more particularly to systems and methods for optically investigating a particular chamber in a sample processing device to determine whether a selected volume of material is present in the chamber. BACKGROUND
[0004] Optical disc systems can be used to perform various biological, chemical or biochemical assays, such as assays based on genetics or immunoassays. In such systems, a multi-chamber rotatable disk can be used as a means to store and process specimens of fluids, such as blood, plasma, serum, urine or other fluids. Multiple chambers on a disc can allow for the simultaneous processing of multiple portions of a sample, or multiple samples, thereby reducing the time and cost of processing multiple samples, or portions of a sample.
[0005] Examples of some reactions that may require accurate temperature control from chamber to chamber, comparable rates of temperature transition and / or rapid transitions between temperatures include, for example, manipulation of nucleic acid samples to help decipher the genetic code. Nucleic acid manipulation techniques can include amplification methods such as the polymerase chain reaction (PCR); methods of amplifying target polynucleotides such as self-sustaining sequence replication (3SR) and cord displacement amplification (SDA); methods based on amplifying a signal attached to the target polynucleotide, such as "branched-chain" DNA amplification; methods based on probe DNA amplification, such as ligase chain reaction (RCL) and QB replicase (QBR) amplification; transcription-based methods, such as ligation-activated transcription (LAT) and nucleic acid sequence-based amplification (NASBA); and several other amplification methods, such as the repair chain reaction (RCR) and the cycle probe reaction (CPR). Other examples of nucleic acid manipulation techniques include, for example, the Sanger sequence arrangement, ligand binding assays, etc.
[0006] PCR can be used for nucleic acid sequence analysis. In particular, PCR can be used for DNA sequencing, cloning, genetic mapping, and other forms of nucleic acid sequence analysis.
[0007] In general, PCR is based on the ability of DNA copying enzymes to remain stable at high temperatures. There are three main steps in PCR: denaturation, annealing and extension. During denaturation, a liquid sample is heated to 94 ° C. During this process, the double strands of DNA "fuse" open like single-stranded DNA and all enzymatic reactions are stopped. During annealing, single-stranded DNA is cooled to 54 ° C. At this temperature, the nucleotides bind "are annealed" to the ends of the DNA strands. During extension, the sample is heated to 75 ° C. At this temperature, the nucleotides are added to the primers and eventually a complementary copy of the DNA template is formed.
[0008] There are a number of existing PCR instruments designed to determine the levels of specific DNA and RNA sequences in the sample during real-time PCR. Many of the instruments are based on the use of fluorescent dyes. In particular, many conventional real-time PCR instruments detect a proportionately produced fluorescent signal during the amplification of a PCR product. SHORT DESCRIPTION
[0009] The systems and methods for processing sample processing devices of the present invention can be used to determine the presence of material in a sample processing device. In some embodiments, the sample processing device may be a "sample to respond", or "disc," consumable device that is processed, manipulated and tested when using a sample processing system and method. Such systems and methods may include means and steps to identify errors or failures in the performance of disks during processing. When errors are identified, a processing run can be interrupted or invalidated, and / or an error or fault report can be generated. In some embodiments, if a disk failure occurs, a material (for example, a sample) cannot be properly moved to a detection chamber, which will be analyzed or investigated later for the presence or absence of an analyte of interest. . As a result, the systems, methods and devices of the present invention can be used to determine whether a material is present in a particular detection chamber to determine or confirm the validity of the test results.
[00010] If the material is not present, it can be inferred that a failure has occurred in the transfer of the material to the detection chamber, and false test results can be avoided.
[00011] Some aspects of the present invention provide a method for processing sample processing devices. The method may include the provision of a sample processing device that comprises a detection chamber; the rotation of the sample processing device about an axis of rotation; and determining whether a selected volume of material is present in the detection chamber, while rotating the sample processing device.
[00012] Some aspects of the present invention provide a method for processing sample processing devices. The method may include the provision of a sample processing device that comprises a detection chamber; the rotation of the sample processing device about an axis of rotation; and the optical verification of the detection chamber for an optical property of a material to determine whether the material is present in the detection chamber, where the optical verification occurs while the sample processing device is rotated.
[00013] Some aspects of the present invention provide a method for processing sample processing devices. The method may include providing a sample processing device that comprises a processing arrangement. The processing arrangement can include an input chamber, a detection chamber, and a channel positioned to fluidly couple with the input chamber and the detection chamber. The method may also include positioning a sample in the input chamber of the sample processing device's processing arrangement, and rotating the sample processing device about an axis of rotation to move the sample into the detection chamber. . The method may further include, after having rotated the sample processing device to move the sample to the detection chamber, the optical investigation of the detection chamber for an optical property of the sample to determine whether the sample has moved into the chamber detection. The sample processing device can be rotated while the detection chamber is optically checked.
[00014] Some aspects of the present invention provide a method for processing sample processing devices. The method may include providing a sample processing device that comprises a processing arrangement. The processing arrangement can include an input chamber, a detection chamber, and a channel positioned to fluidly couple with the input chamber and the detection chamber. The method may further include placing a sample in the input chamber of at least one processing arrangement in the sample processing device; and rotating the sample processing device about an axis of rotation to move the sample into the detection chamber. The method may also include the optical verification of the detection chamber of the processing arrangement before rotating the sample processing device to move the sample to the detection chamber to obtain a first background scan, and the optical verification of the detection chamber of the processing arrangement to obtain a second scan after having rotated the sample processing device to move the sample into the detection chamber. The sample processing device can be rotated around the axis of rotation while optical detection of the detection chamber is performed to obtain at least one of the first scan and the second bottom scan. The method may also include comparing the first scan of the background with the second scan to determine whether there is a boundary change between the first scan of the background and the second scan.
[00015] Some aspects of the present invention provide a system for processing sample processing devices. The system can include a sample processing device that comprises a detection chamber; a motor configured to rotate the sample processing device about an axis of rotation; an optical module operatively positioned relative to the sample processing device and configured to determine whether a selected volume of material is present in the detection chamber of the sample processing device.
[00016] Other features and aspects of the present invention will become apparent when taking into account the detailed description and the accompanying drawings. BRIEF DESCRIPTION OF THE DRAWINGS
[00017] FIG. 1 is a schematic diagram of a sample processing system according to an embodiment of the present invention, wherein the system includes a multiplex fluorescence detection device, a data acquisition device, and a disk manipulation system.
[00018] FIG. 2 is a schematic diagram illustrating an exemplary optical detection module, which can correspond to any of the modules of a plurality of optics of the multiplex fluorescence detection device of FIG. 1.
[00019] FIG. 3 is a front elevation view of a detection device according to an embodiment of the present invention, in which the detection device includes a set of removable optical modules within a housing, which includes a main removable optical module and two modules additional removable optics.
[00020] FIG. 4 is a side elevation view of the detection device of FIG. 3.
[00021] FIG. 5 is a perspective view of the detection device of FIGS. 3-4, with an optical module removed to expose a module connector.
[00022] FIG. 6 is the perspective view of internal components of a main removable optical module exemplifying the detection device of FIGS. 3-5.
[00023] FIG. 7 is a perspective view of internal components of a supplementary removable optical module exemplifying the detection device of FIGS. 3-5.
[00024] FIG. 8 is a side elevation view of the detection device of FIGS. 3-5, with a laser valve control system located over a notch in a disc, and a gantry system.
[00025] FIG. 9 is a schematic block diagram illustrating an example embodiment of the multiplex fluorescence detection device in more detail.
[00026] FIG. 10 is a block diagram of a simple detector coupled to four optical fibers in an optical fiber bundle.
[00027] FIG. 11 is a flow chart illustrating the exemplary operation of the multiplex fluorescence detection device.
[00028] FIG. 12 is a flow chart illustrating the exemplary operation of the laser valve control system for the detection device.
[00029] FIG. 13A is an example diagram of a notch on a disc.
[00030] FIG. 13B is an hourly diagram illustrating an example method for detecting internal and external edges of a notch in a disc.
[00031] FIG. 13C is an hourly diagram illustrating an example method for determining a local position of a laser valve control system.
[00032] FIG. 14 is a flow chart illustrating the exemplary determination of a local position of a laser valve control system.
[00033] FIG. 15 is a flow chart illustrating an exemplary method of detecting light and sampling data from a disk.
[00034] FIG. 16 is a top perspective view of a sample processing device according to an embodiment of the present invention.
[00035] FIG. 17 is a bottom perspective view of the sample processing device of FIG. 16.
[00036] FIG. 18 is a top plan view of the sample processing device of FIGS. 16-17.
[00037] FIG. 19 is a bottom plan view of the sample processing device of FIGS. 16-18.
[00038] FIG. 20 is an approximate top plan view of part of the sample processing device of FIGS. 16-19.
[00039] FIG. 21 is an approximate bottom plan view of the part of the sample processing device shown in FIG. 20.
[00040] FIG. 22 is a cross-sectional side view of the sample processing device of FIGS. 16-21, taken along line 22-22 of FIG. 21.
[00041] FIG. 23 is a bottom plan view of a sample processing device according to another embodiment of the present invention.
[00042] FIG. 24 is an exploded perspective view of a disc handling system according to an embodiment of the present invention.
[00043] FIG. 25 is a schematic graphical representation of an embodiment of a method for comparing two scans of a detection chamber to determine whether a sample is present in the detection chamber.
[00044] FIG. 26 is a flow chart illustrating an exemplary method of processing a sample in a sample processing device and determining whether a sample is present in a detection chamber of a sample processing device.
[00045] FIGS. 27-30 show graphical representations of meniscus detection results for samples of 5 pl, 10 pl, 15 pl and 20 pl, respectively, as reported in Example 1; each figure shows a first scan of the bottom and a second scan of backscattered intensity (arbitrary units) versus the position of the gantry.
[00046] FIG. 31 shows a graphical representation of the detection of the total fluid level when using fluorescence detection, as reported in Example 3, Approach 2; each batch shows the percentage of increase in fluorescence on the bottom versus the position of the gantry. DETAILED DESCRIPTION
[00047] Before any modality of the present invention is explained in detail, it should be understood that the invention is not limited in its application to the details of the construction and the disposition of the components indicated in the description below or illustrated in the drawings below. The invention is liable to other modalities and to be practiced or carried out in several ways. In addition, it should be understood that the phraseology and terminology used here are for the purpose of description and should not be considered as limiting. The use of "includes", "understands" or "has" and its variations should include the items listed below and their equivalents, as well as additional items. Unless otherwise specified or limited, the terms "assembled", "connected", "supported" and "coupled" and variations thereof are used widely and include assemblies, connections, brackets and couplings direct and indirect. In addition, "connected" and "coupled" are not restricted to connections or physical or mechanical couplings. It should be understood that other modalities can be used, and that structural or logical changes can be made without departing from the scope of the present invention. In addition, terms such as "anterior", "posterior", "superior" and "inferior" and the like are only used to describe elements once they are related to each other, but in no way are they suitable to recite specific guidelines device, indicate or imply necessary or required guidance from the device, or specify how the invention described herein will be used, assembled, displayed or positioned in use.
[00048] The present invention relates generally to sample processing systems, methods and devices for processing sample processing devices, and in particular to detecting whether a material is present in a particular chamber of a sample processing device. More particularly, in some embodiments, the systems, methods and devices of the present invention can be used to detect whether a selected volume of a material is present in a particular chamber. In some cases, the sample processing device used to process fluidly and manipulate a sample may include various valve and introduction elements. For example, a sample can be loaded into the sample processing device, several valves, channels, chambers and / or introducing devices can be used to process and move the sample through various compartments of the sample processing device, and finally ending in a processing or detection chamber where the sample will be tested or ascertained (for example, optically) to determine the absence, presence and / or quantity of an analyte of interest in the sample. In order to check whether a fluid processing failure of the sample has occurred in the sample processing device, it may be useful to know whether the sample has been transferred correctly to the process, or to the detection chamber. As a result, the systems, methods and devices of the present invention are concerned with determining whether a sample, or a selected volume of the sample, is present in the detection chamber.
[00049] In some embodiments of the present invention (for example, described below with respect to the sample processing device 300 of FIGS. 16-22), a sample of interest (for example, a crude sample, such as a patient sample raw material, a raw environmental sample, etc.) can be loaded separately from various reagents or media that will be used in processing the sample for a particular assay. In some embodiments, such reagents can be added as a simple cocktail reagent or "master mix" that includes all the reagents needed for an assay of interest. The sample can be suspended or prepared in a diluent, and the diluent can include or be the same as the reagent for the assay of interest. The sample and diluent will be indicated here merely as a "sample" for the sake of simplicity, and a sample combined with a diluent is still generally considered to be a crude sample, since no substantial processing, introduction, lysis has yet been performed , or something like that.
[00050] The sample may include a solid, a liquid, a semi-solid, a gelatinous material, and combinations thereof, such as a suspension of particles in a liquid. In some embodiments, the sample may be an aqueous liquid.
[00051] The sample processing device may then include a means for moving the sample and reagents through the sample processing device and which finally combines the sample and reagents where and when needed. In some embodiments, the reagents (for example, the main reagent mixture) may include one or more internal controls that can be used to validate that the reaction and reagents are working. For example, a channel in a multiplex detection system can be used to detect internal control and confirm that the reagents have been transferred to the sample processing device properly and are functioning properly when no amplification is detected in the other channels of the system. multiplex detection. That is, the internal control can be used to validate false negatives, and the lack of amplification of internal control invalidates the processing round. However, in a raw sample, there is no similar internal control. Therefore, if there is a failure in handling and transferring the sample (for example, in the valve or introducing devices), in such a way that the sample never reaches the detection chamber and is never combined with the main reagent mixture, the Internal control in the main reagent mixture is yet to be amplified, leading to a possible false negative determination. The sample processing systems, methods and devices of the present invention can be used to verify that the sample has moved into the detection chamber, and / or that a selected volume of the sample is present in the detection chamber. If such a check is not found, this can be indicated, for example, when initiating an alert, when generating a fault report, when invalidating a processing run, when interrupting a processing run, etc., or a combination of them.
[00052] The phrase "raw sample" is generally used to refer to a sample that is not subjected to any processing or manipulation before being loaded into the sample processing device, in addition to being merely diluted or suspended in a diluent . That is, a raw sample may include cells, residues, inhibitors, etc., and not have been previously lysed, washed, protected or the like, before being loaded into the sample processing device. A raw sample can also include a sample that is taken directly from one source and transferred from one container to another without manipulation. The raw sample can also include a patient specimen in a variety of media, including, but not limited to, a means of transport, cerebral spinal fluid, whole blood, plasma, serum, etc. For example, a nasal swab sample that contains viral particles obtained from a patient can be transported and / or stored in a buffer or means of transport (which may contain antimicrobials) used to suspend and stabilize the particles before processing. A part of the means of transport with the suspended particles can be considered as the "sample". All "samples" used with the devices and systems of the present invention and discussed herein can be raw samples.
[00053] FIGS. 1-15 generally illustrate a sample processing system according to the present invention, including the characteristics, elements, functions and methods of operation of such a system, including the components and characteristics used for optical detection. Such a sample processing system can be used for processing sample processing devices. The sample processing device can generally be consumable (for example, disposable) and include various fluid elements (i.e., microfluids) capable of directing and manipulating samples of interest. The sample processing system can be used to detect various characteristics of the sample and the sample processing device.
[00054] FIGS. 16-23 illustrate exemplary embodiments of sample processing devices (e.g., "disks") that can be used in accordance with the present invention and that can be employed in the sample processing systems of the present invention.
[00055] FIG. 24 illustrates at least a part of an exemplary disk handling system of the present invention that can form a part of, or be used with, a sample processing system of the present invention. In particular, FIG. 24 shows the interaction of an exemplary sample processing device (i.e., the sample processing device of FIGS. 16-22) with a cover and base plate of the disc handling system. That is, FIG. 24 shows how a "disk" can interact physically (for example, structurally, mechanically and / or thermally) with various components of a sample processing system of the present invention.
[00056] It should be understood that although the sample processing devices of the present invention are illustrated here as being circular in shape and sometimes referred to here as "discs", a variety of other shapes and configurations of the sample processing devices of the present invention is possible, and the present invention is not limited to circular sample processing devices. As a result, the term "disk" is often used here in place of "sample processing device" for the sake of brevity and simplicity, but this term is not intended to be limiting. Sample Processing Systems
[00057] The sample processing systems of the present invention can be used in methods involving thermal processing, for example, sensitive chemical processes such as polymerase chain reaction (PCR) amplification, transcription-mediated amplification (TMA) , nucleic acid sequence-based amplification (NASBA), ligase chain reaction (RCL), self-sustaining sequence replication, kinetic enzyme studies, homogeneous ligand binding assays, immunoassays, such as the immunosorbent assay enzyme linked (ELISA), and more complex biochemical processes or other processes that require precise thermal control and / or rapid thermal variations. Sample processing systems are capable of providing simultaneous rotation of a sample processing device in addition to controlling the temperature of sample materials in processing chambers in the devices.
[00058] Some examples of the appropriate construction techniques or materials that can be adapted for use in connection with the present invention can be described, for example, in US Patents to the same assignee as this patent No. 6,734,401, 6987253, 7435933 , 7164107 and 7,435,933, entitled SAMPLE PROCESSING DEVICES SYSTEMS AND IMPROVED METHODS (Bedingham et al.); U.S. Patent no. 6,720,187, entitled MULTIPLE FORMAT SAMPLING PROCESSING DEVICES (Bedingham et al.); U.S. Patent Publication No. 2004/0179974, entitled MULTIPLE FORMATS AND SYSTEMS SAMPLE PROCESSING DEVICES (Bedingham et al.); U.S. Patent No. 6,889,468, entitled MODULAR SYSTEMS AND METHODS FOR USING SAMPLE PROCESSING DEVICES (Bedingham et al.); U.S. Patent No. 7,569,186, entitled SYSTEMS FOR USING SAMPLE PROCESSING DEVICES (Bedingham et al.); U.S. Patent Publication No. 2009/0263280, entitled THERMAL STRUCTURE FOR SAMPLING PROCESSING DEVICES (Bedingham et al.); U.S. Patent No. 7,322,254 and Patent Publication No. 2010/0167304, entitled VARIABLE VALVE APPARATUS AND METHOD (Bedingham et al.); U.S. Patent No. 7,837,947 and U.S. Patent Publication No. 2011/0027904, entitled MIXING SAMPLES IN A MICROFLUID DEVICE (Bedingham et al.); U.S. Patents No. 7,192,560 and 7,871,827 and U.S. Patent Publication No. 2007/0160504, entitled METHODS AND DEVICES FOR THE REMOVAL OF ORGANIC MOLECULES FROM BIOLOGICAL MIXTURES BY USING ANION EXCHANGE (Parthasarathy et al.); U.S. Patent Publication No. 2005/0142663, entitled METHODS FOR THE INSULATION OF NUCLEIC ACID AND KITS USING A MICROFLUID DEVICE AND CONCENTRATION STEP (Parthasarathy et al.); U.S. Patent No. 7,754,474 and U.S. Patent Publication No. 2010/0240124, entitled SAMPLE PROCESSING DEVICES, SAMPLE SYSTEMS AND METHODS (Aysta et al.); U.S. Patent No. 7,763,210 and U.S. Patent Publication No. 2010/0266456, entitled COMPATIBLE MICROFLUID SAMPLE PROCESSING DISCS (Bedingham et al.); U.S. Patents No. 7,323,660 and 7,767,937, entitled MODULAR SAMPLE PROCESSING APPLIANCES, KITS AND MODULES (Bedingham et al.); U.S. Patent No. 7,709,249, entitled MULTIPLEX FLUORESCENCE DETECTION DEVICE THAT HAS A FIBER BEAM THAT COUPLES MULTIPLE OPTICAL MODULES TO A COMMON detector (Bedingham et al.); U.S. Patent No. 7,507,575, entitled MULTIPLEX FLUORESCENCE DETECTION DEVICE THAT HAS REMOVABLE OPTICAL MODULES (Bedingham et al.); U.S. Patents No. 7,527,763 and 7,867,767, entitled VALVE CONTROL SYSTEM FOR A ROTATING MULTIPLEX FLUORESCENCE DETECTION DEVICE (Bedingham et al.); U.S. Patent Publication No. 2007/0009382, entitled HEATING ELEMENT FOR A ROTATING MULTIPLEX FLUORESCENCE DETECTION DEVICE (Bedingham et al.); U.S. Patent Publication No. 2010/0129878, entitled METHODS FOR NUCLEIC AMPLIFICATION (Parthasarathy et al.); U.S. Patent Publication No. 2008/0149190, entitled THERMAL TRANSFER METHODS AND STRUCTURES FOR MICROFLUID SYSTEMS (Bedingham et al.); U.S. Patent Publication No. 2008/0152546, entitled PERFECTED SAMPLE DEVICES, SYSTEMS AND METHODS OF PROCESSING (Bedingham et al.); U.S. Patent Application Publication No. 2011/0117607, entitled ANNULAR COMPRESSION SYSTEMS AND METHODS FOR SAMPLING PROCESSING DEVICES (Bedingham et al.); U.S. Patent Application Publication No. 2011/0117656, entitled SYSTEMS AND METHODS FOR PROCESSING SAMPLE PROCESSING DEVICES (Robole et al.); U.S. Provisional Patent Application Serial No. 60 / 237,151, filed October 2, 2000 and entitled SAMPLING DEVICES, SYSTEMS AND METHODS (Bedingham et al.); U.S. Patents No. D638550 and D638951, entitled SAMPLE PROCESSING DISK COVER (Bedingham et al.); U.S. Patent Application No. 29 / 384,821, entitled SAMPLE PROCESSING DISK COVER (Bedingham et al.), Filed February 4, 2011; and U.S. Patent No. D564667, entitled ROTARY SAMPLE PROCESSING DISC (Bedingham et al.). The full content of these citations is hereby incorporated by reference.
[00059] Other potential constructions of the device can be found, for example, in U.S. Patent No. 6,627,159, entitled CENTRIFUGAL FILLING OF SAMPLE PROCESSING DEVICES (Bedingham et al.); U.S. Patents No. 7,026,168, 7,855,083 and 7,678,334, and U.S. Patent Publications No. 2006/0228811 and 2011/0053785, entitled SAMPLING PROCESSING DEVICES (Bedingham et al.); U.S. Patents No. 6,814,935 and 7,445,752, entitled SAMPLES AND CARRIER PROCESSING DEVICES (Harms et al.); and U.S. Patent No. 7,595,200, entitled SAMPLES AND CAREER PROCESSING DEVICES (Bedingham et al.). The full content of these citations is hereby incorporated by reference.
[00060] A sample processing system that has the ability to detect multiplex fluorescence, including various characteristics, elements and the operation of such a system, will now be described.
[00061] FIG. 1 is a schematic diagram illustrating an exemplary embodiment of a multiplex fluorescence detection device 10, a data acquisition device 21, and a disk handling system 500 that can be employed as part of a sample processing system 12 The disk handling system 500 will be described in more detail below with reference to FIG. 24. Detection device 10 can be used to detect various characteristics of a sample, including whether a sample, or a selected volume of a sample, is present in a detection chamber of a sample processing device (for example, a rotating disc 13). In some embodiments, the sample processing device may be consumable and replaceable and may not necessarily be considered as part of the sample processing system 12, but, instead, it can be used with, or be processed by, the sample system. sample processing 12.
[00062] In the illustrated example, device 10 has four optical modules 16 which provide four "channels" for optical detection of four different dyes. In particular, device 10 has four optical modules 16 that excite different regions of the spinning disc 13 at any time, and collects the energy from the fluorescent light emitted at different wavelengths than the dyes. As a result, modules 16 can be used to ascertain multiple parallel reactions that occur within sample 22, and / or determine whether sample 22, or a selected volume of sample 22, is located in a desired region (for example, within a private camera) from disk 13.
[00063] Multiple reactions can, for example, occur simultaneously within a single chamber of a spinning disc 13. Each of the optical modules 16 verifies the sample 22 and collects the fluorescent light energy at different wavelengths while the disc 13 rotates. For example, excitation sources within modules 16 can be sequentially activated for sufficient periods to collect data at the corresponding wavelengths. That is, a first optical module 16 can be activated for a period of time to collect data in a first range of selected wavelengths for a first dye that corresponds to a first reaction. The excitation source can then be deactivated, and an excitation source within a second optical module 16 can be activated to ascertain the sample 22 in a second range of selected wavelengths for a second dye that corresponds to a second reaction. This process can continue until data is captured from all optical modules 16. In one embodiment, each of the excitation sources within the optical modules 16 is activated for an initial period of about 0.5 seconds to reach the constant state followed by an investigation period that lasts from 10 to 50 rotations of the disc 13. In other modalities, the excitation sources can be arranged in sequence for shorter periods (for example, 1 or 2 milliseconds) or longer. In some embodiments, more than one optical module can be activated simultaneously for the simultaneous verification of the sample 22 without interrupting the rotation of the disk 13.
[00064] Although a single sample 22 is illustrated, disk 13 may contain a plurality of chambers containing samples. Optical modules 16 can scan some or all of the different chambers at different wavelengths. In one embodiment, disk 13 includes the space of 96 chambers around a circumference of disk 13. With a 96-chamber disk and four optical modules 16, device 10 may be able to acquire data from 384 different species.
[00065] In one embodiment, optical modules 16 include excitation sources which are inexpensive high-power light-emitting diodes (LEDs), which are commercially available in a variety of wavelengths and have long service lives (for example, 100,000 hours or more). In another embodiment, halogen bulbs or conventional mercury lamps can be used as excitation sources.
[00066] As illustrated in FIG. 1, each of the optical modules 16 can be coupled to a leg of an optical fiber bundle 14. The optical fiber bundle 14 provides a flexible mechanism for collecting fluorescent signals from the optical modules 16 without loss of sensitivity. In general, an optical fiber bundle comprises multiple optical fibers placed side by side and joined together at the ends and enclosed in a flexible protective jacket. Alternatively, the optical fiber bundle 14 may comprise a smaller number of fibers of multiple distinct large diameter modes, both glass and plastic, which have a common end. For example, for a device with four optical modules, the optical fiber bundle 16 may comprise four fibers in multiple distinct modes, each of which has a core diameter of 1 mm. The common end of the bundle contains the four fibers connected to each other. In this example, the opening of detector 18 can be 8 mm, which is more than sufficient for coupling to the four fibers.
[00067] In this example, the optical fiber bundle 14 couples the optical modules 16 to a simple detector 18. The optical fibers conduct the fluorescent light collected by the optical modules 16 and effectively transfer the captured light to the detector 18. In one embodiment, the detector 18 is a photomultiplier tube. In another embodiment, the detector may include multiple photomultiplier elements, one for each optical fiber, within the single detector. In other embodiments, one or more solid state detectors can be used.
[00068] The use of a simple detector 18 can be advantageous, since it allows the use of a highly sensitive and possibly expensive detector (for example, a photomultiplier), while maintaining a minimal cost, since only a simple detector needs to be used. A simple detector is discussed here; however, one or more detectors can be included to detect a greater number of dyes. For example, four additional optical modules 16 and a second detector can be added to the system to allow detection of eight different wavelengths emitted from a disc. An exemplary fiber optic bundle coupled to a simple detector for use with the rotating disk 13 is described in US Patent No. 7,709,249 entitled "MULTIPLEX FLUORESCENCE DETECTION DEVICE THAT HAS A MULTIPLEX OPTICAL FIBER BEAM. TO A COMMON DETECTOR ", filed on July 5, 2005, the full content of which is incorporated herein by way of reference.
[00069] The optical modules 16 can be removable from the device and easily interchangeable with other optical modules that are optimized for checking different wavelengths. For example, optical modules 16 can be physically mounted within locations of a module housing. Each of the optical modules 16 can easily be inserted within a respective location of the housing along guides (e.g., recessed grooves) that mate with one or more markings (e.g., guide pins) on the optical module. Each of the optical modules 16 can be fixed inside the car by a lock, a magnet, a screw or another fixing device. Each optical module includes an optical output port (shown in FIGS. 6 and 7) for coupling to a leg of the fiber optic bundle 14. The optical output port can have a screwed end coupled to a screwed connector of the leg. Alternatively, a form of "quick connection" can be used (for example, a sliding connection that has an O-ring and a capturing pin) that allows the fiber optic bundle 14 to be slidably coupled and decoupled from the optical output. In addition, each of the optical modules 16 can have one or more electrical contact pads or flexible circuits to electronically couple to the control unit 23 when fully inserted. The exemplary removable optical modules for use with the rotating disk 13 are described in US Patent No. 7,507,575 entitled "MULTIPLEX FLUORESCENCE DETECTION DEVICE THAT HAS REMOVABLE OPTICAL MODULES" deposited on July 5, 2005, whose full content is here incorporated for reference.
[00070] The modular architecture of the device 10 allows the device to be easily adapted to all fluorescent dyes used in a given analysis environment, such as multiplex PCR. Other chemicals that can be used on device 10 include Invader (Third Wave, Madison, Wisconsin), Transcripted-mediated Amplification (GenProbe, San Diego, California), fluorescently labeled enzyme-linked immunosorbent assay (ELISA), and / or in-hybridization fluorescence (FISH). The modular architecture of the device 10 can provide another advantage, since the sensitivity of each optical module 16 can be optimized by choosing the corresponding excitation source (not shown) and excitation and detection filters for a small specific target range of wavelengths in order to selectively excite and detect a corresponding dye in the multiplex reaction.
[00071] For the purpose of example, device 10 is illustrated in a 4-color multiplex arrangement, but more or less channels can be used with the appropriate fiber optic bundle 14. This modular design allows a user to easily update device 10 in the field simply by adding another optical module 16 to device 10 and inserting a leg of the fiber optic bundle 14 into the new optical module. The optical modules 16 may have integrated electronic components that identify the optical modules and download calibration data to an internal control module or other internal electronic components (for example, the control unit 23) of the device 10.
[00072] In the example of FIG. 1, samples 22 are contained in the chambers of disk 13, which is mounted on a rotating platform under the control of the control unit 23 (a rotating platform embodiment is shown by way of example only in FIG. 24). A notch sensor activator 27 provides an output signal used by the control unit 23 to synchronize the data acquisition device 21 with the position of the camera during the rotation of the disc. The notch activator 27 can be a mechanical, electrical, magnetic or optical sensor. For example, as described in more detail below, the notch activator 27 may include a light source that emits a beam of light through a disc through a notch formed through disc 13 that is detected at each rotation the disc. As another example, the notch sensor activator can detect reflected light for purposes of synchronizing the rotation of disk 13 and the acquisition of data by modules 16 and detector 18. In other embodiments, disk 13 may include a tab, a projection or reflective surface in addition to or in place of the notch. The notch activator 27 can use any physical structure or mechanism to locate the radial position of the disc 13 while rotating. The optical modules 16 can be physically mounted above the rotating platform 25, in such a way that the optical modules 16 are overlapped with different chambers each time.
[00073] The detection device 10 can also include a heating element (not shown in FIG. 1, but an exemplary heating element is shown in FIG. 24 and described below) to modulate the temperature of sample 22 in disk 13 The heating element may comprise a cylindrical halogen bulb contained within a reflective housing. The reflective chamber is shaped to focus the bulb radiation on a radial section of the disc 13. In general, the heated area of the disc 13 may comprise an annular ring while the disc 13 rotates. In this mode, the shape of the reflective casing can be a combination of elliptical and spherical geometries that allow for precise focusing. In other embodiments, the reflective casing may be of a different shape or the bulb may radiate a larger area widely. In other embodiments, the reflective casing can be shaped to focus the bulb radiation on a single area of the disc 13, such as a single processing chamber containing a sample 22.
[00074] In some embodiments, the heating element can heat the air and force the hot air over one or more samples to modulate the temperature. In addition, samples can be heated directly by the disc. In this case, the heating element can be located on platform 25 and thermally coupled to the disc 13. The electrical resistance inside the heating element can heat a selected region of the disc that is controlled by the control unit 23. For example, a region can contain one or more cameras, possibly the entire disk. An exemplary heating element for use with a rotating disc 13 is described in US Patent Application Publication No. 2007/0009382, entitled "HEATING ELEMENT FOR A ROTATING MULTIPLEX FLUORESCENCE DETECTION DEVICE", filed on July 5, 2005, the full content of which is incorporated by reference.
[00075] Alternatively, or in addition, device 10 may also include a cooling component (not shown). A fan may be included in device 10 to provide cold air, that is, air at room temperature, to disk 13. Refrigeration may be necessary to properly modulate the sample temperature and store the samples after an experiment is completed. In other embodiments, the cooling component can include the thermal coupling between the platform 25 and the disc 13, since the platform 25 can reduce its temperature when necessary. For example, some biological samples can be stored at 4 ° C to reduce enzyme activity or protein denaturation.
[00076] Detection device 10 may also have the ability to control the type of reaction contained within a processing chamber. For example, it may be advantageous to load some species into a processing chamber to generate a reaction and add another species to the sample later once the first reaction has ended. A valve control system can be used to control a valve that separates an internal containment chamber from the processing chamber, thereby controlling the addition of the species to the chamber during the rotation of the disc 13. The valve control system can be located inside or mounted on one of the optical modules 16 or separate from the optical modules 16. Directly below the laser, under the disk 13, a laser sensor can be arranged to position the laser in relation to the disk 13.
[00077] In one embodiment, the valve control system includes a near-infrared (NIR) laser that can be directed at two or more levels and power in combination with a sensor. Under a low power setting, the laser can be used to position the disc 13 and target select valves, for example, with the detection by the sensor of the NIR light emitted by the laser through a notch in the disc 13. Once the targeted valve is rotated in position, the control unit 23 can direct the laser to emit a short burst of high power energy to heat the valve and open the target valve. The energy surge forms an empty space in the valve, for example, through drilling, fusion or ablation, causing the valve to open and allowing a fluid to flow through a channel from an internal containment chamber to a processing chamber. external. In some embodiments, disk 13 may contain a plurality of valves of various sizes and materials to generate a plurality of reactions in sequence. More than one set of valve control systems can be used when using a disc that has multiple chamber valves.
[00078] Data acquisition device 21 can collect data from device 10 for each dye both sequentially and in parallel. In one embodiment, the data acquisition system 21 collects data from the optical modules 16 in sequence, and corrects the spatial overlap by a trigger delay for each of the optical modules 16 introduced from the output signal received from the sensor activator notch 27.
[00079] An application for device 10 is real-time PCR, but the techniques described here can be extended to other platforms that use fluorescence detection at multiple wavelengths. The device 10 can combine a rapid thermal cycle, using the heating element, and centrifugally directed microfluidic elements for the isolation, amplification and detection of nucleic acids. By making use of multiplex fluorescence detection, multiple target species can be detected and analyzed in parallel.
[00080] For real-time PCR, fluorescence is used to measure the amount of amplification in one of three general techniques. The first technique is the use of a dye, such as Sybr Green (Molecular Probes, Eugene, Oregon), whose fluorescence increases with binding to double-stranded DNA. The second technique uses fluorescence-labeled probes whose fluorescence changes when linked to the target amplified sequence (hybridization probes, hairpin probes, etc.). This technique is similar to using a double-stranded DNA binding dye, but it is more specific because the probe will only bind to a certain section of the target sequence. The third technique is the use of hydrolysis probes (TaqmanTM, Applied BioSystems, Foster City California), in which the exonuclease activity of the polymerase enzyme cleaves a probe remover molecule during the PCR extension phase, making it fluorescently active .
[00081] In each of the approaches, fluorescence is linearly proportional to the amplified concentration of the target. The data acquisition system 21 measures an output signal from detector 18 (or, alternatively, optionally sampled and communicated by the control unit 23) during the PCR reaction to observe amplification in near real time. In multiplex PCR, multiple targets are labeled with different dyes that are introduced independently. Generally speaking, each dye will have different absorbance and emission spectra. For this reason, optical modules 16 can have excitation sources, lenses and related filters that are selected optically for the verification of sample 22 at different wavelengths.
[00082] FIG. 2 is a schematic diagram illustrating an exemplary optical module 16A, which can correspond to any of the optical modules 16 of FIG. 1. In this example, optical module 16A contains a high power excitation source, LED 30, a collimation lens 32, an excitation filter 34, a dichroic filter 36, a focusing lens 38, a detection filter 40 , and a lens 42 to focus fluorescence on a leg of the fiber optic bundle 14.
[00083] Consequently, the excitation light of LED 30 is collimated by the collimation lens 32, filtered by the excitation filter 34, transmitted through the dichroic filter 36, and focused on the sample 22 by the focusing lens 38. The resulting fluorescence emitted by The sample is collected by the same focusing lens 38, reflected from the dichroic filter 36, and filtered by the detection filter 40 before being focused on a leg of the fiber optic bundle 14. The optical bundle 14 then transfers the light to the detector 18.
[00084] LED 30, collimation lens 32, excitation filter 34, dichroic filter 36, focusing lens 38, detection filter 40 and lens 42 are selected based on the absorption ranges and specific emission of the multiplex dye with which the 16A optical module must be used. In this way, multiple optical modules 16 can be configured and contained within the device 10 to target different dyes.
[00085] The following table lists the exemplifying components that can be used in a 4-channel multiplex fluorescence detection device 10 for a variety of fluorescent dyes. Examples of suitable dyes include, but are not limited to, a 5-carboxy fluorescein dye, i.e., a fluorescein derivative, available under the trade name "FAM" from Applera, Norwalk, California; a 6-carboxy-2 ', 4,4', 5 ', 7,7'-hexachlor fluorescein dye, that is, a fluorescein derivative, available under the trade name "HEX" from Applera; a 6-carboxy-4 ', 5'-dichloro-2', 7'-dimethoxy fluorescein dye, that is, a fluorescein derivative, available under the trade name "JOE" from Applera; a fluorescein derivative dye, available under the trade name "VIC" from Applera; a fluorescein derivative dye, available under the trade name "TET" from Applera; a 6-carboxy-X-rhodamine dye, that is, a rhodamine derivative, available under the trade name "ROX" from Invitrogen, Carlsbad, California; an intercalation dye, available under the trade name "SYBR" from Invitrogen (indicated in the following table as "Sybr Green"); a rhodamine derivative dye available under the trade name "TEXAS RED" from Invitrogen (indicated in the following table as "Tx Red"); a 5-N-N'-diethyl tetramethyl indodicarbocyanine dye, that is, a cyanine derivative, available under the trade name "CY5" from Amersham, Buckinghamshire, United Kingdom (indicated in the table below as "Cy5") ; a phosphoramidite derivative dye available under the trade name "CAL FLUOR RED 610" available from BioSearch Technologies, Novice, California (shown in the table below and in the examples as "CFR610"); and an indocarbocyanine derivative dye, available under the trade name "QUASAR 670" from BioSearch Technologies, Novato, California (indicated in the following table as "QUASAR 670").

[00086] One advantage of the described modular multiplex detection architecture is the flexibility in detecting optimization for a wide variety of dyes and / or for determining whether a material, or a selected volume of material, is present in particular chambers of the disc 13 Conceivably, a user can have a bank of several different optical modules 16 that can be plugged into device 10 as needed, of which N can be used at any time, where N is the maximum number of channels supported by the device. In addition, one or more of the optical channels of one or more of the optical modules 16 can be dedicated to detecting (for example, optically verifying) whether the material, or a selected volume of material, is present in particular chambers on disk 13. For For example, in some embodiments, a FAM optical channel may be particularly suitable for detecting the backscattered reflection of an electromagnetic signal that is directed to disk 13, and in some embodiments, a CFR610 optical channel may be particularly suitable for detecting the presence of material, or a selected volume of material, in the detection chamber when using fluorescence. Therefore, device 10 and optical modules 16 can be used with any fluorescent dye and PCR detection method. A larger fiber optic bundle can be used to support a greater number of detection channels. In addition, multiple bundles of optical fibers can be used with multiple detectors. For example, two bundles of optical fibers with 4 legs can be used with eight optical modules 16 and two detectors 18.
[00087] FIG. 3 illustrates a front view of an exemplary set of removable optical modules within a housing. In the example of FIG. 3, the device 10 includes the base arm 44 and the housing 46 of the module. The main optical module 48, the supplementary optical module 52 and the supplementary optical module 56 are contained within the housing 46 of the module. Optical modules 48, 52 and 56 produce optical output beams 43, 49, 53 and 57, respectively, which sequentially excite processing chambers other than disk 13. In other words, output beams 43, 49, 53 and 57 they follow the curvature of the disc 13 each excites the same radial position of the disc containing the processing chambers. The optical module 48 contains two optical channels, each of which emits different beams 43 and 49. As shown, the notch sensor activator 27 may include an infrared light source 31 that produces the light 35 that is detected by the detector 33 .
[00088] Each of the optical modules 48, 52 and 56 can include a respective release lever 50, 54 or 58, respectively, to couple the housing 46 of the module. Each release lever can provide an upward impulse to engage with a respective lock formed within the housing 46 of the module. A technician or another user can compress the release levers 50, 54 or 58, respectively, in order to unlock and remove the optical module 48, 52 or 56 from the housing 46 of the module. Barcode reader 29 may include laser 62 to identify disk 13.
[00089] The base arm 44 extends from the detection device 10 and provides support for the module housing 46 and the optical modules 48, 52 and 56. The module housing 46 can be firmly mounted on the base arm 44. The module housing 46 may contain a location adapted to receive a respective module from optical modules 48, 52 and 56. Although described for exemplary purposes with respect to module housing 46, detection module module housing 46 may have a plurality of locations for receiving optical modules 48, 52 and 56. In other words, a separate enclosure does not need to be used for optical modules 48, 52 and 56.
[00090] Each location of the module housing 46 may contain one or more rails or guides that help to correctly position the associated optical module within the location when a technician or another user inserts the optical module. These guides can be located along the top, bottom or sides of each location. Each of the optical modules 48, 52 and 56 can include guides or rails that couple with the guides or rails of the locations of the housing 46 of the module. For example, module housing 46 may have protruding guides that mate with indented guides in optical modules 48, 52 and 56.
[00091] In some embodiments, module housing 46 may not completely enclose each of the optical modules 48, 52 and 56. For example, module housing 46 may provide mounting points for securing each of the optical modules 48, 52 and 56 to the base arm 44, but parts or all of each optical module can be exposed. In other embodiments, the module housing 46 may completely enclose each of the optical modules 48, 52 and 56. For example, the module housing 46 may include a single door that closes on the optical modules 48, 52 and 56, or a respective port for each of the modules. This modality may be suitable for applications where the modules are rarely removed or the detection device 10 is subjected to extreme environmental conditions.
[00092] A technician can easily remove any of the optical modules 48, 52 or 56, and this can be completed by using only one hand. For example, the technician can support his index finger under a molded ferrule positioned below the release lever 54 of the optical module 52. The thumb of the technician can then press down on the release lever 54 to release the optical module 52 from the housing 46 of the module. While holding the optical module 52 between the thumb and the index finger, the technician can pull the optical module back to remove the optical module from the detection device 10. Other methods can be used to remove any of the optical modules 48, 52 or 56, including methods using two-handed removal. The insertion of any of the optical modules 48, 52 or 56 can be performed in an inverted manner with one or two hands.
[00093] In the example of FIG. 3, the components of two optical modules are combined to form the main optical module 48. The main optical module 48 can contain light sources that produce two different wavelengths of light and detectors to detect each different fluorescence wavelength of the samples on disk 13. Therefore, the main optical module 48 can connect the two legs of the fiber optic bundle 14. In this way, the main optical module 48 can be seen as a dual-channel optical module that has two excitation and collection optical channels independent. In some embodiments, the main optical module 48 may contain optical components for more than two optical modules. In other cases, module housing 46 contains a plurality (for example, two or more) of single channel optical modules, such as supplementary optical modules 52 and 56. In still other cases, module housing 46 contains a combination of one or more dual channel optical modules 48 and one or more single channel optical modules 52, 56.
[00094] As illustrated in FIG. 3, the main optical module 48 can also contain components for a laser valve control system 51 (located inside the optical module 48). The laser valve control system 51 detects the location of disk 13 by a small notch located near the outer edge of disk 13. A detector (not shown) detects low power laser light 55 to map the location of disk 13 with regarding the motor that rotates the disk. The control unit 23 uses the map to locate the valves (not shown in FIG. 3) on disk 13 and to rotate the targeted valves in position for opening through the laser valve control system 51.
[00095] Once a target valve is in position, the laser valve control system 51 focuses laser light 55 on the valve when using one or more short high power surges. The short spurt forms an empty space in the targeted valve, for example, by means of perforation, fusion or ablation of the valve, allowing the contents of an internal containment chamber to flow into an external processing chamber while the disk 13 rotates. The detection device 10 can then monitor the subsequent reaction in the processing chamber and / or detect whether the content, or a selected volume of it, has been effectively transferred to the processing chamber. The contents inside a chamber can include substances in a fluid or solid state.
[00096] In some embodiments, the laser valve control system 51 can be contained within a single channel optical module, for example, the supplementary optical module 54 or the supplementary optical module 56. In other modalities, the system laser valve control system 51 can be mounted on detection device 10 separate from any of the optical modules 48, 52 or 56. In this case, the laser valve control system 51 can be removable and adapted to fit a location within housing 46 or a housing other than the detection device module 10.
[00097] In the example of FIG. 3, the notch sensor activator 27 is located near the removable modules, on either side of the disc 13. In one embodiment, the notch sensor activator 27 contains a light source 31 to emit infrared (IR) light 35 Detector 33 detects IR light 35 when the notch in disk 13 allows light to pass through the disk towards detector 33. Control unit 23 uses an output signal produced by detector 33 to synchronize the data acquisition of the modules optical 48, 54 and 56 with the rotation of the disc 13. In some embodiments, the notch sensor activator 27 may extend from the base arm 44 to reach the outer edge of the disc 13 during operation of the device 10. In other embodiments, a mechanical detector can be used to detect the position of the disc 13.
[00098] Barcode reader 29 uses laser 62 to read a barcode located on the side edge of disc 13. The barcode identifies the type of disc 13 to allow proper operation of device 10. In some embodiments , the barcode can identify the actual disk to assist a technician in tracking data for specific samples from multiple disks 13.
[00099] All surface components of optical modules 48, 52 and 56 can be constructed of a polymer, a composite, or a metal alloy. For example, a high molecular weight polyurethane can be used to form surface components. In other cases, an aluminum alloy or carbon fiber structure can be created. In any case, the material can be resistant to heat, fatigue, traction and corrosion. Since the detection device 10 can contract with biological materials, the structures can be sterilizable in case the contents of the chamber escape from the disc 13.
[000100] FIG. 4 illustrates a side view of the exemplary set of removable optical modules 48, 52 and 56 within the housing 46 of the detection device module 10. In the example of FIG. 4, the base arm 44 supports the barcode reader 29, as well as the removable optical modules 48, 52 and 56 attached within the housing 46 of the module. Disk 13 is located below optical modules 48, 52 and 56 with samples 22 located under a respective optical path of each of the modules at different times in time.
[000101] Within the housing 46 of the module, the front parts of the supplementary module 56 and the main optical module 48 can be seen. The supplementary module 56 contains the molded ferrule 59 and the release lever 58. As previously described, the molded ferrule 59 can be used to secure the module 56 when the module is removed or inserted into the housing 46 of the module. All optical modules 48, 52 and 56 can have a respective molded ferrule and release lever, or a single release lever can be used to remove all optical modules. In some embodiments, optical modules 48, 52 and 56 may contain a different component for securing the module. For example, each of the optical modules 48, 52 and 56 may contain a handle for removing the respective module in a vertical or horizontal direction from the module housing 46.
[000102] The position of the optical modules 48, 52 and 56 within the housing 46 of the module can be fixed in order to separately excite different samples within the disc 13 at any particular time in time. For example, the main optical module 48 can be located slightly closer to the base arm 44 than the supplementary optical modules 52 and 56, which are moved to one location on either side of the main module. In addition, optical modules 48, 52 and 56 can be moved in a horizontal direction (indicated by the arrow in FIG. 4, where X is the distance the external light beams are displaced from the internal light beams) so that the excitation light beams produced by the modules follow the curvature of the disc 13. In this arrangement, the light beams produced by the optical modules 48, 52 and 56 cross the same path while the disc 13 rotates, thereby exciting and collecting the light from the processing chambers located along the trajectory. In some embodiments, the optical modules 48, 52 and 56 can be aligned in such a way that the excitation light beams cross different paths around the rotating disk 13. In some embodiments, the optical modules 48, 52 and 56 can be aligned in such a way that the excitation light beams cross different paths around the rotating disk 13, the same paths, or a combination of them.
[000103] In this example, the base arm 44 contains the electrical contact plate 66 that extends to the housing 46 of the module. Within the internal housing 46 of the module, the electrical contact plate 66 can contain electrical contacts for each of the optical modules 48, 52 and 56. The electrical contact plate 66 can be electrically coupled to the control unit 23. In some embodiments, each of the optical modules 48, 52 and 56 can have a separate associated electrical contact plate that is connected to the control unit 23. In some embodiments, at least part of the control unit 23 and the data acquisition device 21 can be located outside the device 10 of FIGS. 3-8. In some embodiments, at least a part of the control unit 23 can be located within one or more of the optical modules 48, 52 and 56.
[000104] Fiber optic coupler 68 engages a leg of fiber optic bundle 14 to an optical output port of optical module 56. Although not shown, each of the optical modules 48, 52 and 56 includes an optical output port adapted to couple a respective fiber optic coupler mounted in the housing 46 of the module. The connection between the fiber optic coupler 68 and the fiber optic bundle leg 14 can be a screw screw lock, a pressure fitting or a friction fitting.
[000105] Barcode reader 29 produces laser light 64 to read barcode from disk 13. Laser light 64 follows a direct path where it interacts with the outer edge of disk 13. Light 64 can spread to out to cover a large area of disk 13 at once. In some embodiments, the barcode reader 29 can read the barcode on disk 13 when the disk is rotating at low speeds. In other embodiments, the barcode reader 29 can scan the barcode periodically during operation to make sure that a new disc has not been loaded in device 10. The barcode reader 29 can detect more than one barcode on disc 13 in other modalities.
[000106] In some embodiments, the base arm 44 may be movable with respect to disc 13, for example, in a gantry system between various positions of the gantry. In this case, the base arm 44 can be configurable to detect samples on discs with different dimensions or samples located inside the disc 13. For example, a larger disc containing more processing chambers or larger processing chambers can be used to move the base arm 44 further away from the center of the disc 13. The module housing 46 can also have a configurable position for each of the optical modules 48, 52 or 56 so that each module can be movable for one or more circular paths of processing chambers around the disc 13. In some embodiments, the base arm 44 can be moved radially inward and radially outwardly relative to a center of the disc 13, and the positions of the gantry can generally be indicated as "positions of radial gantry "or" radial positions ".
[000107] FIG. 5 shows device 10 with a module removed to expose a module connector. In particular, the housing 46 of the module is not shown in FIG. 5, and optical module 56 has been removed to expose optical modules 52 and 48 along with connections for the removed module 56.
[000108] The release lever 58 (FIG. 3) of the optical module 56 is firmly attached to the fixing pin 69 mounted on the base arm 44. In this example, the fixing pin 69 extends to the optical module 56 and couples with the release lever 58. In other embodiments, other clamping mechanisms can be used to clamp the optical module 56 to the base arm 44, such as a screw or a pressure clamping device.
[000109] The base arm 44 provides two different operational connections within the housing 46 of the module to receive and couple the optical module 56, once inserted. In particular, the base arm 44 provides electrical contact plate 66, which includes electrical connections 70 for coupling to electrical contacts (not shown) contained within optical module 56. Electrical connections 70 allow the control unit 23 to communicate with electrical components within module 56. For example, module 56 may include electrical circuits, hardware, firmware, or any combination of them. In one example, internal electrical components can store and send unique identification information to the control unit, such as a serial number. Alternatively, or in addition, the electrical components can provide information that describes the specific characteristics of the optical components contained within the removable module 56. For example, the electrical components may include a programmable read-only memory (PROM), a flash memory, or others internal or removable storage media. Other modalities may include a set of resistors, a circuit or an embedded processor to send a unique signature from the optical modules 48, 52 or 56 to the control unit 23. In another example, the optical module 56 may include a laser source and others components that are part of a laser valve control system, that is, the laser valve control system 51.
[000110] The electrical contact plate 66 can be removed and replaced with another version associated with a different removable optical module. This option can support updates to the device's capacity. In other embodiments, connections 70 may contain more or less connection pins.
[000111] In addition, the base arm 44 and the housing 46 of the module provide the optical channel 72 within the location to receive the optical module 56. The optical channel 72 is connected to the fiber optic coupler 68 (FIG. 4) which forms interface with one leg of the fiber optic bundle 14. The optical channel 72 is inserted at a location within the optical module 56. The light captured by the optical module 56 can be directed through the optical channel 72, the fiber optic coupler 68 and the fiber optic bundle 15 to detector 18. The fittings between these connections can be tightened to ensure that the light does not escape or enter the optical path.
[000112] In some modalities, the connections to the optical module 56 can be arranged in a different configuration. For example, connections can be located in another position to accept optical module 56 from another direction. In other embodiments, the electrical connections can be located on one side of the optical module 56 whereas an optical connection is located on a second surface of the module 56. In any case, the electrical and optical connections located within the location of the enclosure 46 of the module accommodate a removable optical module, that is, the optical module 56 in this example.
[000113] The optical and electrical connections of module 56 described in FIG. 5 can be used with any module, including optical modules 48 and 52. In addition, the connections for each optical module may not be identical. Since the connections can be modified to couple with a desired removable optical module, the connections used by any particular optical module inserted within a particular location of the module housing 46 may vary at any time.
[000114] FIG. 6 shows the internal components of the main exemplary removable optical module 48. In the example of FIG. 6, the main optical module 48 includes the release lever 50, the pivot pin 61 and the lock 74. The inner housing 78 separates each side of the module 48 and contains the electrical contact pad 80 connected to the ribbon 81. The optical components include LED 82, collimation lens 84, excitation filter 86, dichroic filter 88, focusing lens 90, detection filter 92 and lens 94. Optical output port 17 couples with a beam leg fiber optics 14. A separate set of optical components for a second optical channel (not shown) is located on the other side of the inner casing 78. In addition, main module 48 includes connector 96, laser diode 98 and lens focusing 100 as part of a laser valve control system 51 controlled by control unit 23.
[000115] The release lever 50 is attached to the optical module 48 by a pivot pin 61. The pivot pin 61 allows the release lever 50 to rotate around the axis of the pin 61. When the release lever 50 is compressed , the arm 63 rotates counterclockwise around the axis of the pin 61 to lift the latch 74. Once the latch 74 is lifted, the optical module 48 can be free to remove the housing 46 from the module. There may be a spring or other mechanism that maintains a pushing force against the release lever 50 to keep latch 74 in a lower position. In some embodiments, a spring may be included around pivot pin 61 to provide a momentary arm that holds latch 74 in the lower or locked position. In other embodiments, other mounting mechanisms can be added or used in place of the described lever. For example, optical module 48 can be attached to module housing 46 by one or more screws or pins.
[000116] The mounting plate 76 can be installed inside the optical module 48 to join the communication strip 81 and the LED 82. The strip 81 is connected to the electrical contact pad 80 and provides a connection between the pad and the electrical components inside the optical module 48. The contact pad 80 and the tape 81 can contain the information required for both sides of the main optical module 48, including the control system 51 and any internal memory of the laser valve or other storage medium. The ribbon 81 can be flexible to be woven into the optical module 48. The ribbon 81 can contain a plurality of electrically conductive wires to communicate signals between the electrical components and the control unit 23 and / or to apply power to the electrical components. In some embodiments, each electrical component may have a separate cable to connect the component to the control unit 23. A technician may have to disconnect a cable or flexible circuit from the housing 46 of the module when removing the optical module 48 from the housing.
[000117] In some embodiments, the optical module 48 may contain a detector to detect the light from disk 13 and electronic components to process and store the data. The electronic components can contain a telemetry circuit for the wireless transmission of data that represents the detected light to the control unit 23. Wireless communication can be performed by infrared light, radio frequency, Bluetooth, or another technique telemetry. The optical module 48 can also include a battery to power the electronic components, which can, for example, be rechargeable by the control unit 23.
[000118] LED 82 is affixed to mounting plate 76 and is electrically coupled to ribbon 81. LED 82 produces excitation light 49 of a predetermined wavelength to excite sample 22. Excitation light 43 is produced by second optical channel (not shown). After light 49 leaves LED 82, the light is expanded by the collimation lens 84 before the light enters the excitation filter 86. Light 49 in a wavelength range is passed through the dichroic filter 88 and focused on a sample by focusing lens 90. Light 49 excites the sample and fluorescence is collected by focusing lens 90 and passed to detection filter 92 by dichroic filter 88. The resulting wavelength range of light is collected by lens 94 and passed to the optical output port 17 where the collected fluorescent light enters a leg of the optical fiber bundle 14 to be conducted to detector 18. Such fluorescence may be indicative of the presence of an analyte of interest (for example, as a result of test by hand), and / or such fluorescence may be indicative of the presence of a selected volume of material, for example, by optically checking a particular position (for example, the radial position) of the chamber to see if the material is present at that particular location or height in the chamber. When the chamber is checked optically, the chamber is checked for an optical property of the material of interest to determine whether that material is present in the chamber. Such an optical property can include a variety of properties, including, but not limited to, absorption, fluorescence, inverse Rayleigh scattering, inverse scattered reflectance of an emitted electromagnetic signal, etc., or combinations thereof.
[000119] A "signal" can be created by checking for any of the above optical properties, and the signal can be an increase and / or a decrease from a baseline. As an example, the signal can come in the following ways: (i) Backscattering (or reflection) - Backscattering can be from the detection of a meniscus in a liquid by changing the refractive index, from the detection of particulates in the material being detected, from the reflection of the back side of a camera on the disc 13 being investigated, or a combination of them. (ii) Fluorescence - by detecting the fluorescence of the detected material or by extinguishing a background fluorescence (for example, if a fluorophore is positioned or on a surface that forms the bottom of the detection chamber, such as when being incorporated into an adhesive , coating, or the like).
[000120] Both of these modes of detection, backscattering and fluorescence, can be impacted by differences in the refractive index between the material being detected and the air in the chamber and potentially the materials on the disc 13. The resulting refraction can either enhance or decrease the sign. In some embodiments, a structured surface can be positioned on a surface that forms the bottom or top of the chamber of interest to help focus the light or disperse the light. For example, a structured material with the same refractive index as the material being detected (= ~ 1) can reflect light outside the detection path when dry, and allows reflection of a straight path when wet, that is, in contact with the material to be detected.
[000121] In addition, both of these detection modes can be impacted by the absorbance of the signal by the material being detected, and / or by a component of the disc 13. In some modalities, the signal can be modulated by placing a chromophore on or on a surface that forms the bottom of the chamber (for example, embedded in an adhesive, coating, or the like). Alternatively, or additionally, in some modalities, the signal can be modulated by adding a chromophore to the material being detected, both before and after the material is loaded onto the disc 13.
[000122] Light 49 can be back-diffused by disk 13, or a part thereof, such as a chamber on disk 13 or a sample 22 positioned within a chamber on disk 13, without necessarily exciting the sample and causing fluorescence. For example, an electromagnetic signal (for example, light 49) can be output to the detection chamber, and a scan can be obtained by detecting the backscattered reflection of the electromagnetic signal from the detection chamber. Such retrodiffuse reflection can be collected and detected in a similar way to fluorescence. That is, the backscattered light can be collected through the lens 94 and passed to the optical output port 17 where the collected backscattered light enters a leg of the fiber optic bundle 14 to be conducted to detector 18. Just as an example, the The delivery and collection of the back-scattered light from disk 13 can be a way of determining (for example, verifying optically) whether a sample, or a selected volume of a sample, is present in a particular chamber on disk 13. If calibrated, the backscattered electromagnetic signal can be used to quantify the amount of material in the chamber.
[000123] The inner shell 78 can support all components included in the sample excitation and detection of the fluorescent light emitted by the sample for a selected wavelength. On the other side of the inner shell 78, a similar configuration of optical components can be included to produce light of a different wavelength and to detect the corresponding different fluorescent wavelength. Separating each side can eliminate light contamination on one side that enters the optical channel on the other side.
[000124] Between each side of module 48, the components of the laser valve control system 51, including connector 96, laser diode 98 and focusing lens 100, can partially be housed. Inner housing 78 can provide physical support for those components. Ribbon 81 is connected to connector 96 to communicate drive and power signals to the laser source. Laser diode 98 is connected to connector 96 and produces laser energy 55 used to open valves on disk 13. Laser diode 98 can pass this near infrared (NIR) light to focusing lens 100 to direct laser energy 55 for specific valves on disk 13. A NIR sensor can be located below disk 13 to locate the particular valves that need to be opened. In other embodiments, these components can be housed separately from the optical components.
[000125] In some embodiments, the emission lens 98 and the focusing lens 100 of the laser valve control system 51 can be contained within a single channel optical module, such as the supplementary optical modules 52 and 56 ( FIG 3).
[000126] FIG. 7 shows the internal components of an additional exemplary optical module that can be easily removed or inserted into the detection device 10. In the example of FIG. 7, the optical module 56 includes the release lever 58, the pivot pin 59 and the lock 102, similar to the main optical module 48. The optical module 56 also the electrical contact pad 106 connected to the tape 107. The tape 107 also can be connected to mounting plate 104. Similar to main optical module 48, optical components include LED 108, collimation lens 110, excitation filter 112, dichroic filter 114, focusing lens 116, filter detection 118 and lens 120. Optical output port 19 couples with a leg of the fiber optic bundle 14. Release lever 58 and lock 102 can operate in substantially the same way as that of optical module 48 shown in FIG. 6 and described above.
[000127] The mounting plate 104 can be installed inside the optical module 56 to secure the communication ribbon 107 and the LED 108. The ribbon 107 is connected to the electrical contact pad 106 and provides a connection between the pad and the electrical components inside the optical module 56. The contact pad 106 and the tape 107 may contain the information required to operate the optical components. The ribbon 107 can be flexible to be woven into the optical module 56. The ribbon 107 can contain a plurality of electrically conductive wires to communicate signals between the components and the control unit 23 and / or to apply power to the electrical components. In some embodiments, each electrical component may have a separate cable to connect the component to the control unit 23. A technician may have to disconnect a cable or flexible circuit from the housing 46 of the module when removing the optical module 56 from the housing.
[000128] Similar to the optical module 48 described above and shown in FIG. 6, in some embodiments, the optical module 56 may contain a detector to detect light from disk 13 and electronic components to process and store the data. The electronic components may contain a telemetry circuit for the wireless transmission of data that represents the detected light to the control unit 23 when using any of the wireless communication modes or technologies described above. Optical module 56 can also include a battery to power electronic components, which can, for example, be rechargeable by control unit 23.
[000129] LED 108 is attached to mounting plate 104 and is electrically coupled to tape 107. LED 108 produces excitation light 101 of a predetermined wavelength to excite sample 22. After light 101 exits the LED 108, the light is expanded by the collimation lens 110 before the light enters the excitation filter 112. The light 101 of a wavelength range is passed through the dichroic filter 114 and focused on a sample by the focusing lens 116. A light 101 excites the sample and fluorescence is collected by the focusing lens 116 and passed to the detection filter 118 by the dichroic filter 114. The resulting wavelength range of light is collected by the lens 120 and passed to the optical output port 19 where the collected fluorescent light enters a leg of the fiber optic bundle 14 to be conducted to the detector 18.
[000130] Similar to optical module 48, optical module 56 (and / or optical module 52) can also (or instead of optical module 48) be used to deliver and detect back-scattered light from disk 13, or a part of same, such as from a chamber on disk 13 or a sample 22 positioned within a chamber on disk 13, without necessarily exciting the sample and causing fluorescence. Such back-scattered light can be collected and detected in a similar way to fluorescence. That is, the backscattered light can be collected through the lens 120 and passed to the optical output port 19 where the collected backscattered light enters a leg of the fiber optic bundle 14 to be conducted to the detector 18. As with the optical module 48 , fluorescence and / or backscattered light can be the means to determine whether a selected volume of material is present in a particular chamber of the disc 13.
[000131] Supplementary optical module 56 may also contain components of the laser valve control system 51. The laser valve control system 51 may be the only system used within device 10 or a plurality of control systems for laser valve. The components used for this system can be similar to the components described in the optical module 48 of FIG. 6.
[000132] The components of the supplementary optical module 56 can be similar to any supplementary optical module or to any optical module used to emit and detect a wavelength range of light. In some embodiments, the components can be changed in configuration to accommodate different experimental applications. For example, all optical modules can be modified to be inserted in a different direction or to be placed inside the device in a different position with respect to disk 13. In any case, the optical modules can be removable to provide flexibility of modification to the device 10.
[000133] FIG. 8 is an illustration of the side view of an exemplary set of removable optical modules 48, 52 and 56 within the device housing with the laser valve control system located over a notch in the disk. The example of FIG. 8 is similar to that of FIG. 4. However, laser valve control system 51 has been positioned to focus laser light 71 from a power source, that is, a laser diode, through notch 75 on disc 13. Sensor 73 detects light laser 71 when the light passes through the notch 75.
[000134] A gantry 60 can be used to move the housing 46 and the optical modules contained 48, 52 and 56 of the module in a horizontal direction (shown as arrows and denoted by "X" in FIG. 8) in relation to a center of the disc 13. In other words, the casing 46 and the optical modules contained 48, 52 and 56 of the module can move radially with respect to the center of the disc 13. Other directions of movement of the gantry 60 can also be employed, for example, on a two-dimensional plane, a three-dimensional space, etc. Laser light 71 can be emitted by the laser at a reduced current to produce low-power radiation (for example, near infrared (NIR) light) to locate notch 75 on disk 13. In some cases, gantry 60 may translate the module housing 46 in the horizontal direction while the laser valve control system 51 emits laser light 71 in order to locate the notch 75.
[000135] Sensor 73 can detect laser light 71 once the laser light travels through notch 75, causing sensor 73 to emit an electrical signal representative of the detected low power laser light 71 to control unit 23. Upon receipt of the electrical signal from sensor 73, control unit 23 maps the detected position of the disc to a known position of the turntable 25 and constructs a position map that identifies the position of each valve on the disc 13 in relation to the known position turntable 25. The control unit 23 can subsequently use the built position map to move the laser, rotate the disc, or both, in order to focus the desired disc 13 valves. In other embodiments, sensor 73 can be located on the same side of the disc 13 as the laser valve control system 51 to detect laser light 71 from a reflective part or parts of the disc 13.
[000136] With the positioning of the laser valve control system 51 over a selected valve, the control unit 23 directs the laser valve control system to apply short pulses of high power energy (for example, 1 second to 1 watt (W)) to open the selected valve. The valves can be constructed from a polymer or similar material that absorbs the electromagnetic energy emitted, that is, laser light 71, causing the polymer to rupture, thereby opening a channel between an internal containment chamber and an external processing chamber. Other energy sources can be used (for example, radio frequency energy sources), and materials that absorb the produced energy and the rupture (ie, open) can be selected. Once the valves are opened, the rotation of the disc 13 directs the contents of the respective internal containment chamber to the respective external processing chamber.
[000137] In some embodiments, the laser valve control system 51 and the notch sensor activator 27 can communicate for effective positioning of the disc 13. For example, the notch sensor activator 27 can generally locate the radial position of disc 13 when detecting the presence of notch 75. The laser valve control system 51 can specifically detect each of the edges of notch 75 for a more accurate radial and angular position of disc 13. Once the edges of the notch notch 75 are smaller features than the notch 75 itself, the laser valve control system 51 can provide a higher spatial resolution detection system than the notch sensor activator 27. Alternatively, the notch sensor activator 27 may be able to provide a higher temporal resolution since the position of the notch 75 can be detected at high speeds of rotation. The edges of the notch 75 may not be detected by the laser valve control system 51 at high speeds of rotation.
[000138] In addition, some modalities may not include a gantry 60 to move the components horizontally (or radially) to align the light paths with the structures on the disc 13. For example, the laser valve control system 51 and the optical modules 48, 52 and 56 can be fixed at appropriate radial distances from a center of disk 13. As another example, the laser valve control system 51 and / or optical modules 48, 52 and 56 can rotate under the direction of the control unit 23 to focus the laser light at different radial positions of the disc 13.
[000139] FIG. 9 is a functional block diagram of the multiplex fluorescence detection device 10. In particular, FIG. 9 indicates the electrical connections between the device's components (shown in solid arrows) and the general light paths through the components (shown in discontinuous arrows). In the example of FIG. 9, device 10 includes at least one processor 122 or other control logic, memory 124, disk motor 126, light source 30, excitation filter 34, lens 38, detection filter 40, collection lens 42, detector 18, notch sensor activator 27, communication interface 130, heating element 134, laser 136 and power supply 132. As shown in FIG. 9, lens 38 and collection lens 42 do not need to be electrically connected to another component. In addition, light source 30, filters 34 and 40, lens 38 and collection lens 42 are representative of an optical module 16. Although not shown in FIG. 9, device 10 may contain additional optical modules 16, as previously described. In that case, each additional optical module may include components arranged substantially similar to those shown in FIG. 9.
[000140] The light follows a certain path through various components in FIG. 9. Once the light is emitted by the light source 30, it enters the excitation filter 34 and exits as the light of a different wavelength. It then passes through the lens 38 where it leaves the detection device 10 and excites the sample 22 inside a processing chamber (not shown). Sample 22 responds by showing fluorescence at a different wavelength or by re-diffusing light, at which time that light enters the lens 38 and is filtered by the detection filter 40. Filter 40 removes the backlight from outside wavelengths of the desired fluorescence or backscattered light from sample 22. The remaining light is sent through the collection lens 42 and enters a leg of the fiber optic bundle 14 before being detected by detector 18. Detector 18 subsequently amplifies the received light signal .
[000141] Processor 122, memory 124 and communication interface 130 can be part of control unit 23 and, as mentioned above, one or more components of control unit 23 can be located inside optical module 16. The Processor 122 controls the disk motor 126 to rotate or rotate the disk 13 as needed to collect optical information (for example, fluorescence) or to move fluid through the disk 13. Processor 122 can use the disk position information received from the slot sensor activator 27 to identify the position of the cameras on the disk 13 during rotation and to synchronize the acquisition of the optical data received from the disk. Processor 122 can also pause, cancel, and / or issue an error, alert, or notification code if a selected volume of material is not detected when needed in a particular disc 13 chamber.
[000142] Processor 122 can also control when light source 30 within optical module 16 is activated and deactivated. In some embodiments, processor 122 controls excitation filter 34 and detection filter 40. Depending on the sample being illuminated, processor 122 can change the filter to allow a different wavelength of the excitation light to reach the sample. or a different fluorescence wavelength reaches the collection lens 42. In some embodiments, one or both of the filters can be optimized for the light source 30 of the particular optical module 16 and not be changed by the processor 122.
[000143] The collection lens 42 is coupled to a fiber bundle leg 14 that provides an optical path for the light from the collection lens to detector 18. Processor 122 can control the operation of detector 18. Although detector 18 can constantly detect all light, some modes may use other modes of acquisition. Processor 122 can determine when detector 18 collects data and can programmatically adjust other configuration parameters of detector 18. In one embodiment, detector 18 is a photomultiplier tube that captures the fluorescence information of the light provided by the collection lens 42 In response, detector 18 produces an output signal 128 (e.g., an analog output signal) representative of the received light. Although not shown in FIG. 9, detector 18 can simultaneously receive light from other optical modules 16 of device 10. In that case, output signal 128 electrically represents a combination of the optical input received by detector 18 from the various optical modules 16, and can also include information which is related to the presence of a selected volume of material in a particular chamber on disk 13.
[000144] Processor 122 can also control the data flow from device 10. Data such as sampled fluorescence or detected back-light from detector 18 (for example, in particular positions (for example, gantry positions) in relation to particular chambers on disk 13 to determine whether a selected volume of material is present in particular chambers (s), the fluorescence sampled from detector 18 (for example, to determine the results of a particular assay), the temperature of samples from the heating element 134 and related sensors, and disk rotation information can be stored in memory 124 for analysis Processor 122 may comprise any one or more of a microprocessor, a digital signal processor (DSP), an integrated circuit application-specific (ASIC), an array of field programmable ports (FPGA), or other digital logic circuits, and processor 122 can provide an environment for firmware, software, or combinations thereof, stored on a medium that can be read by a computer, such as memory 124.
[000145] Memory 124 may include one or more memories to store a variety of information. For example, a memory can contain specific configuration parameters, executable instructions, and one can contain collected data. Therefore, processor 122 can use the data stored in memory 124 to control the operation and calibration of the device. Memory 124 may include any one or more of a random access memory (RAM), a read-only memory (ROM), an electronically erasable programmable ROM (EEPROM), a flash memory, or the like.
[000146] Processor 122 can also control heating element 134. Based on the instructions contained in memory 124, heating element 134 can be selectively directed to control the temperature of one or more chambers according to desired heating profiles . In general, the heating element heats a radial section of the disc 13 while the disc rotates. The heating element 134 may comprise a halogen bulb and a reflector to focus the heating energy on a specific area of the disc 13, or more particularly, on the turntable 25, or on a specific area thereof, in such a way that the Heat can then be conducted from the platform 25 to a specific area of the disc 13. In some embodiments, the heating element 134 can heat one or more chambers sequentially. Such arrangements should require that disk 13 be stationary while a portion of platform 25 and / or disk 13 is heated. In either embodiment, the heating element 134 may be able to switch on and off extremely quickly as needed.
[000147] Laser 136 is used to control the opening of the valve, which allows the contents of a containment chamber to flow to another chamber on disk 13, for example, a processing or detection chamber. Processor 122 and supporting hardware drive laser 136 to selectively open the specific valves contained within disk 13. Processor 122 can interact with a laser sensor (such as sensor 73 in FIG. 8) positioned below, or in relation to disk 13 to determine the position of the laser in relation to the desired valve. The processor 122 can then interact with the disk motor 126 to rotate the turntable 25, and therefore the disk 13, into position. When in position, processor 122 emits signals to direct laser 136 to produce a targeted energy surge at the valve. In some cases, the outbreak can last for about 0.5 seconds, while other modalities may include opening times of a shorter or longer duration. A duration of the laser energy and the pulse can be controlled by the processor 122 through communication with the laser 136.
[000148] Processor 122 uses communication interface 130 to communicate with data acquisition system 21. Communication interface 130 can include a single method or combination of methods for data transfer. Some methods may include a universal serial bus (USB) port or an IEEE 1394 port for spun connectivity with high data transfer rates. In some embodiments, a storage device can be directly attached to one of these ports for data storage or post-processing. The data can be pre-processed by processor 122 and ready for viewing, or the raw data may have to be processed completely before the analysis can begin.
[000149] Communications with the detection device 10 can also be carried out by radio frequency (RF) communication or by a local area network (LAN) connection. In addition, connectivity can be provided by connecting directly or through a network access point, such as a connector or router, which can support wired or wireless communications. For example, the detection device 10 can transmit data at a certain RF frequency for reception by the target data acquisition device 21. The data acquisition device 21 can be a general purpose computer, a notebook computer, a portable computing device, or an application specific device. In addition, multiple data acquisition devices can receive data simultaneously. In other embodiments, the data acquisition device 21 can be included with the detection device 10 as an integrated detection and acquisition system.
[000150] In addition, detection device 10 may be able to download updated software, firmware, and calibration data from a remote device over a network, such as the Internet. Communication interface 130 may also allow processor 122 to monitor inventory or report any failures or errors. If operational problems occur, processor 122 may be able to issue error information to assist a user in the problem in resolving problems by providing operational data. For example, processor 122 can provide information to assist the user in diagnosing a failed heating element, a timing problem, or a failure in various input and / or valve structures on disk 13 (for example, when receiving information of detector 18 which indicate that a selected volume of material is not present in one or more chambers of disc 13).
[000151] Power supply 132 applies operating power to device 10 components. Power supply 132 can use electricity from a standard 115-volt electrical outlet or include a battery and power generation circuit to produce operating power . In some embodiments, the battery may be rechargeable to allow extended operation. For example, device 10 can be portable for detecting biological samples in an emergency, such as a disaster area. Recharging can be done via the 115 volt electrical outlet. In other modalities, traditional batteries can be used.
[000152] FIG. 10 is a functional block diagram of single detector 18 coupled to four optical fibers from the optical fiber bundle 14. In this embodiment, detector 18 is a photomultiplier tube. Each leg of the optical fiber bundle 14, the optical fiber 14A, the optical fiber 14B, the optical fiber 14C and the optical fiber 14D, couples with an optical input interface 138 of detector 18. In this way, the light conducted by any one of optical fibers 14 is provided to a single optical input interface 138 of detector 18. Optical input interface 138 provides the aggregated light to electron multiplier 140. Anode 142 collects electrons and produces a corresponding analog signal as an output signal .
[000153] In other words, as shown, the optical fibers 14 fit within the optical input opening for detector 18. Consequently, detector 18 can be used to simultaneously detect the light from each leg of the optical beam 14. The interface optical input 138 provides light to the electron multiplier 140. For a photomultiplier tube, the photons of the optical fibers first reach a photoemissive cathode, which in turn releases photoelectrons. The photoelectrons then form a cascade when reaching a series of dynodes, and more photoelectrons are emitted upon contact with each dinod. The resulting group of electrons essentially multiplies the small light signals originally transmitted by the optical fibers 14. The increased number of electrons is finally collected by anode 142. This current from anode 142 is transferred by a current to voltage amplifier 144 as a signal of analog output that is representative of the optical fluorescent signals of the sample provided by the plurality of optical modules 16.
[000154] In some embodiments, the control unit 23 may include an analog converter in (A / D) 146 that converts the analog signal into a stream of sampled digital data, that is, a digital signal. Processor 122 receives the digital signal and stores the sampled data in memory 124 for communication to the data acquisition device 21, as described above. In some embodiments, the A / D converter 146 can be contained within the detector 18 instead of preferably forming a part of the control unit 23.
[000155] In this way, a simple detector 18 can be used to collect all the light from the optical beam 14 and produce a signal representative of it. Once the signal is amplified by amplifier 144 and converted to a digital signal, it can be digitally separated into data that corresponds to the light collected by each individual optical module 16. Every signal (ie, aggregate) can be separated by the range of frequency in each detected signal representative of the signal of each fluorescence. These frequencies can be separated by a digital filter applied by the data acquisition device 21 or inside the device 10.
[000156] In other modalities, the amplified signal can be separated by frequency when using analog filters and sent to separate channels before the A / D converter 146. Each channel can then be digitized separately and sent to the data acquisition device. In either case, the simple detector can capture all fluorescence information, or other optical signals or information, from each optical module 16. The data acquisition device 21 can then trace and analyze the signal acquired from each disc well. 13 in real time without the need for multiple detectors.
[000157] In some embodiments, detector 18 may not be a photomultiplier tube. In general, detector 18 can be any type of analog or digital detection device capable of capturing the light from multiple legs of an optical application mechanism, that is, the fiber bundle 14, and producing a transmissible representation of the captured light.
[000158] FIG. 11 is a flow chart illustrating the operation of the multiplex fluorescence detection device 10. Initially, in step 148, a user specifies the program parameters on the data acquisition device 21 or through an interface with the control unit 23. For For example, these parameters can include a speed and time period for the rotating disk 13, defining temperature profiles for the reaction, and sampling locations on the disk 13.
[000159] Then, in step 150, the user can load disk 13 on the detection device 10. With the fixation of device 10, the user can start the program (152), causing the control unit 23 to start rotate the disc (154) at the specified rate. After the disc has started to spin, two simultaneous processes can occur.
[000160] First, in step 156, the detection device 10 can begin to detect fluorescence or other optical signals or information from the excitation light produced by one or more reactions within one or more samples. Detector 18 amplifies the optical signals (e.g., fluorescence) of each sample, which are synchronized for each respective sample and the time when the fluorescence was emitted (158). During this process, processor 122 saves the captured data in memory 124 and can communicate the data to the data acquisition device 21 in real time to monitor the progress of the processing run and for further processing (160). Alternatively, processor 122 can save data within device 10 until the program is complete. Processor 122 continues to detect the fluorescence of the samples and save the data until the program is complete (162). Once the processing run is complete, the control unit 23 stops the disc from turning (164).
[000161] During this process, the control unit 23 can monitor the temperature of the disk (166) and modulate the disk, or the temperature of each sample to reach the target temperature for that time (168). Control unit 23 can continue to monitor and control temperatures until the program is complete (170). Once the processing run is complete, the control unit 23 maintains the temperature of the samples at a target storage temperature, usually 4 degrees Celsius (172).
[000162] The operation of the device 10 can vary from the example of FIG. 11. For example, disc rpm can be modified throughout the program, multiple chambers on disc 13 can be monitored to determine whether a selected volume of a material is present, and / or laser 136 can be used to open valves between chambers in the disc to allow for multiple reactions and / or material movement. These steps can occur in any order within the operation, depending on the program that the user defines.
[000163] FIG. 12 is a flow chart illustrating the exemplary operation of the laser valve control system 51 of the detection device 10. For exemplary purposes, FIG. 12 will be described with reference to disk 13 and device 10, with particular reference to FIG. 8.
[000164] Initially, the control unit 23 places the laser valve control system 51 in a low power mode (also known as "target mode") that uses a reduced current (149). Then, the control unit 23 starts to rotate the disc 13A (151). The sensor 73 (for example, a NIR sensor) sends a trigger signal to the control unit 23 with the detection of the edges of the notch 75 as the disk 13 rotates, allowing the control unit 23 to accurately map the disk orientation 13 and the positions of the valves on the disc 13 to the known position of the turntable 25 of the device 10 (153).
[000165] When using the mapping, the control unit 23 couples the port 60 to move the laser valve control system 51 to the known position of the valves in relation to a center or axis of rotation of the disc 13 (ie , positioned to the left of FIG. 8). The control unit 23 then rotates the disk 13 to the first selected valve to be opened (157). Then, the control unit 23 places the laser valve control system 51 in a high power mode and directs the system to produce a pulse of the high energy laser light 71 to open the valve (159). If an additional valve is to be opened (161), the control unit 23 rotates the disk 13 to the next valve (157) and opens the valve (159). This process continues until all the valves to be opened have been opened. The control unit 23 then rotates the disc 13 to move the fluid, for example, from a chamber located closer to a axis of rotation of the disc 13 (sometimes referred to as "inlet chambers" or "containment chambers") ), through an open valve, and into a chamber (sometimes referred to as a "processing chamber" or a "detection chamber") located further away from the axis of rotation, such as closer to a periphery of the disc 13 ( 163). In other embodiments, the control unit 23 can continuously rotate the disc 13 while directing the laser valve control system 51 to open the valves.
[000166] Finally, the control unit 23 can couple the port 60 to move the optical modules 48, 52 and / or 56 to a radial position on the processing chambers and begin the detection of fluorescence or other optical signals from the materials and / or reactions in the processing chambers (165). In some embodiments, the contents of the containment chambers may act to disable or stabilize products in the processing chambers. In such cases, the detection device 10 may or may not have to monitor the new samples or reactions.
[000167] FIG. 13A shows an example diagram of a notch 75 on a disc. In FIGS. 13A, 13B and 13C, disk 13 will be used as an exemplary disk in device 10. Notch 75 includes outer edge 210, inner edge 214, leading edge 212 and trailing edge 216. The valve control system a laser 51 detects each edge to provide an accurate map of the position of disk 13. Distance D is the radial position of the inner edge subtracted from the radial position of the outer edge of notch 75. Each edge 210, 212, 214 and 216 creates the detectable boundary between the material of the disc 13 and the empty space on the disc described as notch 75. In some embodiments, the notch 75 can be of any shape or size.
[000168] FIG. 13B illustrates an hourly diagram illustrating an example method for detecting the inner and outer edges of a notch in a disc. Control unit 23 moves laser valve control system 51 so that it moves away from disk 13. Disk 13 is rotated when gantry 60 moves laser valve control system 51 to the center, or axis of rotation , from disk 13.
[000169] Sensor 73 detects laser light 71 (FIG. 8) only when notch 75 allows laser light 71 to pass through disc 13. A signal 218 from sensor 73 changes at tip 220 once the outer edge 210 of the notch 75 is detected as the port 60 advances inward. Signal 218 continues to modulate while notch 75 passes intermittently through laser light 71. Tip 222 indicates the last signal change that control unit 23 marks as the inner edge 214 of notch 75. The positions of the frame of the outer edges and internal 210 and 214 of slot 75 are recorded. The control unit 23 now has a radial component of the disk position map 13. The control unit 23 moves the laser valve control system 51 to the radial position midway between the radial positions of the inner and outer edges. This position should be the radial position of the inner edge 214 plus half the distance D. The positioning of the laser valve control system 51 at this location of the notch 75 allows the system to detect the angular position of the notch 75 without rounding a corner of the notch 75, for example, the corner between the inner edge 214 and the rear edge 216, causing an error in the angular position of an edge of the notch 75. In some embodiments, the disc 13 may not have to be rotated for the system laser valve control panel 51 detect the inner and outer edges of the notch 75.
[000170] FIG. 13C illustrates an hourly diagram illustrating an exemplary method for determining the local position of a laser valve control system 51. Signal 224 is passed to control unit 23 which indicates the presence of laser light 71. The control system laser valve 51 locates the front edge 212 and the rear edge 216 of the notch 75 on the disc 13.
[000171] Signal 224 is constant since disk 13 is stationary. Since the disc 13 is slowly rotated clockwise, tip 226 indicates the angular position of that of notch 75. Laser light 71 is detected by sensor 73 until the rear edge 216 is detected as tip 228. The control unit 23 then to disc 13 and slowly rotate disc 13 counterclockwise until tip 230 indicates the presence of rear edge 216 once again. The control unit 23 stores this angular position as a local angular position. The laser valve control system 51 now uses the radial position of FIG. 13B and the angular position of FIG. 13C to locate valves or other structures on the disc 13. In other embodiments, the laser valve control system 51 can only detect the leading edge 212 or trailing edge 216 for effective disk positioning 13.
[000172] In some embodiments, the drive system (for example, including a motor) and / or the turntable 25 can be operated in two different modes - a speed mode and a position mode. The local radial position, or gantry location, can be determined at a constant speed when the drive system is in speed mode (for example, at 1,500 rpm). After the location of the gantry is determined, the motor can be decelerated to a stop and switched to position mode, where it can move slowly from one tic (ie, position) to the next, looking for the local position of the portico. The difference between the speed mode and the position mode can be the proportional integral derivative constants (PID) that are used by the drive system. The position mode can allow restricted control in any position, which, for example, can be used for the valve. The speed mode can be used when a stable speed is required, for example, when acquiring fluorescence data.
[000173] In some embodiments, the disc 13 can be rotated in the opposite direction. In other embodiments, the exemplary signs of FIGS. 13B and 13C can be inverted and in any proportion by relating signal strength to time. In other embodiments, the laser valve control system 51 can first detect the angular position of the disc 13 before detecting the radial position of the disc 13. The order of the described positioning method can be changed to accommodate certain applications, discs or technician preferences.
[000174] FIG. 14 is a flow chart illustrating an exemplary determination of the local position of a laser valve control system. The control unit 23 can start by turning the disc 13 (228). From outside disk 13, port 60 can move laser valve control system 51 to the center of disk 13 (230). The laser valve control system 51 can locate the outer edge 210 of the notch 75 on the disc 13 and save that position radially outward (232). While the port 60 continues to move, the laser valve control system 51 can locate the inner edge 214 of the notch 75 when the laser light 71 is no longer detected by sensor 73 and saves that inner radial position (234). The control unit 23 can store the two radial and rotational positions of the disc 13 (236).
[000175] The control unit 23 can then move the laser valve control system 51 to the radial position directly in the middle between the inner and outer radial positions (238). The control unit 23 can slowly rotate the disk 13 to move both the front edge 212 and the rear edge 216 of the notch 75 in addition to the laser valve control system 51 (240). Once the trailing edge 216 is detected, the control unit can slowly rotate the disc 13 in the opposite direction (242). With the detection of the rear edge 216 of the notch 75 again, the control unit 23 can save the position of the rear edge (244) as zero angular position or local angular position. The control unit 23 now has the radial and angular positions of the notch 75 and can store this information as the local position of the disc 13 (246).
[000176] In some cases, the notch sensor activator 27 can work in conjunction with the laser valve control system 51 to accurately map the position of disk 13. For example, the notch sensor activator 27 can provide high resolution temporal position information whereas laser valve control system 51 provides high resolution spatial position information. Since both systems use the same disk structure 13, cooperative positioning can provide more accurate positioning information.
[000177] FIG. 15 is a flow chart illustrating an exemplary method of detecting light and sampling data from disk 13. Initially, a user specifies which optical modules 48, 52, 56 will detect the fluorescence of disk 13, and the control unit 23 activates the LED of a module (249). Once the LED has heated up to a steady state, the control unit 23 rotates the disc 13, for example, at a rate of about 1,470 revolutions per minute (251) until the disc notch 75 is detected by the notch 27. The control unit 23 can start acquiring fluorescence data for a complete rotation. During this rotation, the module collects fluorescent light from the processing (or "detection") chambers of disk 13 (253), and control unit 23 places a desired number of samples (for example, 16) from each chamber in the BIN memory associated with each processing chamber (255). Control unit 23 can detect the second pass of slot 75 to ensure that data is acquired at the correct motor speed, and control unit 23 can put time-dependent data into memory.
[000178] If disk 13 is to be rotated another rotation (257), control unit 23 performs another rotation of disk 13 (251). If the desired number of revolutions has been sampled, the module has completed the detection with the LED. For example, if 16 rotations were samples, and each rotation takes 16 samples from each processing chamber, each processing chamber was sampled a total of 256 times. After the desired number of revolutions has been completed, the control unit 23 can deactivate the LED (259). If another module is needed to continue detection (261), control unit 23 can rotate over the next module LED (249). If no other modules are needed to collect data, the control unit 23 can stop collecting data from disk 13. The data acquisition device 21 can integrate the individual scans of each module and calculate a histogram value for each well and module, which can be registered in a data file.
[000179] In some embodiments, each processing chamber can be sampled more or less than 16 samples and 16 rotations. The control unit 23 can rotate disc 13 at a faster speed for faster results or rotate disc 13 more slowly to acquire more samples.
[000180] The process illustrated in FIG. 15 can be used to detect the presence or absence of an analyte of interest (for example, when using fluorescence detection), and can also be used to collect information that relates whether a selected volume of material is present in a chamber particularly on disk 13, for example, when using fluorescence and / or backscattered light detection, as described above. While the disc 13 is rotating, the material present in a chamber on the disc 13 will be forced against an outer radial edge of the chamber. As a result, gantry 60 can position one or more optical modules from a radially outward position to an inner radial position, for example, starting after the outermost radial edge of the chamber, and moving to a center of the disc 13 along a lightning. Since the material will be forced against the outermost edge of the chamber when the disc 13 rotates, if the volume of material in the chamber is less than the internal volume of the chamber, a layer of meniscus or a fluid level of the material will be present in a position (for example, a radial position) that lies between an innermost radial edge of the chamber and an outermost radial edge of the chamber. Such a fluid level can be detected, for example, by a change in fluorescence or by a refraction of the reflected backscattered electromagnetic energy.
[000181] Gantry 60 can move an optical module radially (for example, inward) along that radius while disk 13 is rotating, collecting data in a plurality of positions of the gantry (for example, in a plurality of radial positions) , according to the process of FIG. 15. Such data can then be analyzed for such a fluid level or meniscus. For example, a background scan can be performed for each chamber of interest on disk 13 when it is known that no material is present in the chamber (s) of interest, and another scan can be performed for the chamber (s) (s) after it is assumed that the material, or a selected volume of material, must be present in the chamber (s). The two scans can then be compared to determine the radial position at which a fluid level (for example, a meniscus layer) is detected. Alternatively, or in addition, the position of the gantry (for example, radial) can be extrapolated (for example, based on a previous calibration) to a volume. Alternatively, or in addition, a particular position of the gantry can be used as a limit, such that if the position of the gantry where the fluid level is detected is less than a limit number, the data acquisition device 21 can issue a result (for example, an invalid test, an error code, a test failure or interruption, etc.) that a sufficient amount of a material was not present for the test, but if the position of the gantry on which the fluid level is detected is greater than or equal to the limit number, the desired volume of material can be confirmed. Sample Processing Devices
[000182] An exemplary sample processing device, or disk, 300 of the present invention is shown in FIGS. 16-22. The details and additional features of the sample processing device 300 can be found in Design Patent Application U. S. No. 29 / 392.223, filed on May 18, 2011, which is hereby incorporated by reference in its entirety.
[000183] The sample processing device 300 is shown by way of example only as having a circular shape. The sample processing device 300 can include a center 301, and the sample processing device 300 can be rotated about an axis of rotation A-A that extends through the center 301 of the sample processing device 300.
[000184] The sample processing device 300 can be a composite multilayer structure formed by a substrate or a body 302, one or more first layers 304 coupled to an upper surface 306 of the substrate 302, and one or more second layers 308 coupled to a lower surface 309 of the substrate 302. As shown in FIG. 22, substrate 302 includes a stepped configuration with three steps or levels 313 on the upper surface 306. As a result, fluid structures (eg chambers) designed to contain a volume of material (eg, sample) on each step 313 of the sample processing device 300 can be at least partially defined by the substrate 302, a first layer 304, and a second layer 308. In addition, because of the stepped configuration comprising three steps 313, the sample processing device 300 can include three first layers 304, one for each step 313 of the sample processing device 300. This arrangement of fluid structures and stepped configuration is shown by way of example only, and the present invention is not intended to be limited to the design portal.
[000185] The substrate 302 can be formed by a variety of materials, including, but not limited to, polymers, glass, silicon, quartz, ceramics, or combinations thereof. In embodiments where substrate 302 is polymeric, substrate 302 can be formed by relatively easy methods, such as molding. Although substrate 302 is described as a homogeneous, one-piece integral body, it can alternatively be provided as a non-homogeneous body, being formed, for example, from layers of the same or different materials. For sample processing devices 300 where substrate 302 will be in direct contact with sample materials, substrate 302 can be formed from one or more materials that are non-reactive with the sample materials. Examples of some suitable polymeric materials that can be used for the substrate in many different bioanalytical applications include, but are not limited to, polycarbonate, polymethyl methacrylate (PMMA), polypropylene (for example, isotactic polypropylene), polyethylene, polyester, etc., or combinations thereof. Such polymers generally exhibit hydrophobic surfaces that can be useful in defining fluid structures, as described below. Polypropylene is generally more hydrophobic than some of the other polymeric materials, such as polycarbonate or PMMA; however, all of the listed polymeric materials are generally more hydrophobic than the devices of silica-based microelectromechanical systems (MEMS).
[000186] As shown in FIGS. 17 and 19, the sample processing device 300 may include a notch 375 formed through the substrate 302 or another structure (for example, reflective tab, etc.) for the deposition and positioning of the sample processing device 300, for example , in relation to electromagnetic energy sources, optical modules, and others, as described above with respect to FIGS. 12-14.
[000187] The sample processing device 300 includes a plurality of processing or detection chambers 350, each of which defines a volume to contain a sample and any other materials that have to be thermally processed (e.g., chipped) with the sample. As used in connection with the present invention, "thermal processing" (and variations thereof) means controlling (for example, maintaining, raising, or lowering) the temperature of sample materials to obtain desired reactions. As a form of thermal processing, the "thermal cycle" (and its variations) means the sequential change in the temperature of sample materials between two or more stipulated temperature points to obtain desired reactions. A thermal cycle may involve, for example, a cycle between lower and upper temperatures, a cycle between lower and upper temperatures, and at least an intermediate temperature, etc.
[000188] The illustrated device 300 includes eight detection chambers 350, one for each lane 303, although it should be understood that the exact number of the detection chambers 350 provided in relation to a device manufactured in accordance with the present invention may be greater than than or less than eight, as desired.
[000189] The detection chambers 350 in the illustrative device 300 are in the form of chambers, although the detection chambers in the devices of the present invention can be provided in the form of capillaries, passages, channels, grooves, or any other appropriately defined volume.
[000190] In some embodiments, the substrate 302, the first layers 304 and the second layers 308 of the sample processing device 300 can be joined or bonded to each other with sufficient strength to resist the expansion forces that can be developed within of the detection chambers 350 such as, for example, the constituents located there which are heated rapidly during thermal processing. The robustness of the connections between the components can be particularly important if the device 300 is to be used for thermal cycle processes, for example, PCR amplification. Repetitive heating and cooling involved in such a thermal cycle can place more intense demands on the connection between the sides of the sample processing device 300. Another potential problem solved by a more robust connection between the components is any difference in the coefficients of thermal expansion of the different materials used to manufacture the components.
[000191] The first layers 304 may be formed by a transparent or opaque or translucent film or sheet, such as adhesive-coated polyester, polypropylene or thin metal foil, or combinations thereof, in such a way that the underlying structures of the Sample processing device 300 is visible. Second layers 308 may be transparent, or opaque, but are often formed of a thermally conductive metal (for example, a sheet of metal) or another material that is suitably thermally conductive to transmit heat or cold by conducting a plate and / or a thermal structure (for example, attached to or part of the turntable 25) to which the sample processing device 300 is physically attached (and / or forced to contact) to the sample processing device 300, and in particular, the detection chambers 350, when necessary.
[000192] The first and second layers 304 and 308 can be used in combination with any desired passivation layers, adhesive layers, other suitable layers, or combinations thereof, as described in US Patent Application Publication No. 6,734 .401, and in US Patent Nos. 2008/0314895 and 2008-0152546. In addition, the first and second layers 304 and 308 can be coupled to substrate 302 using any desired technique or combination of techniques, including, but not limited to, adhesives, welding (chemical, thermal and / or sonic), etc., as described in US Patent Application Publication No. 6,734,401, and in US Patent Nos. 2008/0314895 and 2008/0152546.
[000193] For example only, the sample processing device 300 is shown to include eight different tracks, wedges, parts or sections 303, wherein each track 303 is fluidly isolated from the other tracks 303, in such a way that eight different samples can be processed in the sample processing device 300, at the same time or at different times (for example, sequentially). To inhibit cross-contamination between lanes 303, each lane can be fluidly isolated from the environment, prior to use and during use, for example, after a raw sample has been loaded onto a particular lane 303 of the processing device samples 300. For example, as shown in FIG. 16, in some embodiments, the sample processing device 300 may include a pre-used layer 305 (e.g., a film, sheet, or the like comprising a pressure sensitive adhesive) as the first innermost layer 304 which can be adhered to at least a portion of the upper surface 306 of the sample processing device 300 prior to use, and which can be selectively removed (e.g., when pulled out) from a given track 303 prior to the use of that particular track.
[000194] As shown in FIG. 16, in some embodiments, the pre-use layer 305 may include folds, perforations or marking lines 312 to facilitate the removal of only part of the pre-use layer 305 at a time to selectively expose one or more tracks 303 of the sample processing device 300 as desired. In addition, in some embodiments, as shown in FIG. 16, the pre-use layer 305 can include one or more flaps (for example, one flap per lane 303) to facilitate retention of an edge of the pre-use layer 305 for removal. In some embodiments, the sample processing device 300 and / or the pre-use layer 305 can be numbered adjacent to each of the lanes 303 to clearly differentiate the lanes 303 from each other. As shown by way of example in FIG. 16, the pre-use layer 305 has been removed from track numbers 1-3 of sample processing device 300, but not from track numbers 4-8. Where the pre-use layer 305 has been removed from the sample processing device 300, a first inlet opening or port 310 designated as "SAMPLE" and a second inlet opening or port 360 designated as "R" for the reagent are revealed .
[000195] Furthermore, to further inhibit cross-contamination between lanes 303, between a reagent material handling part of a lane 303 and a sample material handling part of lane 303, and / or between the environment and the interior of the sample processing device 300, one or both of the first and second inlet openings 310 and 360 can be closed or stopped, for example, with a plug 307 such as that shown in FIG. 16. A variety of materials, shapes and constructions can be used to fill inlet openings 310 and 360, and shutter 307 is shown by way of example only as a combination shutter that can be inserted with a finger pressure into the first inlet opening 310 and second inlet opening 360. Alternatively, in some embodiments, the pre-use layer 305 can also serve as a seal or cover layer and can be reapplied to the top surface 306 of a particular lane 303 after a sample and / or reagent was loaded onto lane 303 to seal lane 303 against the environment. In such embodiments, the flap of each section of the pre-use layer 305 can be removed from the remainder of layer 305 (for example, torn along perforations) after layer 305 has been reapplied to the upper surface 306 of the corresponding lane 303. Removing the flap can inhibit any interference that may occur between the flap and any processing steps, such as the valve, disk rotation, etc. Furthermore, in such embodiments, the pre-use layer 305 can be pulled back just enough to expose the first and second inlet openings 310 and 360, and then placed back on the upper surface 306, in such a way that the pre-use layer 305 is never completely removed from the top surface 306. For example, in some embodiments, perforations or marking lines 312 between adjacent sections of the pre-use layer 305 may end in a through hole that can act as a tear switch. Such a through hole can be positioned radially outside the innermost edge of the pre-use layer 305, such that the inner part of each section of the pre-use layer 305 does not need to be completely removed from the top surface 306.
[000196] As shown in FIGS. 17, 19 and 21, in the illustrated embodiment of FIGS. 16-22, each lane 303 of the sample processing device 300 includes a sample manipulation part or side 311 of track 303 and a reagent manipulation part or side 361 of track 303, and sample manipulation part 311 and the reagent handling part 361 can be fluidly isolated from each other, until the two sides are placed in fluid communication with each other, for example, by opening one or more valves, as described below. Each lane 303 can sometimes be referred to as "a distribution system" or "processing arrangement" or, in some embodiments, each side 311, 361 of lane 303 can be indicated as a "distribution system" or "disposal arrangement" processing". In general, however, a "processing arrangement" refers to an input chamber, a detection chamber, and any fluid connections between them.
[000197] With reference to FIGS. 17, 19 and 21, the first inlet opening 310 opens to a cavity or inlet chamber 315. A similar inlet chamber 365 is located on the reagent handling side 361 of lane 303 for which the second inlet opening 360 opens up. The separate sample and reagent inlet openings 310 and 360, the inlet chambers 315 and 365, and the handling sides 311 and 361 of each lane 303 allow raw unprocessed samples to be loaded onto the sample processing device 300 to the analysis without requiring pre-processing, dilution, introduction, mixing of substances or any of them, or others. In this way, the sample and / or the reagent can be added without introduction or precise processing. As a result, sample processing device 300 can sometimes be referred to as a "moderately complex" disk, because relatively complex "on-board" processing can be performed on sample processing device 300 without requiring much or no pre-processing. processing. That is, the sample processing device 300 may include plate insertion structures that can be used to apply a selected volume of a sample and / or a reagent medium from an input chamber 315, 365 to a detection chamber 350 By applying the selected volumes to the detection chamber 350, the desired relationships between the sample and the reagent can be obtained, without requiring a user to accurately insert and load specific volumes of the sample or reagent into the sample processing device 300 Instead, the user can load a non-specific amount of sample and / or reagent into the sample processing device 300, and the sample processing device 300 itself can introduce a desired amount of materials into the detection chamber 350 The sample handling side 311 will be described first.
[000198] As shown, in some embodiments, the inlet chamber 315 may include one or more deflectors or walls or other suitable fluid-guiding structures 316 that are positioned to divide the inlet chamber 315 into at least one part, chamber or loading reservoir 318 and part, chamber or dump reservoir 320. Deflectors 316 may function to direct and / or contain fluid in the inlet chamber 315.
[000199] As shown in the illustrated embodiment, a sample can be loaded into the sample processing device 300 on one or more tracks 303 through the inlet opening 310. Once the sample processing device 300 is rotated around the axis of rotation AA, the sample must then be directed (for example, by one or more baffles 316) to the loading reservoir 318. The loading reservoir 318 is configured to hold or contain a selected volume of a material, and any excess is directed to the dump reservoir 320. In some embodiments, the inlet chamber 315, or a part thereof, can be indicated as a "first chamber" or a "first processing chamber", and the detection chamber 350 may be indicated such as a "second chamber" or a "second processing chamber".
[000200] As shown in FIGS. 21 and 22, the loading reservoir 318 includes a first end 322 positioned towards the center 301 of the sample processing device 300 and the axis of rotation AA, and a second end 324 positioned away from the center 301 and the axis of rotation AA (i.e., radially out of the first end 322), such that when, as the sample processing device 300 is rotated, the sample is forced into the second end 324 of the loading reservoir 318. One or more deflectors or walls 316 that define the second end 324 of the loading reservoir 318 may include a base 323 and a side wall 326 (e.g., a partial side wall; see FIG. 21) that are arranged to define a selected volume. Sidewall 326 is arranged and formed to allow any volume in excess of the selected volume to overflow sidewall 326 and exit towards dump reservoir 320. As a result, at least part of dump reservoir 320 can be positioned radially outward the loading reservoir 318 or the rest of the inlet chamber 315, to facilitate the movement of the additional volume of material in the dump reservoir 320 and to prevent the excess volume from moving back to the loading reservoir 318 under a directed force radially outward (for example, when the sample processing device 300 is rotated about the axis of rotation AA).
[000201] In other words, with continued reference to FIG. 21, the inlet chamber 315 may include one or more first baffles 316A which are positioned to direct material from the inlet opening 310 to the loading reservoir 318, and one or more second baffles 316B which are positioned to contain fluid from a selected volume and / or to direct fluid in excess of the selected volume to the 320 dump reservoir.
[000202] As shown, the base 323 can include an opening or fluid passage 328 formed therein that can be configured to make at least part of a capillary valve 330. As a result, the cross-sectional area of the fluid passage 328 can be small enough in relation to the loading reservoir 318 (or the volume of fluid retained in the loading reservoir 318) that the fluid is prevented from flowing into the fluid passage 328 due to capillary forces. As a result, in some embodiments, fluid passage 328 can be indicated as a "constriction" or "constricted passage".
[000203] In some embodiments, the loading reservoir 318, the dumping reservoir 320, one or more of the baffles 316 (for example, the base 323, the side wall 326, and optionally one or more first baffles 316A), and the fluid passage 328 (or capillary valve 330) can be indicated together as an "introducing structure" responsible for containing a selected volume of material, for example, which can be passed to the downstream fluid structures when desired.
[000204] For example only, when the sample processing device 300 is rotated about the axis of rotation AA at a first speed (e.g. angular speed, rpm), a first centrifugal force is exerted on the material in the device sample processing 300. The loading reservoir 318 and the fluid passage 328 can be configured (for example, in terms of surface energies, relative dimensions and cross-sectional areas, etc.) in such a way that the first centrifugal force is insufficient to cause the sample with a certain surface tension to be forced into the relatively narrow fluid passage 328. However, when the sample processing device 300 is rotated at a second speed (for example, angular speed, rpm), a second centrifugal force is exerted on the material in the sample processing device 300. The loading reservoir 318 and the fluid passage 328 g must be configured in such a way that the second centrifugal force is sufficient to cause the sample with a certain surface tension to be forced into the fluid 328. Alternatively, additives (eg surfactants) can be added to the sample to change the its surface tension to cause the sample to flow into the fluid passage 328 when desired. In some embodiments, the first and second forces can be at least partially controlled by controlling the acceleration profiles and the speeds at which the sample processing device 300 is rotated at different processing stages. Such speeds and accelerations are described in more detail with respect to FIG. 26.
[000205] In some embodiments, the aspect ratio of an area in cross section of the fluid passage 328 in relation to a volume of the inlet chamber 315 (or a part of it, such as the loading reservoir 318) can be controlled to at least partially ensure that the fluid will not flow into the fluid passage 328 until it is desired, for example, for a fluid with a certain surface tension.
[000206] For example, in some embodiments, the relationship between the cross-sectional area of the fluid passage (Ap) (for example, at the entrance of the fluid passage 328 at the base 323 of the loading reservoir 318) and the volume (V ) of the reservoir (for example, the inlet chamber 315, or a part of it, such as the loading reservoir 318) from which the fluid can move to the fluid passage 328, i.e. AP: V, may vary from about 1:25 to about 1: 500, in some embodiments it can range from about 1:50 to about 1: 300, and in some embodiments it can range from about 1: 100 to about 1: 200. In another way, in some modalities, the Ap / V fraction can be at least about 0.01, in some modalities at least about 0.02, and in some modalities at least about 0, 04. In some modalities, the Ap / V fraction may be no greater than about 0.005, in some modalities no greater than about 0.003, and in some modalities no greater than about 0.002. Still indicated in another way, in some modalities, the fraction of V / Ap, or the relation between V and Ap, can be at least about 25 (that is, 25 to 1), in some modalities of at least about 50 (that is, about 50 to 1), and in some embodiments at least about 100 (that is, about 100 to 1). In some modalities, the fraction of V / Ap, or the ratio between V and Ap, can be no greater than about 500 (that is, about 500 to 1), in some modalities no greater than about 300 ( that is, about 300 to 1), and in some embodiments no greater than about 200 (that is, about 200 to 1).
[000207] In some embodiments, these relationships can be obtained by employing various dimensions in the fluid passage 328. For example, in some embodiments, the fluid passage 328 may have a transverse dimension (for example, perpendicular to its length along a radius from the center 101, such as a diameter, width, depth, thickness, etc.) of no more than about 0.5 mm, in some embodiments of no more than about 0.25 mm, and in some embodiments of no more than about 0.1 mm. In some embodiments, the cross-sectional area Ap of the fluid passage 328 may be no greater than about 0.1 mm2, in some embodiments no greater than about 0.075 mm2, and in some embodiments no greater than about 0.5 mm2. In some embodiments, the fluid passage 328 may be at least about 0.1 mm in length, in some embodiments at least about 0.5 mm, and in some embodiments at least about 1 mm. In some embodiments, fluid passage 328 may be no more than about 0.5 mm in length, in some embodiments no more than about 0.25 mm, and in some embodiments no more than about 0.1 mm. In some embodiments, for example, fluid passage 328 can be about 0.25 mm wide, about 0.25 mm deep (i.e., a cross-sectional area of about 0.0625 mm2) and a length of about 0.25 mm.
[000208] As shown in FIGS. 17, 19, 21 and 22, the capillary valve 330 can be located in fluid communication with the second end 324 of the loading reservoir 318, such that the fluid passage 328 is positioned radially out of the loading reservoir 318, in with respect to the axis of rotation AA. Capillary valve 330 can be configured to prevent fluid (i.e. liquid) from moving from the loading reservoir 318 to the fluid passage 328, depending on at least one of the dimensions of the fluid passage 328, the surface energy of the surfaces that define the loading reservoir 318 and / or the fluid passage 328, the surface tension of the fluid, the force exerted on the fluid, any back pressure that may exist (for example, as a result of a retention of vapor formed downstream, such as as described below), and their combinations. As a result, fluid passage 328 (for example, constriction) can be configured (for example, sized) to prevent fluid from entering the valve chamber 334 until a force exerted on the fluid (for example, by rotating the sample processing device 300 around the axis of rotation AA), the surface tension of the fluid, and / or the surface energy of the fluid passage 328 is sufficient to move the fluid beyond the fluid passage 328.
[000209] As shown in the illustrated embodiment, capillary valve 330 can be arranged in series with a septum valve 332, such that capillary valve 330 is positioned radially into the septum valve 332 and in fluid communication with a septum valve inlet 332. septum valve 332 may include a valve chamber 334 and a septum 336 of the valve. In a given orientation (for example, substantially horizontal) on a turntable, the capillary force can be balanced and displaced by the centrifugal force to control fluid flow. The septum valve 332 (also sometimes referred to as a "phase change type valve") can be receptive to a heat source (for example, electromagnetic energy) that can cause the septum 336 of the valve to melt to open a through the valve septum 336.
[000210] The septum 336 can be located between the valve chamber 334 and one or more fluid structures downstream in the sample processing device 300. In this way, the detection chamber 350 can be in fluid communication with a valve outlet. septum 332 (i.e., the valve chamber 334) and can be positioned at least partially radially out of the valve chamber 334, relative to the axis of rotation AA and the center 301. The septum 336 can include (i) a closed configuration in which the septum 336 is impermeable to fluids (and in particular to liquids), and positioned to fluidly isolate the valve chamber 334 from all downstream fluid structures; and (ii) an open configuration in which the septum 336 is permeable to fluids, in particular liquids (for example, includes one or more openings sized to encourage the sample to flow through it) and allows fluid communication between the chamber 334 valve and all downstream fluid structures. That is, the valve septum 336 can prevent fluids (i.e., liquids) from moving between the valve chamber 334 and all fluid structures downstream when it is intact.
[000211] Various characteristics and details of the valve structure and process are described in US Patent Applications No. 61 / 487,669, filed on May 18, 2011, and No. 61 / 490,012, filed on May 25, 2011, each of which is incorporated herein by reference in its entirety.
[000212] The septum 336 of the valve may include or be formed by an impermeable barrier that is opaque or absorbs electromagnetic energy, such as electromagnetic energy in the visible, infrared and / or ultraviolet spectra. As used in connection with the present invention, the term "electromagnetic energy" (and its variations) refers to electromagnetic energy (regardless of wavelength / frequency) that can be applied by a source to a location or material desired in the absence of physical contact. Non-limiting examples of electromagnetic energy include laser energy, radio frequency (RF), microwave radiation, light energy (including the spectrum from infrared to ultraviolet), etc. In some embodiments, electromagnetic energy may be limited to energy that falls within the spectrum of ultraviolet to infrared radiation (including the visible spectrum).
[000213] The valve septum 336, or a part thereof, may be distinct from substrate 302 (for example, made of a material that is different from the material used for substrate 302). Using different materials for substrate 302 and valve septum 336, each material can be selected for its desired characteristics. Alternatively, the valve septum 336 can be integral with the substrate 302 and made of the same material as the substrate 302. For example, the valve septum 336 can simply be molded into the substrate 302. If this is done, it can be coated or impregnated to enhance its ability to absorb electromagnetic energy.
[000214] The septum 336 of the valve can be made of any suitable material, although it can be particularly useful if the material of the septum 336 forms empty spaces (that is, when the septum 336 is opened) without the production of any by-products, waste, etc. significant that can interfere with the reactions or processes that occur in the sample processing device 300. An example of a class of materials that can be used as valve septum 336, or a part thereof, includes pigmented oriented polymeric films such as, for example, films used in the manufacture of commercially available can liners or bags. A suitable film can be a 1.18 mil thick black tin liner, available from Himolene Incorporated, Danbury, Connecticut under the designation 406230E. However, in some embodiments, the septum 336 may be formed of the same material as the substrate 302 itself, but may be less thick than other parts of the substrate 302. The thickness of the septum can be controlled by the mold or tool used to form the substrate 302 in such a way that the septum must be thin enough to be opened sufficiently to absorb the energy of an electromagnetic signal.
[000215] In some embodiments, the septum 336 of the valve may have a cross-sectional area of at least about 1 mm2, in some embodiments of at least about 2 mm2, and in some embodiments of at least about 5 mm2. In some embodiments, the valve septum 336 may have a cross-sectional area of no more than about 10 mm2, in some embodiments of no more than about 8 mm2, and in some embodiments of no more than about 6 mm2.
[000216] In some embodiments, the valve septum 336 can be at least about 0.1 mm thick, in some embodiments at least about 0.25 mm, and in some embodiments at least about 0, 4 mm. In some embodiments, the valve septum 336 may have a thickness of no more than about 1 mm, in some embodiments of no more than about 0.75 mm, and in some embodiments of no more than about 0 mm , 5 mm.
[000217] In some embodiments, the valve septum 336 may have a generally circular shape, may have a diameter of about 1.5 mm (that is, a cross-sectional area of about 5.3 mm2), and a thickness of about 0.4 mm.
[000218] In some embodiments, the valve septum 336 may include a material capable of absorbing electromagnetic energy of selected wavelengths and converting that energy to heat, resulting in the formation of an empty space in the valve septum 336. The absorbent material can be contained within the septum 336 of the valve, or part of it (for example, impregnated in the material (resin) that forms the septum), or be coated on a surface thereof. For example, as shown in FIG. 20, the valve septum 336 can be configured to be radiated with electromagnetic energy from top to bottom (i.e., on the top surface 306 of substrate 302). As a result, the first layer 304 over the valve septum region (see FIG. 16) can be transparent to the selected wavelength, or the range of wavelengths, of the electromagnetic energy used to create an empty space in the septum 336 of the valve, and the valve septum 336 can absorb such wavelength (s).
[000219] Capillary valve 330 is shown in the embodiment illustrated in FIGS. 16-22 as connected in series with the septum valve 332, and in particular, as connected upstream and in fluid communication with an inlet or an upstream end of the septum valve 332. Such a configuration of the capillary valve 330 and the septum 332 can create a vapor trap (i.e., in the valve chamber 334) when the septum 336 of the valve is in the closed configuration and a sample is moved and pressures are developed in the sample processing device 300. Such a configuration can also allow a user to control when the fluid (i.e. liquid) can enter the valve chamber 334 and be collected adjacent the valve septum 336 (for example, by controlling the speed at which the sample processing device 300 is rotated, which affects the centrifugal force exerted on the sample, for example, when the surface tension of the sample remains constant; and / or when controlling the surface tension of the sample). That is, capillary valve 330 can prevent fluid (i.e. liquids) from entering the valve chamber 334 and being pooled or collected adjacent to the valve septum 336 before opening the septum valve 332, that is, when the septum 336 of the valve is in the closed configuration.
[000220] Capillary valve 330 and septum valve 332 can, together or separately, be indicated as a "valve" or "valve structure" of the sample processing device 300. That is, the valve structure of the device sample processing method 300 is generally described above as including a capillary valve and a septum valve; however, it should be understood that, in some embodiments, the valve or valve structure of the sample processing device 300 can simply be described as including the fluid passage 328, the valve chamber 334, and the valve septum 336 . In addition, in some embodiments, the fluid passage 328 can be described as forming a part of the inlet chamber 315 (for example, as forming a part of the loading reservoir 318), such that the downstream end 324 includes a fluid passage 328 which is configured to prevent fluid from entering the valve chamber 334 until desired.
[000221] By preventing fluid (i.e. liquid) from being collected adjacent to one side of the valve septum 336, the valve septum 336 can be opened, that is, have the shape changed from a closed configuration to an open configuration , without the interference of another matter. For example, in some embodiments, the valve septum 336 can be opened by forming an empty space in the valve septum 336 by directing electromagnetic energy of an appropriate wavelength on one side of the valve septum 336 (for example, on the surface higher than 306 of sample processing device 300). The authors of the present invention have found that, in some cases, if the liquid is collected on the opposite side of the valve septum 336, the liquid can interfere with the process of empty space formation (for example, melting) by functioning as a heat sink for electromagnetic energy, which can increase the energy and / or time needed to form an empty space in the valve septum 336. As a result, by preventing fluid (i.e. liquid) from being collected adjacent to one side of the valve septum 336, the valve septum 336 can be opened by directing electromagnetic energy on a first side of the valve septum 336 when none fluid (for example, a liquid, such as a sample or a reagent) is present on a second side of the valve septum 336. By preventing fluid (eg, liquid) from collecting at the rear side of the valve septum 336, the septum valve 332 can be reliably opened through a variety of valve conditions, such as laser power (eg , 440, 560, 670, 780 and 890 milliwatts (mW)), the width or duration of the laser pulse (for example, 1 or 2 seconds), and the number of laser pulses (for example, 1 or 2 pulses ).
[000222] As a result, capillary valve 330 works to (i) effectively form a closed end of loading reservoir 318 so that a selected volume of a sample can be introduced and passed to the detection chamber 350 downstream, and ( ii) effectively prevent fluids (eg liquids) from being collected adjacent to one side of the valve septum 336 when the valve septum 336 is in its closed configuration, for example, by creating a vapor trap in the chamber 334 of the valve valve.
[000223] In some embodiments, the valve structure may include a longitudinal direction oriented substantially radially to the center 301 of the sample processing device 300. In some embodiments, the valve septum 336 may include a length that extends in the direction longitudinal greater than the dimensions of one or more opening or voids that can be formed in the valve septum 336, such that one or more openings can be formed along the length of the valve septum 336 as desired. That is, in some embodiments, it may be possible to remove the selected aliquots from a sample by forming openings at selected locations along the length in the valve septum 336. The selected volume of the aliquot can be determined based on the radial distance between the openings (for example, measured in relation to the axis of rotation A-A) and the cross-sectional area of the valve chamber 334 between openings. Other modalities and details of such a "variable valve" can be found in U.S. Patent No. 2010/0167304 and in U.S. Patent Application Publication No. 7,322,254.
[000224] After an opening or an empty space has been formed in the valve septum 336, the valve chamber 334 is in fluid communication with the downstream fluid structures, such as the detection chamber 350, through the empty space in the septum 336 of the valve. As mentioned above, after a sample has been loaded on the sample handling side 311 of lane 303, the first inlet opening 310 can be closed, sealed and / or closed. In this way, the sample processing device 300 can be sealed from the environment or "no flow" during processing.
[000225] As used in connection with the present invention, a "flow-free processing arrangement" or "flow-free distribution system" is a distribution system (i.e., "processing chamber arrangement", "processing arrangement" , or "track" 303) in which the only openings leading to the volume of fluid structures present therein are located in the inlet chamber 315 for the sample (or in the inlet chamber 365 for the reagent). In other words, to reach the detection chamber 350 within the dispensing system without flow, the sample (and / or reagent) materials are passed to the inlet chamber 315 (or the inlet chamber 365), and the chamber inlet 315 is subsequently sealed from the environment. As shown in FIGS. 16-22, such a flowless delivery system may include one or more dedicated channels for transferring the sample materials to the detection chamber 350 (for example, in a downstream direction) and one or more dedicated channels to allow air or other fluids leave the detection chamber 350 through a path separate from that in which the sample is moving. On the other hand, a flow-free distribution system must be open to the environment during processing and also likely to include air vents positioned at one or more locations along the distribution system, such as in the vicinity of the detection chamber 350. As mentioned above, the flowless delivery system inhibits contamination between an environment and the interior of the sample processing device 300 (for example, the leakage of the sample processing device 300, or the introduction of contaminants from an environment or a user on the sample processing device 300), and also prevents cross-contamination between multiple samples or lanes 303 on a sample processing device 300.
[000226] As shown in FIGS. 17, 19 and 21, to facilitate the flow of fluid in the sample processing device 300 during processing, lane 303 may include one or more balancing channels 355 positioned to fluidly couple a part downstream or radially out of the lane 303 (for example, the detection chamber 350) with one or more fluid structures that are upstream or radially into the detection chamber 350 (for example, at least a part of the inlet chamber 315, at least a part inlet chamber 3654 on reagent handling side 361, or both).
[000227] Just by way of example, each lane 303 of the illustrated sample processing device 300, as shown in FIGS. 20 and 21, includes an equilibrium channel 355 positioned to fluidly couple the detection chamber 350 with an upstream part, or radially inward (i.e., relative to the center 301) of the reagent inlet chamber 365 on the side handling reagent 361 from lane 303. Balance channel 355 is an additional channel that allows upstream movement of the fluid (eg gases, such as trapped air) or trapped steam downstream of parts of the fluid to facilitate movement downstream of another fluid (eg, a sample material, liquids, etc.) to these other vapor trapped regions of the sample processing device 300. Such a balance channel 355 allows the fluid structures in the sample processing device 300 remain empty or closed to the environment during sample processing, that is, during the movement of fluid in the sample processing device 300. As a result, in some but modalities, the balance channel 355 can be indicated as an "internal exhaust" or an "exhaust channel", and the process of releasing the trapped fluid to facilitate the movement of the material can be indicated as "internal flow".
[000228] Indicated in another way, in some embodiments, the flow of a sample (or reagent) from an inlet chamber 315 (or from the reagent inlet chamber 365) to the detection chamber 350 can define a first direction of movement, and the balance channel 355 can define a second direction of movement that is different from the first direction. In particular, the second direction is opposite, or substantially opposite, to the first direction. When a sample (or reagent) is moved into the detection chamber 350 by a force (for example, the centrifugal force), the first direction can be oriented generally along the direction of the force, and the second direction can be oriented generally opposite to the direction of the force.
[000229] When the valve septum 336 is switched to the open configuration (for example, by emitting electromagnetic energy in the septum 336), the vapor retention in the valve chamber 334 may be released, at least in part because of the connection of the balance channel 355 at the downstream side of the septum 336 back to the inlet chamber 365. The release of the vapor retention may allow the fluid (e.g. liquid) to flow into the fluid passage 328 to the valve chamber 334 , and for the detection chamber 350. In some embodiments, this phenomenon can be facilitated when the channels and chambers are hydrophobic, or in general defined by hydrophobic surfaces. This is, in some embodiments, the substrate 302 and any covers or layers 304, 305, and 308 (or adhesives coated thereon, for example, comprising silicone and polyurea) that at least partially define the channel, and the chambers can be formed from hydrophobic materials or include hydrophobic surfaces, particularly in comparison to samples and / or aqueous reagent materials.
[000230] In some embodiments, the hydrophobic capacity of a material surface can be determined by measuring the angle of contact between a drop of a liquid of interest and the surface of interest. In the present case, such measurement can be made between various materials in the sample and / or the reagent and a material that is used in the formation of at least some surface of a sample processing device that must come in contact with the sample and / or the reagent. In some embodiments, the sample and / or reagent materials may be aqueous liquids (for example, suspensions, or the like). In some embodiments, the contact angle between a sample and / or a reagent of the present invention and a substrate material that make up at least part of the sample processing device 300 may be at least about 70 °, in some embodiments at least about 75 °, in some embodiments of at least about 80 °, in some embodiments of at least about 90 °, in some embodiments of at least about 95 °, and in some embodiments of at least about 99 °.
[000231] In some embodiments, the fluid may flow into the fluid passage 328 when sufficient force is exerted on the fluid (for example, when a limit force on the fluid is obtained, for example, when the rotation of the fluid processing device 300 samples around the axis of rotation AA exceeds a limit acceleration or the acceleration of rotation). After the fluid has overcome the capillary forces at the capillary valve 330, the fluid can flow through the open septum 336 of the valve to the downstream fluid structures (e.g., the sensing chamber 350).
[000232] As discussed throughout the present invention, the surface tension of the sample and / or the reagent material being moved through the sample processing device 300 can affect the amount of force required to move that material into the passage fluid 328 and overcome capillary forces. In general, the lower the surface tension of the material being moved through the sample processing device 300, the lower the force exerted on the material in order to overcome capillary forces. In some embodiments, the surface tension of the sample and / or reagent material may be at least about 40 mN / m, in some embodiments at least about 43 mN / m, in some embodiments at least about 45 mN / m, in some modalities of at least about 50 mN / m, and in some modalities of at least about 54 mN / m. In some modalities, the surface tension may be no greater than about 80 nM / m, in some modalities no greater than about 75 mN / m, in some modalities no greater than about 72 mN / m, in some modalities modalities not greater than about 70 mN / m, and in some modalities not greater than about 60 mN / m.
[000233] In some embodiments, the density of the sample and / or reagent material being moved through the sample processing device 300 may be at least about 1.00 g / ml, in some embodiments at least about 1.02 g / ml, and in some embodiments at least about 1.04 g / ml. In some embodiments, the density may be no greater than about 1.08 g / ml, in some embodiments no greater than about 1.06 g / ml, and in some embodiments no greater than about 1.05 g / ml.
[000234] In some embodiments, the viscosity of the sample and / or reagent material being moved through the sample processing device can be at least about 0.001 Pa.s (1 centipoise - nMs / m2), in some modalities of at least about 0.0015 Pa.s (1.5 centipoise), and in some modalities of at least about 0.00175 Pa.s (1.75 centipoise). In some modalities, the viscosity may be no greater than about 0.0025 Pa.s (2.5 centipoises), in some modalities no greater than about 0.00225 Pa.s (2.25 centipoises), and in some modalities no greater than about 0.002 Pa.s (2.00 centipoises). In some embodiments, the viscosity can be 0.0010019 Pa.s (1.0019 centipoise) or 0.002089 Pa.s (2.089 centipoises).
[000235] The following table includes various data for the aqueous media that can be employed in the present invention, both as sample diluents and / or as reagents. An example is the Copan Universal Transport Media ("UTM") medium for viruses, Chlamydia, Mycoplasma, and Ureaplasma, 3.0 ml tube, part number 330C, lot 39P505 (Copan Diagnostics, Murrietta, GA). This UTM is used as a sample in the examples. Another example is a main reagent mixture ("Reagent"), available from Focus Diagnostics (Cypress, CA). The viscosity and density data for water at 25 ° C and 25% glycerol in water are included in the following table, because some sample and / or reagent materials of the present invention may have material properties that vary with respect to to those in water to that of 25% glycerol in water, inclusive. The contact angle measurements in the table below were made in black polypropylene, which was formed by combining, in the press, the product No. P4G3Z-039 Polypropylene, natural, from Flint Hills Resources (Wichita, Kansas) with Clariant Colorant UN0055P, Deep Black (carbon black), 3% LDR, available from Clariant Corporation (Muttenz, Switzerland). This black polypropylene can be used in some embodiments to form at least a part (for example, substrate 302) of a sample processing device of the present invention (for example, the sample processing device 300).

[000236] The moving sample material within the sample processing devices that include flow-free distribution systems can be facilitated by alternately accelerating and decelerating the device during rotation, essentially expelling the sample materials through the various channels and chambers. Rotation can be performed by using at least two acceleration / deceleration cycles, that is, an initial acceleration, followed by deceleration, a second round of acceleration, and a second round of deceleration.
[000237] Acceleration / deceleration cycles may not be necessary in the modalities of processing devices (for example, the sample processing device 300) that include distribution systems with balance channels such as the balance channel 355. The channel Equilibrium 355 can help prevent air or other fluids from interfering with the flow of sample materials through fluid structures. The balance channel 355 can provide passages for displaced air or other fluids to exit the detection chamber 350 to balance the pressure within the distribution system, which can minimize the need for acceleration and / or deceleration to "expel" the system of distribution. However, the acceleration and / or deceleration technique can still be used to further facilitate the distribution of the sample materials through the flow-free distribution system. The acceleration and / or deceleration technique can also be useful to assist in the movement of liquids on and / or around uneven surfaces such as the rough edges created by the EM-induced valve, imperfect molded channels / chambers, etc.
[000238] It can also be useful if the acceleration and / or deceleration are fast. In some embodiments, the rotation may only be in one direction, that is, it may not be necessary to reverse the direction of rotation during the loading process. Such a loading process allows the sample materials to displace air in those parts of the system that are located further away from the center 301 of rotation of the sample processing device 300 than the opening (s) in the system.
[000239] Actual rates of acceleration and deceleration may vary based on a variety of factors such as temperature, device size, sample material distance from the axis of rotation, materials used to manufacture the devices, properties sample materials (eg viscosity), etc. An example of a useful acceleration / deceleration process may include an initial acceleration at about 4,000 revolutions per minute (rpm), followed by deceleration at around 1,000 rpm for a period of about 1 second, with fluctuations in the speed of rotation of the device between 1,000 rpm and 4,000 rpm at 1 second intervals until the sample materials have moved the desired distance.
[000240] Another example of a useful loading process may include an initial acceleration of at least about 20 revolutions / s2 for the first rotation speed of about 500 rpm, followed by a 5 second hold at the first rotation speed , followed by a second acceleration of at least about 20 revolutions / s2 to a second rotation speed of about 1,000 rpm, followed by a 5 second hold at the second rotation speed. Another example of a useful loading process may include an initial acceleration of at least about 20 revolutions / s2 to a rotation speed of about 1,800 rpm, followed by a 10 second hold at that rotation speed.
[000241] As shown in FIGS. 20 and 21, the balance channel 355 may be formed by a series of channels on the upper surface 306 and / or on the lower surface 309 of the substrate 302, and one or more pathways extending between the upper surface 306 and the lower surface 309 , which can help traverse the staggered parts on the upper surface 306 of the substrate 302. Specifically, as shown in FIG. 20, the illustrated balance channel 355 includes a first channel or part 356 that extends along the upper surface 306 of the outermost step 313; a first track 357 extending from the upper surface 306 to the lower surface 309 to prevent the balance channel 355 from traversing the staggered portion of the upper surface 306; and a second channel or part 358 (see FIG. 21) which extends radially into the entrance chamber 365.
[000242] Air or other fluid within the detection chamber 350 can be displaced when the detection chamber 350 receives a sample material or another material. The balance channel 355 can provide a passage for the displaced air or the other displaced fluid to pass out of the sensing chamber 350. The balance channel 355 can assist in more efficient movement of the fluid through the sample processing device 300 with the pressure balance within each distribution system of the sample processing device 300 (for example, the inlet chamber 315 and the detection chamber 350, and the various channels connecting the inlet chamber 315 and the detection chamber 350) allowing some channels of the distribution system to be dedicated to the flow of a fluid in one direction (for example, an upstream or downstream direction). In the embodiment illustrated in FIGS. 16-22, the sample generally flows downstream and radially outward (for example, when the sample processing device 300 is rotated around the center 301) from the inlet chamber 315, through the capillary valve 330 and the septum 332, and through the distribution channel 340, to the detection chamber 350. The other fluid (for example, the gases present in the detection chamber 350) can generally flow upstream or radially inward, that is, in a way general as opposed to the direction of movement of the sample, from the detection chamber 350, through the balance channel 355, to the entrance chamber 365.
[000243] Returning to the valve structure, the downstream side of the valve septum 336 (i.e., which faces the upper surface 306 of the illustrated sample processing device 300; see FIGS. 20 and 22) faces and eventually opens (for example, after an opening or an empty space is formed in the septum 336 of the valve) to a distribution channel 340 that fluidly couples the valve chamber 334 (and finally the inlet chamber 315 and in in particular the loading reservoir 318) and the detection chamber 350. Similar to the balance channel 355, the distribution channel 340 can be formed from a series of channels on the upper surface 306 and / or on the lower surface 309 of the substrate 302 and one or more pathways extending between the upper surface 306 and the lower surface 309, which can help to pass through the staggered parts on the upper surface 306 of the substrate 302. For example, as shown in FIGS. 20-22, in some embodiments, the delivery channel 340 may include a first channel or part 342 (see FIGS. 20 and 22) that extends along the upper surface 306 of the middle step 313 of the substrate 302; a first path 344 (see FIGS. 20-22) extending from the upper surface 306 to the lower surface 309; a second channel or part 346 (see FIGS. 21 and 22) which extends along the lower surface 309 to prevent crossing the stepped upper surface 306; a second path 347 (see FIGS. 20-22) that extends from the lower surface 309 to the upper surface 306, and a third channel or part 348 (see FIGS. 20 and 22) that extends along the upper surface 306 and empties into the detection chamber 350.
[000244] All layers and covers are removed from the sample processing device 300 in FIGS. 18-22 for simplicity purposes, such that substrate 302 is shown alone; however, it should be understood that any channels and chambers formed on the lower surface 309 can also be defined at least partially by the second layer (s) 308, and that any channels and chambers formed on the upper surface 306 can also be defined be defined at least partially by the first layer (s) 304, as shown in FIGS. 16-17.
[000245] A force can be exerted on a sample to cause it to move from the inlet chamber 315 (ie, the loading reservoir 318), through the passage of fluid 328, to the chamber 334 of the valve, through an empty space in the valve septum 336, along the distribution channel 340, and towards the detection chamber 350. As mentioned above, such force can be the centrifugal force that can be generated while the sample processing device is rotated 300, for example, around the axis of rotation AA, to move the sample radially out of the axis of rotation Aa (that is, because at least part of the detection chamber 350 is located radially out of the inlet chamber 315) . However, such a force can also be established by a pressure differential (for example, positive and / or negative pressure), and / or by the gravitational force. Under appropriate force, the sample can pass through various fluid structures, including pathways, to finally reside in the detection chamber 350. In particular, a selected volume, as controlled by the loading reservoir 318 (i.e., the deflectors 316 and the dump reservoir 320), the sample will be moved to the detection chamber 350 after the septum valve 332 is opened and sufficient force is exerted on the sample to move the sample through the fluid passage 328 of the capillary valve 330.
[000246] In the embodiment illustrated in FIGS. 16-22, the valve septum 336 is located between the valve chamber 334 and the detection (or processing) chamber 350, and in particular is located between the valve chamber 334 and the distribution channel 340 leading to the chamber of detection 350. Although the distribution channel 340 is shown by way of example only, it should be understood that, in some embodiments, the valve chamber 334 can open directly in the detection chamber 350, such that the septum 336 of the valve it is positioned directly between the valve chamber 334 and the detection chamber 350.
[000247] The 361 of lane 303 can be configured substantially similarly to that of the sample handling side 311 of lane 303. Therefore, any of its details, characteristics or alternatives to the characteristics of the sample handling side 311 described above can be extended to the characteristics of the reagent handling side 361. As shown in FIGS. 17, 19 and 21, reagent handling side 361 includes the second inlet opening 360 that opens into the inlet chamber or cavity 365. As shown, in some embodiments, the inlet chamber 365 may include one or more baffles or walls 366 or other suitable fluid directing structures which are positioned to divide the inlet chamber 365 into at least a part, chamber, or loading reservoir 368 and a part, chamber or dump reservoir 370. Deflectors 366 can operate to direct and / or contain fluid in the inlet chamber 365. As shown in the illustrated embodiment, a reagent can be loaded onto the sample processing device 300 on the same track 303 as the corresponding sample through the inlet opening 360. In In some embodiments, the reagent may include a cocktail of complete reagent or master mix that can be loaded at the desired time for a given run. However, in some embodiments, the reagent may include multiple portions that are loaded at different times, as needed for a particular assay. Particular advantages have been observed where the reagent is in the form of a test cocktail or main mixture, in such a way that all enzymes, fluorescent labels, probes, and others, which are necessary for a particular test can be loaded (for example, by a non-expert user) at once and subsequently measured and distributed (by the sample processing device 300) to the sample where appropriate.
[000248] After the reagent is loaded into the sample processing device 300, the sample processing device 300 can be rotated around the axis of rotation AA, directing (for example, by one or more baffles 366) the reagent to the loading reservoir 368. The loading reservoir 368 is configured to hold or contain a selected volume of a material, and any excess is directed to the dumping reservoir 370. In some embodiments, the inlet chamber 365, or a part of it , can be indicated as a "first chamber", a "first processing chamber", and the detection chamber 350 can be indicated as a "second chamber" or a "second processing chamber".
[000249] As shown in FIG. 21, the loading reservoir 368 includes a first end 372 positioned towards the center 301 of the sample processing device 300 and the axis of rotation AA, and a second end 374 positioned away from the center 301 and the axis of rotation AA ( that is, radially out of the first end 372), such that as the sample processing device 300 is rotated, the reagent is forced to the second end 374 of the loading reservoir 368. One or more deflectors or walls 366 that defining the second end 374 of the loading reservoir 368 may include a base 373 and a side wall 376 (for example, a partial side wall) which are arranged to define a selected volume. Sidewall 376 is arranged and formed to allow any volume in excess of the selected volume to overflow sidewall 376 and exits into dump reservoir 370. As a result, at least part of dump reservoir 370 can be positioned radially out of the loading reservoir 368 or the remainder of the inlet chamber 365, to facilitate the movement of the additional volume of material in the dump reservoir 370 and to prevent the additional volume from moving back to the loading reservoir 368 when the processing device of samples 300 is rotated.
[000250] In other words, with continued reference to FIG. 21, inlet chamber 365 may include one or more first baffles 366A which are positioned to direct material from inlet opening 360 to loading reservoir 368, and one or more second baffles 366B which are positioned to contain fluid from a volume selected and / or to direct the fluid in excess of the selected volume to the 370 dump reservoir.
[000251] As shown, the base 373 can include an opening or fluid passage 378 formed therein that can be configured to form at least part of a capillary valve 380. Capillary valve 380 and loading reservoir 368 can function in the same way as the capillary valve 330 and the loading reservoir 318 on the sample handling side 311 of the lane 303. In addition, the aspect ratios of the fluid passage 378, and their ranges, may be the same as those described above with respect to capillary valve 330.
[000252] As shown in FIGS. 17, 19 and 21, in some embodiments, the reagent loading reservoir 368 can be configured to retain a larger volume than the sample loading reservoir 318. As a result, a desired (and relatively smaller) sample volume required for a particular assay can be retained by the sample loading reservoir 318 and sent downstream (for example, through valve structure 330, 332 and distribution channel 340) to the detection chamber 350 for processing, and a desired volume ( and relatively larger) of the reagent needed for a particular assay (or a step thereof) can be retained by reagent loading reservoir 368 and sent downstream to detection chamber 350 for processing through the structures that will now be described.
[000253] Similar to the sample handling side 311, the capillary valve 380 on the reagent handling side 361 can be arranged in series with a septum valve 382. The septum valve 382 can include a valve chamber 384 and a septum 386 of the valve. As described above with respect to septum 336, septum 386 can be located between the valve chamber 384 and one or more fluid structures downstream in the sample processing device 300, and septum 386 can include a closed configuration and a open configuration, and can prevent fluids (i.e. liquids) from moving between the valve chamber 384 and any fluid structures downstream when intact.
[000254] The valve septum 386 can include or be formed from any of the materials described above with respect to the valve septum 336, and can be configured and operated similarly. In some embodiments, the septum 386 of the reagent valve may be susceptible to a wavelength or a wavelength range of electromagnetic energy different from that of the septum 336 of the sample valve, but in some embodiments the two septa 336 and 386 of the valve can be substantially the same and susceptible to the same electromagnetic energy, in such a way that an energy source (e.g., a laser) can be used to open all valves 330 and 380 of the septum in the sample processing device 300.
[000255] After an opening or an empty space has been formed in the valve septum 386, the valve chamber 384 is in fluid communication with the downstream fluid structures, such as the detection chamber 350, through the empty space in the septum 386 of the valve, where the reagent can be combined with the sample. After a reagent has been loaded on the reagent handling side 361 of lane 303, the second inlet opening 360 can be closed, sealed and / or closed. In this way, the sample processing device 300 can be sealed from the environment or "not exhaled" during processing.
[000256] In the embodiment illustrated in FIGS. 16-22, the same balance channel 355 can facilitate the movement of the fluid in a downstream direction on both the sample handling side 311 and the reagent handling side 361 to assist in the movement of the sample and reagent into the chamber detection 350, which can occur simultaneously or at different times.
[000257] The downstream side of the valve septum 386 (ie, which faces the upper surface 306 of the illustrated sample processing device 300; see FIG. 20) faces and opens eventually (for example, after that an opening or void is formed in the valve septum 336) for a distribution channel 390 fluidly coupling the valve chamber 384 (and finally, the inlet chamber 365 and in particular the loading reservoir 368) and detection chamber 350. Similar to balance channel 355 and sample distribution channel 340, distribution channel 390 may be formed by a series of channels on the upper surface 306 and / or the lower surface 309 of the substrate 302 , and one or more pathways extending between the upper surface 306 and the lower surface 309, which can assist in crossing staggered parts on the upper surface 306 of the substrate 302. For example, as shown in FIGS. 20 and 21, in some embodiments, the distribution channel 390 may include a first channel or part 392 (see FIG. 20) that extends along the upper surface 306 of the middle step 313 of the substrate 302; a first path 394 (see FIGS. 20 and 21) extending from the upper surface 306 to the lower surface 309; a second channel or part 396 (see FIG. 21) that extends along the lower surface 309 to prevent crossing the stepped upper surface 306; a second path 397 (see FIGS. 20 and 21) that extends from the lower surface 309 to the upper surface 306, and a third channel or part 398 (see FIG. 20) that extends along the upper surface 306 and empties in the detection chamber 350.
[000258] A force can be exerted on a reagent to cause it to move from the inlet chamber 365 (that is, the loading reservoir 368), through the passage of fluid 378, to the chamber 384 of the valve, through a valve void in the valve septum 386, along the distribution channel 390, and to the detection chamber 350, where the reagent and a sample can be combined. As mentioned above, such a force can be the centrifugal force that can be generated while the sample processing device 300 is rotated, for example, around the axis of rotation AA, but such force can also be established by a pressure differential (for example, positive and / or negative pressure), and / or by gravitational force. Under appropriate force, the reagent can pass through various fluid structures, including pathways, to finally reside in the detection chamber 350. In particular, a selected volume, as controlled by the loading reservoir 368 (i.e., and deflectors 366 and the dump reservoir 370), of the reagent will be moved to the detection chamber 350 after the septum valve 382 is opened and sufficient force is exerted on the reagent to move the reagent through the fluid passage 378 of the capillary valve 380.
[000259] In the embodiment illustrated in FIGS. 16-22, the valve septum 386 is located between the valve chamber 384 and the detection (or processing) chamber 350, and in particular is located between the valve chamber 384 and the distribution channel 390 leading to the chamber of detection 350. Although the distribution channel 390 is shown by way of example only, it should be understood that, in some embodiments, the valve chamber 384 may open directly to the detection chamber 350, in such a way that the septum 386 of the valve is positioned directly between the valve chamber 384 and the detection chamber 350. In addition, in some embodiments, neither the sample distribution channel 340 nor the reagent distribution channel 390 is employed, or only one of the distribution channels 340, 390 is employed, instead of both, as illustrated in the embodiment of FIGS. 16-22.
[000260] Sample processing device 300 was used in Examples 2 and 3 and in FIG. 31.
[000261] FIG. 23 illustrates a track 403 of another sample processing device 400 according to another embodiment of the present invention, wherein the same numerals represent the same elements. The sample processing device 400 shares many of the same elements and characteristics described above with reference to the illustrated embodiment of FIGS. 16-22. Therefore, the elements and characteristics that correspond to the elements and characteristics in the illustrated embodiment of FIGS. 16-22 are indicated with the same reference numbers in the 400 series. Reference is made to the above description of FIGS. 16-22 in annex for a more complete description of the characteristics and elements (and alternatives of such characteristics and elements) of the modality illustrated in FIG. 23.
[000262] Sample processing device 400 also generally has a circular or disc shape, and a 403 track is shown by way of example only in FIG. 23. The sample processing device 400 includes a center 401 around which the sample processing device 400 can be rotated to move material through it. The sample processing device 400 includes a sample handling side 411 and a reagent handling side 461. The sample processing device 400 includes a substrate 402, a bottom surface 409 which is shown in FIG. 23, and may also include first and second layers (including pre-use layers), such as those described above with respect to the sample processing device 300 of FIGS. 16-22. The sample processing device 400 may include a notch 475 formed through the substrate 402 or another structure (for example, reflective tab, etc.) to arrange and position the sample processing device 400, for example, with respect to sources of electromagnetic energy, optical modules, and the like, as described above with respect to FIGS. 12-14.
[000263] Each side 411, 461 includes an inlet opening 410, 460, an inlet chamber 415, 465, and a distribution channel 440, 490 for transporting the sample and reagent, respectively, to a detection chamber 450, in which the sample and the reagent can be combined. As shown in FIG. 23, in some embodiments, the reagent inlet chamber 465 can be sized larger than the sample inlet chamber 415 to accommodate a greater volume of reagent than sample.
[000264] Unlike the sample processing device 300, the sample processing device 400 does not include any specific loading structure or valve. However, the aspect ratios of the cross-sectional area of an inlet of the distribution channels 440, 490 with respect to the volume of the respective inlet chambers 415, 465 can be the same as that described above with respect to the passage of fluid 328 of the sample processing device 300, such that the timing of transferring the sample and / or reagent from the input chamber 415, 465 to the detection chamber 450 can be controlled. In addition, the aspect ratio of the sample distribution channel 440 need not be the same as that of the reagent distribution channel 490, such that even if the sample and reagent are loaded simultaneously into the sample processing device 400 , the sample and the reagent can still be transferred to the detection chamber 450 at different times, depending on the force exerted on the materials (for example, due to the speed of rotation).
[000265] In some embodiments, the sample can first be loaded onto the sample processing device 400 and transferred to the detection chamber 450 while the sample processing device 400 is rotated, and then the reagent can be loaded, and the device Sample processing 400 can be rotated to transfer the reagent to the detection chamber 450 where it can be combined with the sample, and optionally thermally processed.
[000266] In some cases, the sample processing device 400 of FIG. 23 can be used to test processes and systems to determine whether a material, or a selected volume of material, is present in a particular chamber of a sample processing device, because the input and valve structures variable is removed. Sample processing device 400 was used in Example 1 and FIGS. 27-30. Exemplary disk handling system that includes an exemplary sample processing device
[000267] Some embodiments of the sample processing systems of the present invention may include a disk handling system. Such disk handling systems may include base plates (such as the turntable 25 described previously) joined to a drive system in a manner that provides for rotation of the base plate about an axis of rotation. When a sample processing device is attached to the base plate, the sample processing device can be rotated with the base plate. The base plate can include at least one thermal structure that can be used to heat parts of the sample processing device and can also include a variety of other components, for example, temperature sensors, resistance heaters, thermoelectric modules, light sources , light detectors, transmitters, receivers, etc.
[000268] Other elements and characteristics of the systems and methods for processing sample processing and / or handling devices can be found in US Patent Application Publication No. 2011/0117607, which is incorporated herein by reference in its entirety.
[000269] An illustrative disk handling system 500 is shown in FIG. 24. The system 500 shown in FIG. 24 is generally configured to manipulate a sample processing device (for example, sample processing device 300), including rotating the sample processing device and positioning the sample processing device in one location relative to the other components of the sample processing system 12 (e.g., optical modules, etc., not shown in FIG. 24). In addition, system 500 can be configured to heat and / or cool the sample processing device, for example, for thermal processing.
[000270] As shown in FIG. 24, the system 500 can include a base plate 510 that rotates about an axis of rotation 511. Base plate 510 can also be joined to a drive system 520, for example, through a mechanical axis 522. However, it should be understood that the base plate 510 can be coupled to the drive system 520 through any suitable alternative arrangement, for example, belts or a drive wheel that operates directly on the base plate 510, etc.
[000271] They are also shown in FIG. 24 the sample processing device 300 and an annular cover 560 that can be used in relation to the base plate 510. In some embodiments, the disc handling systems and / or the sample processing systems of the present invention may not include in the A sample processing device is true because, in some instances, sample processing devices are consumable devices that are used to perform a variety of tests, etc., and are then discarded. As a result, the systems of the present invention can be used with a variety of different sample processing devices, and the sample processing device 300 is shown by way of example only.
[000272] As shown in FIG. 24, the illustrated base plate 510 includes a thermal structure 530 which may include a thermal transfer surface 532 exposed on the upper surface 512 of the base plate 510. The term "exposed" means that the transfer surface 532 of the thermal structure 530 can be placed in physical contact with a part of the sample processing device 300 in such a way that the thermal structure 530 and the sample processing device 550 are thermally coupled to transfer thermal energy through conduction. In some embodiments, the transfer surface 532 of the thermal structure 530 may be located directly below the selected parts of the sample processing device 300 during sample processing. For example, in some embodiments, selected parts of the sample processing device 300 may include one or more processing chambers, such as processing chambers 350, which can be considered as "thermal processing chambers". Process chambers, for example, can include those discussed, for example, in U.S. Patent No. 6,734,401 entitled ENHANCED SAMPLE PROCESSING SYSTEMS, SYSTEMS AND METHODS (Bedingham et al.). Still as an example, the sample processing device 300 may include various characteristics and elements, such as those described in U.S. Patent Publication No. 2007/0009391 entitled COMPATIBLE MICROFLUID SAMPLE PROCESSING DISCS (Bedingham et al.).
[000273] As a result, just for example, the inlet chambers 315, 365 of the sample processing device 300 can sometimes be referred to as "non-thermal" chambers or "non-thermal" processing chambers, positioned in fluid communication with the thermal processing chambers 350. A sample can be loaded into the sample processing device 300 and moved through channels (e.g., microfluidic channels) and / or valves, as described above with respect to FIGS. 16-22, for other chambers and / or finally to thermal processing chambers 350.
[000274] In some embodiments, as shown in FIG. 24, the inlet openings 310, 360 can be positioned between a center 301 of the sample processing device 300 and at least one of the thermal processing chambers 350. In addition, the annular cover 560 can be configured to allow access to a part of the sample processing device 300 which includes the inlet openings 310, 360, such that the inlet openings 310, 360 can be accessed when the cover 560 is positioned adjacent to or coupled to the sample processing device 300.
[000275] As shown in FIG. 24, the annular cover 560 can, together with the base plate 510, compress the sample processing device 300 positioned between them, for example, to increase the thermal coupling between the thermal structure 530 on the base plate 510 and the measuring device sample processing 300. In addition, annular cap 560 can function to contain and / or maintain sample processing device 300 on base plate 510, such that sample processing device 300 and / or cap 560 can rotate with the base plate 510 while it is rotated around the axis 511 by the drive system 520. The rotation axis 511 can define a z axis of the system 500.
[000276] As used herein, the term "annular" or the derivations thereof may refer to a structure that has an outer edge and an inner edge, such that the inner edge defines an opening. For example, an annular cover can have a circular or round shape (for example, a circular ring) or any other suitable shape, including, but not limited to, triangular, rectangular, square, trapezoidal, polygonal, etc., or combinations thereof. In addition, a "ring crown" of the present invention need not necessarily be symmetrical, but, instead, it can be an asymmetric or irregular shape; however, certain advantages may be possible with symmetrical and / or circular shapes.
[000277] The compressive forces developed between the base plate 510 and the cover 560 can be provided when using a variety of different structures or a combination of structures. An exemplary compression structure illustrated in the embodiment of FIG. 24 includes the magnetic elements 570 located (or at least operatively coupled) on the cover 560 and the corresponding magnetic elements 572 located (or at least operatively coupled) on the base plate 510. The magnetic attraction between the magnetic elements 570 and 572 can be used to drag the cap 560 and the base plate 510 towards each other, thereby compressing, securing and / or deforming the sample processing device 300 located between them. As a result, the magnetic elements 570 and 572 can be configured to attract each other to force the annular cap 560 in a first direction D1 along the z axis of the system 500, in such a way that at least a part of the processing device samples 300 is urged to come into contact with the transfer surface 532 of the base plate 510.
[000278] As used herein, a "magnetic element" is a structure or article that exhibits or is influenced by magnetic fields. In some embodiments, the magnetic fields may have sufficient power to develop the desired compression force that results in the thermal coupling between the sample processing device 300 and the thermal structure 530 of the base plate 510 as discussed herein. Magnetic elements can include magnetic materials, that is, materials that exhibit a permanent magnetic field, materials that are capable of exhibiting a temporary magnetic field, and / or else materials that are influenced by permanent or temporary magnetic fields.
[000279] Some examples of potentially suitable magnetic materials include, for example, magnetic ferrite or "ferrite", which is a substance that includes mixed oxides of iron and one or more other metals, for example, nanocrystalline cobalt ferrite. However, other ferrite materials can be used. Other magnetic materials that can be used in the 500 system may include, but are not limited to, ceramics AND flexible magnetic materials made from ferrous strontium oxide that can be combined with a polymeric substance (such as, for example, plastic, rubber, etc.); NdFeB (this magnetic material can also include dysprosium); neodymium boride; SmCo (samarium cobalt); and combinations of aluminum, nickel, cobalt, copper, iron, titanium, etc .; as well as other materials. Magnetic materials can also include, for example, stainless steel, paramagnetic materials, or other magnetizable materials that can become sufficiently magnetic by subjecting the magnetizable material to a sufficient electric and / or magnetic field.
[000280] In some embodiments, the magnetic elements 570 and / or the magnetic elements 572 may include a strongly ferromagnetic material to reduce the loss of magnetization over time, such that the magnetic elements 570 and 572 can be coupled with a reliable magnetic force, without a substantial loss of that force over time.
[000281] In addition, in some embodiments, the magnetic elements of the present invention may include electromagnets, in which the magnetic fields can be switched on and off between a first magnetic state and a second non-magnetic state to activate magnetic fields in various areas of the system 500 in desired settings when desired.
[000282] In some embodiments, the magnetic elements 570 and 572 can be separate articles coupled to cover the lid 560 and the base plate 510, as illustrated in FIG. 24 (where the magnetic elements 570 and 572 are individual cylindrical shaped articles). However, in some embodiments, the base plate 510, the thermal structure 530 and / or the cover 560 may include sufficient magnetic material (for example, molded or otherwise provided in the component structure), in such a way that separate separate magnetic elements do not are required. In some embodiments, a combination of distinct magnetic elements and sufficient magnetic material (for example, molded or otherwise) can be employed.
[000283] As shown in FIG. 24, the annular cap 560 includes a center 501 which, in the illustrated embodiment, is aligned with the axis of rotation 511 when the cap 560 is coupled to the base plate 510, an inner edge 563 which at least partially defines an opening 566, and an edge external 565. As described above, opening 566 can facilitate access to at least a part of the sample processing device 300 (for example, a part comprising inlet openings 310, 360), for example, even when the annular cover 560 is positioned adjacent to or coupled to sample processing device 300. As shown in FIG. 24, the inner edge 563 of the annular cover 560 can be configured to be positioned inside (for example, radially inside) of the thermal processing chambers 350, in relation to the center 501 of the annular cover 560, for example, when the annular cover 560 is positioned adjacent the sample processing device 300. In addition, the inner edge 563 of the annular cover 560 can be configured to be positioned radially outwardly from the inlet openings 310, 360. In addition, in some embodiments, as shown in FIG . 24, the outer edge 565 of annular cover 560 can be configured to be positioned outside (e.g., radially outside) thermal processing chambers 350 (and also outside inlet openings 310, 360).
[000284] The inner edge 563 can be positioned at a first distance di (for example, a first radial distance or a "first radius") from the center 501 of the annular cover 560. In such embodiments, if the annular cover 560 is shaped of substantially circular ring, opening 566 may have a diameter equal to twice the first distance di. In addition, the outer edge 565 can be positioned a second distance d2 (for example, a second radial distance or a "second radius") from the center 501 of the annular cover 560.
[000285] Furthermore, annular cover 560 may include an inner wall 562 (for example, "an inner circumferential wall" or "inner radial wall"; which may function as an inner compression ring, in some embodiments, such as described below) and an outer wall 564 (for example, an "outer circumferential wall" or "outer radial wall"; which may function as an external compression ring, in some embodiments, as described below). In some embodiments, the inner and outer walls 562 and 564 may include or define the inner and outer edges 563 and 565, respectively, in such a way that the inner wall 562 can be positioned inside (for example, radially inside) the processing chambers thermal 350, and the outer wall 564 can be positioned outside (e.g., radially outside) the thermal processing chambers 350. As also shown in FIG. 24, in some embodiments, the inner wall 562 may include the magnetic elements 570, such that the magnetic elements 570 are part of or are coupled to the inner wall 562. For example, in some embodiments, the magnetic elements 570 can be embedded (e.g. molded) on the inner wall 562. As shown in FIG. 24, annular cover 560 can also include an upper wall 567 which can be positioned to cover a part of the sample processing device 300, such as a part comprising the thermal processing chambers 350.
[000286] In some embodiments, the upper wall 567 may extend inward (for example, radially inward) of the inner wall 562 and the magnetic elements 570. In the embodiment illustrated in FIG. 24, the upper wall 567 does not extend far into the inner wall 562. However, in some embodiments, the upper wall 567 may extend further into the inner wall 562 and / or the magnetic elements 570 (for example, for the center 501 of the cap 560), for example, in such a way that the size of the opening 566 is smaller than that shown in FIG. 24. In addition, in some embodiments, the upper wall 567 may define the inner edge 563 and / or the outer edge 565.
[000287] In some embodiments, at least a part of the lid 560, such as one or more of the inner wall 562, the outer wall 564 and the top wall 567, may be optically transparent. As used herein, the phrase "optically transparent" can refer to an object that is transparent to electromagnetic radiation ranging from the infrared to ultraviolet spectrum (for example, from about 10 nm to about 10 pm (10,000 nm)); however, in some embodiments, the phrase "optically transparent" can refer to an object that is transparent to electromagnetic radiation in the visible spectrum (for example, from about 400 nm to about 700 nm). In some embodiments, the phrase "optically transparent" can refer to an object with a transmittance of at least about 80% within the above wavelength ranges.
[000288] Such ring cap configurations 560 may work to effectively or substantially isolate thermal processing chambers 350 from sample processing device 300 when cap 560 is coupled to or positioned adjacent to sample processing device 300. For example, For example, cover 560 may physically, optically and / or thermally isolate a part of the sample processing device 300, such as a part comprising the thermal processing chambers 350. In some embodiments, the sample processing device 300 may include one or more thermal processing chambers 350, and furthermore, in some embodiments, one or more thermal processing chambers 350 can be arranged in an annular crown around the center 301 of the sample processing device 300, which can sometimes be indicated as an "an annular processing ring." In such embodiments, the annular cover 560 can be adapted to cover and / or insulate a part of the sample processing device 300 that includes the annular processing ring or thermal processing chambers 350. For example, the annular cover 560 includes the inner wall 562, outer wall 564 and upper wall 567 to cover and / or insulate the part of the sample processing device 300 that includes thermal processing chambers 350. In some embodiments, one or more of the inner wall 562, the outer wall 564 and the upper wall 567 can be a continuous wall, as shown, or can be formed from a plurality of parts that work together as an inner or outer wall (or inner or outer compression ring), or an upper wall. In some embodiments, increased physical and / or thermal insulation can be achieved when at least one of the inner wall 562, the outer wall 564 and the upper wall 567 is a continuous wall.
[000289] Furthermore, in some embodiments, the ability of the annular cover 560 to effectively cover and thermally insulate thermal processing chambers 350 from the environment and / or other parts of the system 500 may be important, because otherwise, since the base plate 510 and the sample processing device 300 are rotated around the axis of rotation 511, the air can be caused to move quickly after the thermal processing chambers 350, which, for example, can cool down heat processing chambers 350 undesirably when chambers 350 are to be heated. Thus, in some embodiments, depending on the configuration of the sample processing device 300, one or more of the inner wall 562, the upper wall 567 and the outer wall 564 may be important for thermal insulation.
[000290] As shown in FIG. 24, in some embodiments, the substrate 302 of the sample processing device 300 may include a ferrule, flange or outer wall 395. In some embodiments, as shown, outer wall 395 may include a portion 391 adapted to cooperate with the base plate 510 and a part 399 adapted to cooperate with the annular cover 560. For example, as shown, the annular cover 560 (for example, the outer wall 564) can be sized to be received within the area circumscribed by the outer wall 395 of the sample processing device 300. As a result, in some embodiments, the outer wall 395 of the sample processing device 300 may cooperate with the annular cover 560 to cover and / or insulate the thermal processing chambers 350. Such cooperation also can facilitate the positioning of the annular cover 560 with respect to the sample processing device 300 in such a way that the thermal processing chambers 350 are protected s and covered without compression of the annular cover 560 or contact of any of the thermal processing chambers 350.
[000291] In some embodiments, on the outer wall 395 of the sample processing device 300 and one or more steps 313 (e.g., the middle step 313 shown in FIG. 24) of the sample processing device 300 can effectively define a recess (for example, an annular recess) 353 on the sample processing device 300 (for example, on an upper surface of the sample processing device 300) on which at least a part of the annular cover 560 can be positioned. For example, as shown in FIG. 24, the inner wall 562 (for example, including the magnetic elements 570) and the outer wall 564 can be positioned in the recess 353 of the sample processing device 300 when the annular cover 560 is positioned on or coupled to the sample processing device 300. As a result, in some embodiments, the outer wall 395, the steps 313 and / or the recess 353 can provide reliable positioning of the lid 560 with respect to the sample processing device 300.
[000292] In some embodiments, as shown, the magnetic elements 570 of the cap 560 form at least a part of or are coupled to the inner wall 562, in such a way that the magnetic elements 570 can function as at least part of the ring internal compression 562 to compress, secure and / or deform the sample processing device 300 against the thermal transfer surface 532 of the thermal structure 530 of the base plate 510. As shown in FIG. 24, one or both of the magnetic elements 570 and 572 may be arranged in an annular crown, for example, around the axis of rotation 511. In addition, in some embodiments, at least one of the magnetic elements 570 and 572 may include a distribution substantially uniform magnetic force around such an annular crown.
[000293] Furthermore, the arrangement of the magnetic elements 570 in the cover 560 and the corresponding arrangement of the magnetic elements 572 in the base plate 510 can provide additional positioning aid for the cover 560 with respect to one or both of the sample processing device 300 and the base plate 510. For example, in some embodiments, each of the magnetic elements 570 and 572 may include sections of alternating polarity and / or a specific configuration or arrangement of magnetic elements, such that the magnetic elements 570 of the cover 560 and the magnetic elements 572 of the base plate 510 can be "keyed" with respect to each other to allow the cover 560 to be reliably positioned in a desired orientation (for example, the angular position in relation to the axis of rotation 511) with at least one of the sample processing device 300 and the base plate 510.
[000294] Although not shown explicitly in FIG. 24, in some embodiments, the base plate 510 can be constructed in such a way that the thermal structure 530 is exposed on the first upper surface 512 as well as on a second lower surface 514 of the base plate 510. With the exposure of the thermal structure 530 on the surface upper 512 of the base plate 510 (for example, alone or in addition to the lower surface 514), a direct thermal passage can be provided between the transfer surface 532 of the thermal structure 530 and a sample processing device 300 located between the cover 560 and the base plate 510.
[000295] Alternatively or additionally, the exposure of the thermal structure 530 on the lower surface 514 of the base plate 510 can provide an advantage when the thermal structure 530 has to be heated by the electromagnetic energy emitted by a source that directs the electromagnetic energy to the lower surface 514 of the base plate 510.
[000296] For example only, the system 500 includes an electromagnetic energy source 590 positioned to transfer thermal energy to the thermal structure 530, with the electromagnetic energy emitted by the source 590 directed to the bottom surface 514 of the base plate 510 and the part of the thermal structure 530 exposed on the bottom surface 514 of the base plate 510. Examples of some suitable electromagnetic energy sources may include, but are not limited to, lasers, broadband electromagnetic energy sources (for example, white light) , etc.
[000297] Although system 500 has been illustrated as including the source of electromagnetic energy 590, in some embodiments, the temperature of thermal structure 530 can be controlled by any appropriate energy source that can transfer thermal energy to thermal structure 530. The examples of energy sources potentially suitable for use in connection with the present invention other than sources of electromagnetic energy may include, for example, Peltier elements, electrical resistance heaters, etc.
[000298] System 500 is an example of a part of a sample processing system (ie, a disk handling system) that can be configured to contain, manipulate, rotate, position and / or thermally process a device sample processing of the present invention. System 500 can be incorporated into system 12 of FIGS. 1-15. For example, with reference to FIG. 8, the sample processing device 300 can take the place of disk 13, and the system 500 can be used to position the sample processing device 300 with respect to the other components (for example, in a gantry 60) of the system 12 In addition, the sample 22 can be located in a thermal processing chamber 350 in the sample processing device 300. In addition, the base plate 510 and the drive system 520 can be used as the turntable of FIG. 1. As a result, it is evident from the above description and the attached figures how a disk or a sample processing device of the present invention can be contained, manipulated, rotated, thermally processed and / or positioned in relation to the other components (for example, example, the detection device 10) of system 12.
[000299] Although various embodiments of the present invention have been shown in the accompanying drawings as an example only, it should be understood that a variety of combinations of the embodiments described and illustrated herein can be employed without departing from the scope of the present invention. For example, the sample processing device 300 is shown in use with the system 500 of FIG. 24, however, it should be understood that the sample processing device 400 of FIG. 23 can preferably be employed with the system 500. In addition, various features of the system 500 can be employed as part of the total system 12 of FIGS. 1-15. In addition, various features of the sample processing device 300 of FIGS. 16-22 can be employed in the sample processing device 400 of FIG. 23, and vice versa. As a result, the present invention must be taken as a whole for all of the various characteristics, elements, and alternatives to the characteristics and elements described herein, as well as the possible combinations of such characteristics and elements. Processes for determining whether a selected volume of material is present
[000300] An exemplary process for loading a sample and a reagent into a sample processing device and verifying whether a selected volume of the sample has been moved to, or is present in, the detection chamber 350 will now be described with reference to the sample processing system. samples 12 of FIGS. 1-15, to system 500 of FIG. 24 and the sample processing device 300 of FIGS. 16-22. In particular, a track 303 of the sample processing device 300 will be described with respect to the movement of the sample.
[000301] As mentioned above, in order to detect whether a sample has moved to, or is present in, the detection chamber 350 of a given lane 303, a variety of methodologies can be used: (1) the detection chamber 350 can be scanned only after the sample has been loaded, all necessary valves have been opened (for example, on the sample handling side 311 of lane 303), and the sample processing device 300 has been rotated to move the sample to detection chamber 350; (2) the detection chamber 350 can be scanned only after the reagent has been loaded, all the necessary valves have been opened (for example, on the reagent handling side 361 of lane 303), and the sample processing device 300 has been rotated to move the reagent into the detection chamber 350; (3) the detection chamber 350 can be scanned after the sample and reagent have been loaded, all necessary valves have been opened (for example, on both sides 311, 361 of lane 303), and the processing device of samples 300 has been rotated to move the sample and the reagent into the detection chamber 350; and / or (4) a combination of any of the above methods. An example of the methodology (4) may include creating a first scan of the detection chamber 350 only after the reagent has been transferred, and then creating a second scan of the detection chamber 350 after the sample has also been added to the chamber detection 350, and then the two scans are compared. Further development of this example is described below.
[000302] In some embodiments (for example, in methodology (1)), the fluorescence detection capabilities of the detection device 10 can be used to detect the backscattered reflection of an optical signal to detect a meniscus layer in the material. However, in some embodiments, the detection device 10 can detect the fluorescence signal from one or more fluorescent probes in the material (for example, in the reagent), and the 'edge' of such a signal (for example, peak) should indicate the amount of fluid in the detection cavity. In addition, in some embodiments, a combination of these detection schemes can be employed.
[000303] In either type of detection scheme (i.e., backscatter and / or fluorescence), the detection chamber 350 can be scanned in one or more of the following ways: (a) the detection chamber 350 can be scanned from one radial end to another radial end before and after moving the sample (or the sample and the reagent), and two scans can be created, which represent the detection chamber 350 from one end to the other (for example, where in the graphical representation of such a scan the x-axis can represent the gantry or the radial position) before and after the material has been moved; (b) the detection chamber 350 can be scanned in a radial position before and after moving the sample (or the sample and the reagent) into the detection chamber 350 to determine whether the scan changes when a material is present; or (c) a combination thereof.
[000304] In any scanning method, the presence or absence of the material can be detected, and / or the amount of material can be determined. All scanning methods can be performed while the sample processing device 300 is rotating to explore the phenomenon that all material present in the detection chamber 350 will be subjected to a centrifugal force, and will have a higher level that will generally be well defined and located between an innermost radial end (or "inner perimeter") 351 and the outermost radial end (or "outer perimeter") 352 of the detection chamber 350 (see FIG. 20). That is, the rotation of the sample processing device 300 about the axis of rotation AA can force any material present in the detection chamber 350 to a position in the detection chamber 350 which is located further away from the axis of rotation AA, in such a way such that the material is forced against the outer perimeter 352 of the detection chamber 350.
[000305] Furthermore, as mentioned above, the desired volumes of the sample and the reagent can be moved into the detection chamber 350, either by loading, as is the case for the sample processing device 300 of FIGS. 16-22, as for the precise loading of a desired volume of each into the inlet wells, as is the case for the sample processing device 400 of FIG. 23. As a result, system 12 can be calibrated to correlate a radial position (e.g., a gantry position of gantry 60 of FIG. 8) in the detection chamber 350 with a volume of material.
[000306] If, for example, methodology (1) is used, and if the volume Vi (for example, 10 microliters) of the sample is transferred to the detection chamber 350, system 12 can be calibrated to correlate a position Pi (for example, a radial or gantry position; see FIG. 20) with the Vi volume, or the Pi position can be chosen to be below, or immediately below, the Vi volume level. Such position Pi will be correlated with volume Vi when the sample processing device 300 is rotated in such a way that the material is forced against the outermost radial wall of the detection chamber 350.
[000307] If, for example, methodology (2) is used, and if the volume V2 (for example, 40 microliters) of the reagent is transferred to the detection chamber 350, system 12 can be calibrated to correlate a position P2 (see FIG. 20) with volume V2, or position P2 can be chosen to be below, or immediately below, volume level V2.
[000308] Furthermore, if the user knows that a total V3 volume (for example, 50 microliters if 40 microliters of the reagent and 10 microliters of the sample are loaded) must be present in the detection chamber 350 after the sample and the reagent are taken moving to the detection chamber 350, system 12 can be calibrated to correlate a position P3 (see FIG. 20) with volume V3, or position P3 can be chosen to be below, or immediately below, the level of volume V3. In some embodiments, the position P3 may be a radial position close to the inner perimeter 351 of the detection chamber 350.
[000309] With reference to FIG. 20 and FIG. 25, in some embodiments, the phenomenon of fluorescence dilution in the reagent after the sample and the reagent are combined can be explored to confirm that the sample, or a selected volume of the sample, has been properly moved to the 350 detection chamber. For example, in some embodiments, a first scan of reagent Si alone (i.e., from outer perimeter 352 to inner perimeter 351 of detection chamber 350) can be compared to a second scan of sample + reagent S2. Due to the fact that the concentration of fluorescent probes should generally decrease due to the dilution of the signal when the sample is added to the reagent, the peak fluorescence of the first scan (ie, only reagent) Si will in general be greater than the peak fluorescence of the second scan (i.e., sample + reagent) S2, and in particular at the p2 position. However, since no material will be present at position P3 on the first scan Si, the signal at position P3 on the first scan Si must be very low. In contrast, in the second scan S2, the fluorescence at position P2 will be decreased due to the reduced concentration of fluorescence, but the fluorescence at position P3 should be higher than that of the first scan S1, since the material will be present at position P3 when the sample and the reagent are present. As a result, the difference between the fluorescence of the two Si, S2 scans (or the percentage of decrease) in the P2 position, and / or the difference between the fluorescence of the two Si, S2 scans (or the percentage of increase) in the P3 position can be used to confirm that the sample, or a selected volume of it, has moved into the detection chamber 350. In some embodiments, the "signal" units can be relative units of fluorescence intensity, and in some embodiments, they can be a percentage of the change from a fund signal.
[000310] In order to determine if the sample has been moved to the detection chamber 350 or if a desired volume of the sample has been moved, the detection chamber 350 can be scanned before and after the sample (or the sample and the reagent) moved to the detection chamber 350, and scans can be compared. That is, a first "bottom scan" can be done when the detection chamber 350 is assumed to be empty, and that scan can be compared to a second scan when it is assumed that (i) the sample, (ii) the reagent and / or (iii) the sample and the reagent are present in the detection chamber 350. If a change or limit difference (for example, percentage of change) exists between the first background scan and the second scan (for example, in a desired radial position), it can be determined that the sample, or a selected volume of the sample, is present in the detection chamber 350. In some embodiments, the volume of the material in the detection chamber 350 can be determined by first determining the position radial in the detection chamber 350 where the limit change is found, and then the radial position is correlated to a volume in order to determine the volume of material that is present in the detection chamber 350.
[000311] In order to avoid any change in potential optical signal as a result of temperature variation during the processing of a sample, the scanning of the bottom of the detection chamber 350 can be done at the same processing temperature at which subsequent scans will be made ( for example, at a cell lysis temperature). However, in some embodiments, the sample processing device 300 cannot be "preheated" in this way, and the bottom scan can be performed at room temperature. It should be noted that the bottom scan can be done before any material (for example, sample) is loaded into the sample processing device 300, or after the material is loaded, but before any valves are opened (ie, before moving any material to the detection chamber 350).
[000312] The details of the example process 600 will now be described with reference to FIG. 26.
[000313] For example only, for example process 600, the sample and reagent will both be loaded into sample processing device 300 before sample processing device 300 is positioned in system 500. However, it must be It is understood that the sample and the reagent can preferably be loaded into the sample processing device 300 after a scan of the bottom of the detection chambers 350 has been obtained.
[000314] The sample and reagent are loaded onto the sample processing device or "disk" 300 (step 602 in FIG. 26) by removing the pre-use layer 305 on the 303 track of interest and injecting (for example , with a pipette) the raw sample in the inlet chamber 315 through the inlet opening 310 on the sample handling side 311 of lane 303. The reagent can also be loaded at that time, so for this example, it will be assumed that the reagent is also loaded onto disc 300 at that time by injecting reagent into inlet chamber 365 through inlet opening 360 on reagent handling side 361 of lane 303. A plug 307, or other appropriate seal, film, or cap, they can then be used to seal the openings 310, 360 of the environment, as described above. For example, in some embodiments, the pre-use layer 305 can simply be replaced over the inlet openings 310, 360.
[000315] The disc 300 can be loaded in the disc handling system 500 (step 604), and coupled between the base plate 510 and the cap 560, in such a way that the disc 300, and in particular the detection chambers (or the thermal processing chambers) 350 is forced to come into contact with the transfer surface 532 of the base plate 510.
[000316] The drive system 520 can be operated to rotate the base plate 510 around the axis of rotation 511, which causes the disc 300 to rotate around its center 301, which is aligned with the axis of rotation 511. Disc 300 can be rotated at a first speed (or speed profile) and a first acceleration (or acceleration profile) sufficient to force the sample and reagent into their respective loading reservoirs 318, 368, where any excess in relation to the desired volumes is directed to the respective dumping reservoirs 320, 370 (step 606).
[000317] For example, in some embodiments, a first speed profile may include the following: the disc 300 is (i) rotated at a first speed to move the materials into their respective loading tanks 318, 368 without force any material for dump reservoirs 320, 370, (ii) held for a period of time (for example, 3 seconds), and (iii) rotated at a second speed to make any amount of material larger than the volume of the reservoir load 318, 368 overflows to the dump reservoir 320, 370. Such a rotation scheme can be indicated as a "loading profile", "loading scheme" or the like, as it allows materials to be moved to the respective loading reservoirs 318, 368 while ensuring that materials are not fully forced into the dumping reservoirs 320, 370. In such an example, speed and acceleration are kept below a speed e and acceleration that should cause the sample and / or the reagent to move to the respective fluid passage 328, 378 and "wet" the septum 336 of the valve, 386. Due to the fact that the speed and acceleration profiles are sufficient to load the sample and reagent while remaining below those that can cause the septa 336, 386 to humidify, they can simply be described as a "first" speed and acceleration. That is, the first speed and acceleration is insufficient to force the sample or the reagent into the respective fluid passages 328, 378, such that the loaded volumes of the sample and the reagent remain in the respective inlet chamber 315, 365.
[000318] Various characteristics and details of the loading system and process are described in US Patent Applications No. 61 / 487,672, filed on May 18, 2011, and 61 / 490,014, filed on May 25, 2011, each of which it is incorporated herein by reference in its entirety.
[000319] The disc 300 can continue to rotate, and a scan of the bottom can then be made from the detection chamber 350, generally by following the procedure outlined in FIG. 15 and described above (step 608). The electromagnetic source 590 can be activated in such a way that the electromagnetic source 590 heats the thermal structure 530 while the disk 300 is rotated, and the transfer surface 532 of the thermal structure 530 heats the detection chambers 350 by means of conduction. Such heating may function as "preheating" of the disc 300 described above.
[000320] The detection device 10, and in particular one or more of the optical modules 48, 52, 56, can be moved along a radius with respect to the center 301 of the sample processing device 300 by the port 60. The module optical 48 will be described by way of example only. The optical module 48 can optically scan the detection chamber 350 according to one or the other detection scheme described above (i.e., backscatter and / or fluorescence), and develops a scan of the bottom from a more radial outer position of the detection chamber 350 all the time to a more internal radial position of the detection chamber 350. Alternatively, as described above, the optical module 48 can scan the detection chamber 350 in one or more distinct radial positions (for example, the position Pi, P2 and / or P3).
[000321] At that time, disk 300 may stop rotating and one or both of the sample septum valve 332 and reagent septum valve 382 may be opened, for example, with the formation of an empty space in the (s) valve septum (s) 336, 386 when using the laser valve control system 51. For the purposes of this example, it is assumed that a single sample scan will be performed before moving the reagent into the detection chamber 350, such that the sample septum valve 332 will be opened first (step 610). The septum 336 of the sample valve can be located and opened according to the processes outlined in FIGS. 12 and 14 and described above, to place the inlet chamber 315 and the detection chamber 350 in fluid communication through a downstream direction.
[000322] Disc 300 can then be rotated at a second speed (or speed profile) and the first acceleration (or acceleration profile) sufficient to move the sample to the fluid passage 328 (i.e., sufficient to open the valve capillary 330 and allow the sample to move through it), through the opening formed in the septum 336, through the distribution channel 340, and to the detection chamber 350 (step 612). Meanwhile, any fluid (for example, gas) present in the detection chamber 350 can be moved to the equilibrium channel 355 while the sample is moved to the detection chamber 350. These rotation and acceleration speeds may be sufficient to move the sample to the detection chamber 350, but not sufficient to cause the reagent to move into the fluid passage 378 of the capillary valve 380 and moisten the septum 386.
[000323] The disc 300 can then be rotated, and a single scan of the sample from the detection chamber 350 can be performed (step 614) when operating the optical module 48 and the gantry 60, as described above. The rotation of the disc 300 that occurs during this detection step can be at the same speed of rotation and acceleration or at a speed of rotation and acceleration different from the second speed and acceleration. In addition, disk 300 can be stopped after the sample is moved to the detection chamber 350 and then rotated again for detection, disk 300 can simply continue to be rotated after the sample is assumed to be moved to the detection chamber 350, or a combination thereof. This step can also include heating (for example, when using the electromagnetic source 390 and thermal structure 530) of the detection chambers 350 (for example, up to 75 ° C). Such a heating step can cause cell lysis in the sample, for example. In some embodiments, it is important that the reagent is not present in the detection chamber 350 for this heating step, since the temperatures required for the thermal lysis of the cell can denature the necessary enzymes (for example, reverse transcriptase) present in the reagent. Thermal cell lysis is described only as an example, however, it should be understood that other lysis protocols (eg, chemistry) may be used instead.
[000324] Disc 300 can then stop rotating and reagent septum valve 382 can be opened (step 616). The valve 382 can be opened by using the laser valve control system 51 (i.e., according to the processes outlined in FIGS. 12 and 14) to form an empty space in the septum 386 of the reagent valve to place the chamber input 365 in fluid communication with the detection chamber 350 through a downstream direction.
[000325] The disc 200 can then be rotated the second speed (or speed profile) and the second acceleration (or acceleration profile), or a higher speed and / or acceleration than the second speed and acceleration, to transfer the reagent to detection chamber 350 (step 618). That is, the speed of rotation and acceleration may be sufficient to move the reagent into the fluid passage 378 (ie, sufficient to open the capillary valve 380 and allow the reagent to move through it) through the opening formed in the septum 386, through the distribution channel 390, and to the detection chamber 350. Meanwhile, any additional fluid (for example, gas) present in the detection chamber 350 can be moved to the balance channel 355 while the reagent is moved for the detection chamber 350. This is made possible in particular by modalities such as the disc 300, since, when the disc 300 is rotating, any liquid present in the detection chamber 350 (for example, the sample) is forced against the outermost end 352, in such a way that any liquid present in the detection chamber 350 will be located radially out of the positions where the distribution channel 390 and the balance channel 355 connect with the detection 350, so that gas exchange can occur. In another way, when the disc 300 is rotating, the distribution channel 390 and the balance channel 355 connect with the detection chamber 350 in a position that is upstream (for example, radially inside) of the fluid level in the detection chamber 350.
[000326] Step 618 of the process may also include operating one or more optical modules to perform an additional scan of the detection chamber 350 to determine whether a material, or a selected volume of material, is present in the detection chamber 350. For example, in some embodiments, a background scan can be obtained, a first scan of the sample (or reagent only) can be obtained, and then a second sample + reagent scan can be obtained. As mentioned above, any or all of these scans can include a scan across all radial positions of the detection chamber 350, in multiple different radial positions, or in a different radial position. In addition, the rotation step used to move the reagent into the detection chamber 350 can be continued for detection, the disc 300 can be stopped and then rotated again for detection, or a combination thereof.
[000327] The rotation of the disc 300 can then be continued as needed for a desired reaction and detection scheme (step 620). For example, now that the reagent is present in detection chamber 350, detection chamber 350 can be heated to a temperature necessary to begin reverse transcription (for example, 47 ° C). An additional thermal cycle can be employed as needed, such as the heating and cooling cycles required for PCR, etc.
[000328] Various forces can be exerted on the materials in the sample processing device 300 at various processing stages. As evidenced by the speed and acceleration scheme reported in FIG. 26 and described above, such forces can be at least partially controlled by controlling the speeds of rotation and the acceleration profiles (for example, angular acceleration, reported in revolutions or revolutions per second squared (revolutions / s2)) of the processing device of samples 300. Some modalities may include: (i) a first velocity and a first acceleration that can be used to load liquids into one or more processing arrangements 100 in a sample processing device and are insufficient to cause the liquids to move into fluid passages 128 of any processing arrangement 100 in that sample processing device; (ii) a second speed and a first acceleration that can be used to move a fluid to the fluid passage 128 of at least one of the processing arrangements 100 in a sample processing device (for example, in a processing arrangement 100 where the valve 132 of the downstream septum was opened and the vapor retention in the chamber 134 of the valve was released, while still preventing the fluids from moving into the fluid passages 128 of the remaining processing arrangements 100 in which the valve 132 of the downstream septum has not been opened); and (iii) a third speed and a second acceleration that can be used to move the fluids into the fluid passages 128 of all processing arrangements 100 in the sample processing device.
[000329] In some modalities, the first speed may be no greater than about 1,000 rpm, in some modalities no greater than about 975 rpm, in some modalities no greater than about 750 rpm, and in some modalities no greater than about 525 rpm. In some embodiments, the "first speed" can actually include two distinct speeds - one to move material into loading reservoir 118, and another to then load material by overloading loading reservoir 118 and allowing excess to move for dump reservoir 120. In some embodiments, the first transfer speed may be about 525 rpm, and the second introduction speed may be about 975 rpm. Both can occur at the same acceleration.
[000330] In some modalities, the first acceleration can be no greater than about 75 revolutions / s2, in some modalities no greater than about 50 revolutions / s2, in some modalities no greater than about 30 revolutions / s2 , in some modalities no greater than about 25 revolutions / sec2, and in some modalities no greater than about 20 revolutions / sec2. In some embodiments, the first acceleration can be around 24.4 revolutions / s2.
[000331] In some modalities, the second speed can be no greater than about 2,000 rpm, in some modalities no greater than about 1,800 rpm, in some modalities no greater than about 1,500 rpm, and in some modalities no greater than about 1,200 rpm.
[000332] In some modalities, the second acceleration may be at least about 150 revolutions / s2, in some modalities at least about 200 revolutions / s2, and in some modalities at least about 250 revolutions / s2. In some embodiments, the second acceleration can be about 244 revolutions / s2.
[000333] In some modalities, the third speed may be at least about 3,000 rpm, in some modalities at least about 3,500 rpm, in some modalities at least about 4,000 rpm, and in some modalities at least about 4,500 rpm. However, in some embodiments, the third speed may be the same as the second speed, as long as the speed and acceleration profiles are sufficient to overcome capillary forces in the respective fluid passages 128.
[000334] It should be noted that process 600 of FIG. 26 can be employed on one track 303 at a time on disk 300, or one or more tracks can be loaded and processed simultaneously according to process 600 of FIG. 26.
[000335] The modalities of the present invention below should be illustrative and not limiting. MODALITIES
[000336] Mode 1 is a method for processing sample processing devices, wherein the method comprises: providing a sample processing device comprising a detection chamber; the rotation of the sample processing device about an axis of rotation; and determining whether a selected volume of material is present in the detection chamber, while rotating the sample processing device.
[000337] Mode 2 is the method of mode 1, wherein determining whether a selected volume of material is present in the detection chamber includes determining whether a selected volume of a sample is present in the detection chamber.
[000338] Mode 3 is the method of mode 1, wherein determining whether a selected volume of material is present in the detection chamber includes determining whether a total selected volume of a sample and a reagent medium is present in the detection chamber .
[000339] Mode 4 is the method of any one of modalities 1-3, in which the determination of whether a selected volume of material is present in the detection chamber includes the optical verification of the detection chamber in a selected position to determine whether the material is present in the selected position.
[000340] Mode 5 is the method of any one of modalities 1-4, in which the determination of whether a selected volume of material is present in the detection chamber includes the optical investigation of the detection chamber for an optical property of a sample to determine if the sample is present in the detection chamber.
[000341] Mode 6 is the method of any of modalities 1-5, in which the detection chamber includes an internal perimeter located closest to the axis of rotation, and in which the determination of whether a selected volume of material is present in the Detection chamber includes the optical verification of the detection chamber in a position of the gantry close to the internal perimeter of the detection chamber.
[000342] Mode 7 is the method of any of modalities 4-6, wherein the optical verification of the detection chamber includes the optical verification of the detection chamber for a meniscus.
[000343] Modality 8 is the method of any of modalities 4-7, in which the optical verification of the detection chamber includes the emission of an electromagnetic signal to the detection chamber, and the performance of a scan for the detection of reflection retrodiffuse the electromagnetic signal, after the electromagnetic signal is emitted to the detection chamber.
[000344] Mode 9 is the method of mode 8, in which obtaining a scan includes: performing a first scan of the bottom of the detection chamber, performing a second scan of the detection chamber after positioning a sample in the detection chamber, and comparing the first background scan with the second scan to determine whether a selected volume of the sample is located in the detection chamber.
[000345] Mode 10 is the method of mode 9, in which the comparison of the first scan of the background with the second scan to determine whether a selected volume of the sample is located in the detection chamber includes the determination of whether there is a limit change between the first scan of the background and the second scan.
[000346] Mode 11 is the method of mode 10, which further comprises the provision of an optical module operatively positioned in relation to the sample processing device in a gantry, in which the optical verification of the detection chamber includes the optical verification of the detection chamber with the optical module in a plurality of radial positions, in relation to the axis of rotation.
[000347] Mode 12 is the method of mode 11, which further comprises: determining a radial position in which a limit change is located between the first scan of the bottom and the second scan; and the use of the radial position to determine the sample volume that is located in the detection chamber.
[000348] Modality 13 is the method of any of the modalities 8-12, in which the realization of a scan by detecting the retrodiffuse reflection of the electromagnetic signal is performed when using an optical FAM channel.
[000349] Modality 14 is the method of any of modalities 4-7, in which the optical investigation includes the emission of an electromagnetic signal to the detection chamber, and the performance of a scan by detecting the fluorescence emitted by a material in the detection chamber, after the emission of the electromagnetic signal to the detection chamber.
[000350] Mode 15 is the method of mode 14, in which obtaining a scan includes: performing a first scan of the bottom of the detection chamber, performing a second scan of the detection chamber after positioning a sample in the detection chamber, and comparing the first background scan with the second scan to determine whether a selected volume of the sample is present in the detection chamber.
[000351] Mode 16 is the method of mode 15, in which the comparison of the first scan of the background with the second scan to determine whether a selected volume of the sample is located in the detection chamber includes the determination of whether there is a limit change in fluorescence between the first background scan and the second scan.
[000352] Modality 17 is the method of modality 16, which further comprises the provision of an optical module operatively positioned in relation to the sample processing device in a gantry, in which the verification of the detection chamber includes the optical verification of the detection chamber with the optical module in a plurality of radial positions, in relation to the axis of rotation.
[000353] Mode 18 is the method of mode 17, which further comprises: determining a radial position in which a limit change in fluorescence is located between the first scan of the background and the second scan; and the use of the radial position to determine the volume of the sample that is present in the detection chamber.
[000354] Mode 19 is the method of any of modalities 1-18, which further comprises: heating the detection chamber, in which the determination whether a selected volume of material is present in the detection chamber occurs while it is heated the detection chamber.
[000355] Mode 20 is the method of any of modalities 4-19, in which the optical investigation includes the emission of an electromagnetic signal to the detection chamber at a first wavelength, and the detection of the electromagnetic signals emitted from the detection chamber at a second wavelength, after the emission of the electromagnetic to the detection chamber at a first wavelength.
[000356] Mode 21 is the method of any of modalities 4-20, in which the material includes a sample to be analyzed and a reagent medium, and in which the optical verification of the detection chamber includes the optical verification of the detection chamber. detection for an optical property of at least one of the sample and the reagent medium in the detection chamber.
[000357] Mode 22 is the method of any of modalities 4-21, which further comprises the provision of an optical module operatively positioned in relation to the sample processing device in a gantry, and in which the optical investigation of the chamber The detection module includes the optical verification of the detection chamber with the optical module positioned in a predetermined position of the gantry.
[000358] Mode 23 is the method of any of modalities 4-21, which further comprises the provision of an optical module operatively positioned in relation to the sample processing device in a gantry, and in which the optical verification of the chamber The detection method includes the optical verification of the detection chamber with the optical module in a plurality of positions of the gantry.
[000359] Mode 24 is the method of mode 23, in which each position of the plurality of positions of the gantry is associated with a quantity of material, and which also comprises: the detection of a limit signal in a position of the gantry; and correlating the position of the gantry to an amount of material that is present in the detection chamber.
[000360] Mode 25 is the method of mode 23 or 24, in which the plurality of positions of the gantry include different radial positions in the detection chamber, in relation to the axis of rotation.
[000361] Mode 26 is the method of any of modalities 23-25, in which a first position of the gantry is positioned radially out of a second position of the gantry.
[000362] Mode 27 is the method of any of modes 11-12, 17-18 and 22-26, in which the optical module is configured for the detection of multiplex fluorescence.
[000363] Mode 28 is the method of any of modalities 1-27, in which the sample processing device includes a plurality of detection chambers, and in which the optical verification of the detection chamber includes the optical verification of at least at least one chamber of the plurality of detection chambers while the sample processing device is rotated.
[000364] Mode 29 is the method of any of modalities 1-28, wherein the rotation of the sample processing device when it is determined whether a selected volume of material is present in the detection chamber forces any material present in the detection chamber. detection to a position in the detection chamber that is located furthest from the axis of rotation.
[000365] Mode 30 is the method of any of modalities 1-29, in which the detection chamber includes an external perimeter positioned further away from the axis of rotation, and in which the rotation of the sample processing device when it is determined if a selected volume of material is present in the detection chamber forces any material present in the detection chamber to the outer perimeter of the detection chamber.
[000366] Mode 31 is the method of any of modalities 1-30, wherein the sample processing device comprises a processing arrangement comprising: an input chamber, a detection chamber, and a channel positioned to couple fluidly the entrance chamber and the detection chamber; and which also comprises: positioning a sample in the sample processing device's input chamber; wherein the rotation of the sample processing device about an axis of rotation causes the sample to move into the detection chamber.
[000367] Mode 32 is the method of mode 31, in which the sample processing device also includes a valve positioned in the channel, such that the inlet chamber and the detection chamber are not in fluid communication through the channel when the valve is closed and are in fluid communication through the channel when the valve is open, and which also comprises the opening of the valve, wherein the rotation of the sample processing device about an axis of rotation to move the sample for the detection chamber occurs after the valve is opened.
[000368] Mode 33 is the method of mode 31 or 32, wherein the rotation of the sample processing device about an axis of rotation to move the sample into the detection chamber includes loading a selected quantity of the sample in the detection chamber.
[000369] Modality 34 is the method of any of modalities 31-33, wherein the rotation of the sample processing device about an axis of rotation to move the sample into the detection chamber includes the displacement of a medium reagent into the detection chamber.
[000370] Mode 35 is the method of any of modalities 1-34, in which the determination of whether a selected volume of material is present in the detection chamber includes the optical verification of the detection chamber.
[000371] Mode 36 is a method for processing sample processing devices, wherein the method comprises: providing a sample processing device comprising a detection chamber; the rotation of the sample processing device about an axis of rotation; and the optical verification of the detection chamber for an optical property of a material to determine whether the material is present in the detection chamber, where the optical verification occurs while the sample processing device is rotated.
[000372] Mode 37 is the method of mode 36, in which the detection chamber is part of a processing arrangement in the sample processing device, and which also comprises positioning a sample in the processing arrangement of the sampling device. sample processing.
[000373] Mode 38 is the method of mode 36, in which the rotation of the sample processing device around an axis of rotation causes the sample to move into the detection chamber.
[000374] Method 39 is a method for processing sample processing devices, wherein the method comprises: providing a sample processing device comprising a processing arrangement, wherein the processing arrangement comprises: a chamber inlet, a detection chamber, and a channel positioned to fluidly couple the inlet chamber and the detection chamber; positioning a sample in the input chamber of the processing arrangement of the sample processing device; rotating the sample processing device about an axis of rotation to move the sample into the detection chamber; after the rotation of the sample processing device to move the sample to the detection chamber, the optical investigation of the detection chamber for an optical property of the sample to determine whether the sample has moved into the detection chamber; and rotating the sample processing device while optical detection of the detection chamber is performed.
[000375] Mode 40 is the method of mode 39, in which the sample processing device also includes a valve positioned in the channel, in such a way that the inlet chamber and the detection chamber are not in fluid communication through the channel when the valve is closed and are in fluid communication through the channel when the valve is open, and which also comprises the opening of the valve, wherein the rotation of the sample processing device about an axis of rotation to move the sample for the detection chamber occurs after the valve is opened.
[000376] Mode 41 is the method of mode 39 or 40, wherein the rotation of the sample processing device about an axis of rotation to move the sample into the detection chamber includes loading a selected quantity of the sample in the detection chamber.
[000377] Mode 42 is the method of any of modes 39-41, wherein the rotation of the sample processing device about an axis of rotation to move the sample into the detection chamber includes displacement of a medium reagent into the detection chamber.
[000378] Mode 43 is the method of any of modes 39-42, in which the rotation of the sample processing device while the optical verification of the detection chamber is made forces any material present in the detection chamber to a position in the detection chamber which is located furthest from the axis of rotation.
[000379] Mode 44 is the method of any of modes 39-43, in which the detection chamber includes an external perimeter positioned further away from the axis of rotation, and in which the rotation of the sample processing device while it is done the optical verification of the detection chamber forces any material present in the detection chamber to the outer perimeter of the detection chamber.
[000380] Mode 45 is the method of any of modes 39-44, in which the sample processing device is rotated continuously from the first rotation step through to the second rotation step, such that the processing device of samples does not stop rotating between the rotation steps.
[000381] Mode 46 is the method of any of modes 39-45, wherein the optical finding of the detection chamber includes the optical finding of the detection chamber for a meniscus.
[000382] Mode 47 is the method of any of modes 39-46, in which the optical investigation of the detection chamber includes the emission of an electromagnetic signal to the detection chamber, and the performance of a scan for the detection of reflection retrodiffuse the electromagnetic signal, after the electromagnetic signal is emitted to the detection chamber.
[000383] Mode 48 is the method of mode 47, in which obtaining a scan includes: performing a first scan of the bottom of the detection chamber before rotating the sample processing device to move the sample into the chamber detection, conducting a second scan of the detection chamber after rotating the sample processing device to move the sample to the detection chamber, and comparing the first background scan with the second scan to determine whether a selected volume of the sample is located in the detection chamber.
[000384] Mode 49 is the method of mode 48, in which the comparison of the first scan of the bottom with the second scan to determine whether a selected volume of the sample is located in the detection chamber includes the determination of whether there is a limit change between the first scan of the background and the second scan.
[000385] Mode 50 is the method of mode 49, which further comprises the provision of an optical module operatively positioned in relation to the sample processing device, in which the optical verification of the detection chamber includes the optical verification of the detection chamber. detection with the optical module in a plurality of radial positions, in relation to the axis of rotation.
[000386] Mode 51 is the method of mode 50, which further comprises: determining a radial position in which a limit change is located between the first sweep of the bottom and the second sweep; and the use of the radial position to determine the amount of the sample that is present in the detection chamber.
[000387] Mode 52 is the method of any of modalities 47-51, in which the performance of a scan by detecting the retrodiffused reflection of the electromagnetic signal is performed when using an optical FAM channel.
[000388] Mode 53 is the method of any one of modes 39-46, in which the optical investigation includes the emission of an electromagnetic signal to the detection chamber, and the performance of a scan by detecting the fluorescence emitted by a material in the detection chamber, after the emission of the electromagnetic signal to the detection chamber.
[000389] Mode 54 is the method of mode 53, in which obtaining a scan includes: performing a first scan of the bottom of the detection chamber before turning the sample processing device to move the sample into the chamber detection, performing a second scan of the detection chamber after rotating the sample processing device to move the sample for detection, and comparing the first background scan with the second scan to determine whether a selected sample volume is present in the detection chamber.
[000390] Mode 55 is the method of mode 54, in which the comparison of the first scan of the background with the second scan to determine whether a selected volume of the sample is present in the detection chamber includes the determination of whether there is a limit change in fluorescence between the first background scan and the second scan.
[000391] Mode 56 is the method of mode 55, which further comprises the provision of an optical module operatively positioned in relation to the sample processing device, in which the optical verification of the detection chamber includes the optical verification of the detection chamber. detection with the optical module in a plurality of radial positions, in relation to the axis of rotation.
[000392] Mode 57 is the method of mode 56, which further comprises: determining a radial position in which a limit change in fluorescence is located between the first scan of the background and the second scan; and the use of the radial position to determine the amount of the sample that is present in the detection chamber.
[000393] Mode 58 is the method of any of modes 39-57, which further comprises: heating the detection chamber, in which the determination whether a selected volume of material is present in the detection chamber occurs while it is heated the detection chamber.
[000394] Modality 59 is the method of any of the 38-58 modalities, in which the optical investigation includes the emission of an electromagnetic signal to the detection chamber at a first wavelength, and the detection of the electromagnetic signals emitted from the detection chamber at a second wavelength, after the emission of the electromagnetic signal to the detection chamber at a first wavelength.
[000395] Mode 60 is the method of any of modes 39-59, in which the sample includes a sample to be analyzed and a reagent medium, and in which the optical verification of the detection chamber includes the optical verification of the detection chamber. detection for an optical property of at least one of the sample and the reagent medium in the detection chamber.
[000396] Mode 61 is the method of any of modes 39-60, which further comprises the provision of an optical module operatively positioned in relation to the sample processing device in a gantry, and in which the optical investigation of the chamber The detection module includes the optical verification of the detection chamber with the optical module positioned in a predetermined position of the gantry.
[000397] Mode 62 is the method of any of modes 39-61, which further comprises the provision of an optical module operatively positioned in relation to the sample processing device in a gantry, and in which the optical investigation of the chamber The detection method includes the optical verification of the detection chamber with the optical module in a plurality of positions of the gantry.
[000398] Mode 63 is the method of mode 62, in which each position of the plurality of positions of the gantry is associated with a quantity of material, and which also comprises: the detection of a limit signal in a position of the gantry; and correlating the position of the gantry to an amount of material that is present in the detection chamber.
[000399] Mode 64 is the method of mode 62 or 63, in which the plurality of positions of the gantry include different radial positions in the detection chamber, in relation to the axis of rotation.
[000400] Mode 65 is the method of any of modes 62-64, in which a first position of the gantry is positioned radially out of a second position of the gantry.
[000401] Mode 66 is the method of any of modes 50-51, 56-57 and 61-65, in which the optical module is configured for the detection of multiplex fluorescence.
[000402] Mode 67 is the method of any of modes 39-66, which further comprises the optical investigation of the detection chamber to determine a quantity of sample that is present in the detection chamber.
[000403] Mode 68 is the method of any of modes 39-67, in which the sample processing device includes a plurality of processing arrangements and a plurality of detection chambers, and in which the optical verification of the Detection includes the optical verification of at least one chamber of the plurality of detection chambers while the sample processing device is rotated.
[000404] Mode 69 is a method for processing sample processing devices, wherein the method comprises: providing a sample processing device comprising a processing arrangement, wherein the processing arrangement comprises: a entrance chamber, a detection chamber, and a channel positioned to fluidly couple the entrance chamber and the detection chamber; positioning a sample in the input chamber of at least one processing arrangement in the sample processing device; rotating the sample processing device about an axis of rotation to move the sample into the detection chamber; optically checking the detection chamber of the processing arrangement before rotating the sample processing device to move the sample into the detection chamber to obtain a first scan of the bottom; optically checking the detection chamber of the processing arrangement to obtain a second scan after rotation of the sample processing device to move the sample into the detection chamber; the rotation of the sample processing device about the axis of rotation while the optical detection of the detection chamber is carried out to obtain the second scan; and comparing the first scan of the background with the second scan to determine whether there is a boundary change between the first scan of the background and the second scan.
[000405] Mode 70 is the method of mode 69, in which the optical verification of the detection chamber to generate a first scan of the bottom and the optical verification of the detection chamber to generate a second scan occur at the same temperature.
[000406] Mode 71 is a system for processing sample processing devices, wherein the system comprises: a sample processing device comprising a detection chamber; a motor configured to rotate the sample processing device about an axis of rotation; an optical module operatively positioned relative to the sample processing device and configured to determine whether a selected volume of material is present in the detection chamber of the sample processing device.
[000407] Mode 72 is the system of mode 71, in which the optical module is configured to determine whether a selected volume of material is present in the detection chamber while the engine rotates the sample processing device around the axis of rotation .
[000408] Mode 73 is the system of mode 71 or 72, in which the optical module includes a plurality of optical channels, and in which at least one of the optical channels is configured to determine whether a selected volume of material is present in the chamber detection of the sample processing device.
[000409] Mode 74 is the system of any of modalities 71-73, in which the sample processing device also includes an input chamber, and a channel positioned to fluidly couple the input chamber and the detection.
[000410] Mode 75 is the system of mode 74, in which the sample processing device also includes a valve positioned in the channel, in which, when the valve is closed, the inlet chamber and the detection chamber are not in fluid communication across the channel, and where when the valve is open, the inlet chamber and the detection chamber are in fluid communication across the channel.
[000411] Mode 76 is the system of mode 74 or 75, in which the input chamber includes a loading chamber configured to load a selected quantity of a sample into the detection chamber.
[000412] Mode 77 is the system of any of modalities 71-76, in which the optical module is positioned operatively in relation to the sample processing device through a gantry, and in which the optical module is configured to be positioned in a plurality of positions of the gantry, in relation to the axis of rotation, and is also configured to optically check the detection chamber in a plurality of positions of the gantry.
[000413] Mode 78 is the system of mode 77, in which the plurality of positions of the gantry correspond to different radial positions in the detection chamber, in relation to the axis of rotation.
[000414] Mode 79 is the system of mode 77 or 78, in which a first frame position is positioned radially out of a second frame position.
[000415] Mode 80 is the system of any of modes 71-76, in which the optical module is operatively positioned in relation to the sample processing device through a gantry, and in which the optical module is configured to be positioned at a predetermined position of the gantry, in relation to the axis of rotation, and is also configured to optically check the detection chamber at the predetermined position of the gantry.
[000416] Mode 81 is the system of mode 80, in which the detection chamber includes an internal perimeter located closer to the axis of rotation, and in which the optical module is configured to verify the detection chamber optically in a position of the gantry near the internal perimeter of the detection chamber.
[000417] Mode 82 is the system of any of modes 71-81, in which the optical module is configured to optically check the detection chamber to determine whether a selected volume of material is present in the detection chamber.
[000418] Mode 83 is the system of any of modalities 71-82, in which the optical module is configured for the detection of multiplex fluorescence.
[000419] Mode 84 is the system of any of modalities 71-83, in which the optical module is configured to determine whether a selected volume of material is present in the detection chamber through the emission of an electromagnetic signal for the detection chamber, and the detection of backscattered reflection of the electromagnetic signal.
[000420] Mode 85 is the system of any of modalities 71-84, in which the optical module is configured to determine whether a selected volume of material is present in the detection chamber through the emission of an electromagnetic signal for the detection chamber, and the detection of fluorescence emitted by a material in the detection chamber.
[000421] Mode 86 is the system of any of modalities 71-85, in which the optical module is configured to determine whether a selected volume of material is present in the detection chamber through the emission of an electromagnetic signal for the detection chamber at a first wavelength, and detecting the electromagnetic signals emitted from the detection chamber at a second wavelength, after an electromagnetic signal is emitted to the detection chamber at a first wavelength.
[000422] Mode 87 is the system of any of modalities 71-86, in which the optical module is also configured to determine a quantity of material that is present in the detection chamber.
[000423] The following practical examples should be illustrative and not limiting of the present invention. EXAMPLES EXAMPLE 1
[000424] Example 1 demonstrated direct sample (fluid) detection in the detection chambers of a Channel Development Disc. Materials:
[000425] Sample: Copan Universal Transport Medium (UTM) for viruses, Chlamydia, Mycoplasma and Ureaplasma, 3.0 ml tube, part number 330C, lot 39P505 (Copan Diagnostics, Murrietta, GA). Equipments:
[000426] A "Channel Development Disc", described above and shown in FIG. 23, available from 3M Company of St. Paul, MN, was used as a sample processing device or "disk" in this example.
[000427] An Integrated Cycler Model 3954, available from 3M Company of St. Paul, MN, was used with the Channel Development Disc as a sample processing system or "instrument" in this example. The instrument contained a FAM module (blue LED, 475 nm excitation filter, 520 nm detection filter). Procedure for Analysis of Sample Fluid Detection on the Channel Development Disc: 1. Empty Channel Development Disc added to the Integrated Cycler instrument. 2. Laser arrangement performed according to the method described above with respect to FIG. 14. 3. Background scan performed for all detection chambers; initial frame = 4000 to final frame = 8000; step size = 100; stipulated temperature = 25 ° C, when using the FAM module. 4. Disc stopped and disc removed from the instrument. 5. Various added amounts of UTM sample to different tracks on the disc: a. Lane 5: 5 pl of means of transport b. Lane 6: 10 pl of means of transport c. Lane 7: 15 pl of means of transport d. Lane 8: 20 pl of means of transport 6. Loaded disc replaced back in the instrument. 7. Laser arrangement performed, again according to the method described above with respect to FIG. 14. 8. Fluid loaded in detection chambers by rotating the disc, according to the following rotation scheme: 5 cycles a. Accelerated to 4,500 rpm at an acceleration of 244 revolutions / s2. B. Held at 4,500 for 1 second. ç. Decelerated to 750 rpm to a deceleration of 244 revolutions / s2. d. Maintained at 750 rpm for 1 second. 9. Sample detection scan performed; initial frame = 4000 to final frame = 9000; step size = 100; stipulated temperature = 25 ° C, when using the FAM module.
[000428] See Fig. 27: 5 pl of UTM in the detection chamber of track No.5
[000429] See Fig. 28: 10pl of UTM in the detection chamber of track No.6
[000430] See Fig. 29: 15pl of UTM in the detection chamber of track No.7
[000431] See Fig. 30: 20pl of UTM in the detection chamber of track No.8
[000432] FIGS. 27-30 represent the results of meniscus detection for samples of 5 pl, 10 pl, 15 pl and 20 pl, respectively. Each of the lots is a backscattered intensity scan (arbitrary units) versus the position of the gantry, with the gantry moving radially inward, such that the gantry position increases when the gantry is moved from a radially outward position to a radially inward position. The meniscus caused a refraction of the excitation beam and the retrodiffused intensity, which appeared as a depression between the positions of the 6000-7000 gantry. The largest and most reliable measurement was obtained in the FAM module. The magnitude of the depressions ranged from 10-15% of the value of the bottom scan. The result for 5 pl of the sample, shown in FIG. 27, indicated that at this low fluid level, the meniscus cannot be reliably detected. However, at sample fluid levels of 10 pl, 15 pl and 20 pl, the meniscus can be detected. EXAMPLE 2
[000433] Example 2 was the determination of the ideal position of the frame and the limit to automatically detect a 10 pl sample on a Moderately Complex Disc. Materials:
[000434] Sample: Copan Universal Transport Medium (UTM) for viruses, Chlamydia, Mycoplasma and Ureaplasma, 3.0 ml tube, part number 330C, lot 39P505 (Copan Diagnostics, Murrietta, GA). Equipments:
[000435] An Integrated Cycler instrument, model 3954, containing a FAM module (blue LED, 475 nm excitation filter, 520 nm detection filter), available from the 3M Company of St. Paul, MN, and two " Moderately Complex Discs "described above and shown in FIGS. 16-22, available as product no. 3958 with the 3M Company of St. Paul, MN, were used as a sample processing device or "disk" in this example. The first disc, representing the case of the "present sample", was loaded with 50 pl of UTM in the sample port of lanes 1-8. The second disc, representing the case of the "missing sample", was not loaded with any material. Both discs were processed identically with the following procedure: 1. The disc was placed in the Integrated Cycler instrument. 2. Measurement performed: The disk was rotated at 525 rpm with an acceleration of 24.4 revolutions / s2, maintained for 5 seconds, and then rotated at 975 RPM with an acceleration of 24.4 revolutions / s2, and maintained for 5 seconds. 3. Laser arrangement performed, according to the process shown in FIG. 14 and described above. The laser used was a high power density laser diode, part number SLD323V, available from Sony Corporation, Tokyo, Japan. 4. Background scanning performed from the detection chambers as a function of the frame position (initial frame = 4000, final frame = 9000, step size = 100) when using the FAM module. 5. The engine was stopped and the sample valves were opened with a 2 second laser pulse at 800 milliwatts (mW), according to the process shown in FIG. 12 and described above. 6. Sample transferred to the detection chambers by rotating the disc at 1,800 rpm with an acceleration of 24.4 revolutions / s2, and held for 10 seconds. 7. The detection chambers were scanned as a function of the gantry position, when using the FAM module; initial frame = 4000, final frame = 9000, step size = 100.
[000436] For each detection chamber on each disk, the percentage of change in the bottom signal was calculated as a function of the position of the gantry for the FAM module. A portion of the data in different positions of the gantry is shown in Table 1 below. Each detection chamber on disk 1 (sample present) had the largest signal change at position 5900 of the gantry. Each detection chamber on disk 2 (missing sample) had an insignificant percentage of change in the 5900 position of the gantry; in fact, an insignificant percentage of the change in all positions of the gantry. The mean and standard deviations of the data for each disk were calculated and are shown in Tables 1 and 2, below. TABLE 1 EXAMPLE 1 Disc 1 "Sample present"
TABLE 2 EXAMPLE 1 Disc 2 "Sample missing"


[000437] The data shows a significant difference between the sample and present sample disks. A limit value for automatically detecting the presence of the sample in a clinical trial at the ideal 5900 gantry position was calculated by subtracting 3 standard deviations from the mean value of the percent change in gantry position 5900, for disk 1. The calculated limit value was 12,298- (3x 1,814) = 6.85. EXAMPLE 3
[000438] Example 3 demonstrated two different fluid detection approaches on a Moderately Complex Disc with a main fluorescent reagent mix. Materials:
[000439] Sample: Copan Universal Transport Medium (UTM) for viruses, Chlamydia, Mycoplasma and Ureaplasma, 3.0 ml tube, part number 330C, lot 39P505 (Copan Diagnostics, Murrietta, GA).
[000440] Main reagent mix: Applied Biosystems (Foster City, CA) 10x PCR buffer, P / N 4376230, lot number 1006020, diluted to 1x with water without nuclease, spiked with ROX Reference Dye, Invitrogen (Carlsbad, CA) P / N 12223-012, lot number 786140. The final concentration of the dye was 800 nM. Equipments:
[000441] A "Moderately Complex Disc" described above and shown in FIGS. 16-22, available as product no. 3958 with the 3M Company of St. Paul, MN, was used as a sample processing device or "disk" in this example.
[000442] An Integrated Cycler Model 3954, with FAM module (see Examples 1 and 2) and the CFR610 module (yellow LED, 580 nm excitation filter, and 610 nm emission filter), available from 3M Company of St. Paul, MN, was used as a sample processing system or "instrument" in this example. Procedure for Detecting Sample and Total Fluid on the Moderately Complex Disc: 1. Each track on the disc was loaded in the following manner: TABLE 3
2. The loaded disc was positioned on the instrument. 3. Sample and reagent fluids loaded (10 µl sample and 40 µl reagent) into the loading reservoirs by the following procedure: the disc was spun at 525 rpm with an acceleration of 24.4 revolutions / s2, maintained for 5 seconds, then spun at 975 rpm with an acceleration of 24.4 revolutions / s2, and held for 5 seconds. 4. Laser layout performed, according to the process shown in FIG. 14 and described above. The laser used was a high power density laser diode, part number SLD323V, available from Sony Corporation, Tokyo, Japan. 5. Background scanning performed from the detection chambers as a function of the frame position (initial frame = 4000, final frame = 9000, step size = 100) when using the FAM module. 6. Engine stopped and sample septum valves open with a 2 second laser pulse at 800 mW, according to the process shown in FIG. 12 and described above. 7. Sample of UTM transferred to the detection chambers by rotating the disk at 1,800 rpm with an acceleration of 24.4 revolutions / s2, and maintained for 10 seconds. 8. The detection chambers were scanned as a function of the gantry position, when using the FAM module; initial frame = 4000, final frame = 9000, step size = 100. 9. Engine stopped and reagent septum valves open with a 2 second laser pulse at 800 mW, according to the method described above with respect to FIG . 12. 10. PCR buffer + ROX reagent transferred to the detection chambers by rotating the disk at 2,250 rpm with an acceleration of 244 revolutions / s2, and held for 10 seconds. 11. Detection chambers scanned as a function of the frame position when using the CFR610 module (initial frame = 4000, final frame = 9000, step size = 100).
[000443] Approach 1: Detection of the meniscus only from samples when using the FAM module
[000444] After the sample was transferred to the detection chamber (Step 7), the data collected in Step 8 was used to calculate the percentage change in backscattered intensity at the meniscus level at position 5900 of the gantry. The limit of 6.85 to automatically detect the presence of the sample in the detection chamber, determined in Example 2, was applied to the percentage change results shown in Table 4. The presence and absence of the sample in the detection chamber were determined with such accuracy as shown by the results in Table 4. TABLE 4. Detection of the sample meniscus, FAM module, gantry position 5900

[000445] Approach 2: Detection of total fluid (sample + reagent) when using the CFR610 module
[000446] The data for the CFR610 module acquired from Step 11 was processed for a detection of total fluid level. In this case, the signal was the fluorescence of the ROX dye in the buffer. There was no signal in the sample and empty detection chambers. The signal detected only from reagent (PCR buffer + ROX) had a higher peak and at a lower position of the gantry with respect to the sample + reagent cases because of the effect of the dilution of 10 pl of sample being added to 40 pl of buffer, and the highest volume that comes closest to the inner edge of the detection chambers. FIG. 31 illustrates this example by showing, for example, the large% increase for detection chambers 3 and 5 compared to detection chambers 1 and 7. Lanes 2, 4, 6 and 8 have been omitted in FIG. 31, since they were replicas of lanes 1, 3, 5 and 7, respectively.
[000447] A series of discs with detection chambers containing (i) the PCR + ROX buffer or (ii) the PCR + ROX buffer and sample was used to determine the position and the ideal limit of the gantry to outline the cases reagent chambers versus reagent + sample, following a process similar to that of Example 2. The ideal position of the gantry was determined as the positions in which there was the greatest difference in signal between the reagent only chambers and the reagent + sample chambers . The ideal position of the gantry was determined to be 7600, and the limit was determined to be 1398%. At a 7600 gantry position and using a 1398% limit, the presence of total 50 pl fluid in detection chambers 3 and 4 was accurately detected. Detection chambers 1 and 2 contain 10 µl of sample only (UTM); detection chambers 3 and 4 contain 40 µl reagent only (PCR buffer + ROX); and empty detection chambers 7 and 8 all had percentage change values below the 1398 limit and were thus designated as not having the correct total fluid level. Table 5 shows the results of applying the total fluid level detection approach to the disk in Example 3 when using the gantry position = 7600. TABLE 5. Detection of the total fluid level when using fluorescence, CFR610, gantry 7600


[000448] The modalities described above and illustrated in the figures are presented by way of example only and are not intended as a limitation on the concepts and principles of the present invention. In this way, it will be appreciated by an element skilled in the art that several changes in the elements and their configuration and arrangement are possible without deviating from the character and scope of the present invention.
[000449] All references and publications cited herein are hereby incorporated by reference in their entirety in this description.
[000450] Various features and aspects of the present invention are presented in the following claims.

权利要求:
Claims (26)
[0001]
1. A method for processing sample processing devices, the method comprising: providing a sample processing device (300) comprising a detection chamber (350); and rotating the sample processing device (300) about an axis of rotation; characterized by the fact that the method still comprises optically checking the detection chamber (350) to determine whether a selected volume of material is present in the detection chamber (350), while rotating the sample processing device (300).
[0002]
2. Method according to claim 1, characterized by the fact that optically verifying the detection chamber (350) includes the optical verification of the detection chamber (350) in a selected position to determine whether the material is present in the selected position .
[0003]
3. Method according to claim 1 or 2, characterized by the fact that optically checking the detection chamber (350) includes the optical checking of the detection chamber for an optical property of a sample to determine whether a selected volume of the sample is present in the detection chamber (350).
[0004]
Method according to any one of claims 1 to 3, characterized by the fact that the detection chamber (350) includes an internal perimeter (351) located closer to the axis of rotation (A), and in which to verify optically the detection chamber (350) includes optical verification of the detection chamber (350) in a gantry position close to the internal perimeter (351) of the detection chamber (350).
[0005]
Method according to any one of claims 2 to 4, characterized by the fact that optically checking the detection chamber (350) includes the optical checking of the detection chamber (350) for a meniscus.
[0006]
Method according to any one of claims 2 to 5, characterized by the fact that optically verifying the detection chamber (350) includes emitting an electromagnetic signal (49) to the detection chamber (350), and obtaining a scan by detecting backscattered reflection of the electromagnetic signal (49), after sending the electromagnetic signal (49) to the detection chamber (350).
[0007]
Method according to any one of claims 2 to 5, characterized by the fact that optically verifying the detection chamber (350) includes emitting an electromagnetic signal (49) to the detection chamber (350), and obtaining a scan by detecting the fluorescence emitted by a material in the detection chamber (350), after emitting the electromagnetic signal (49) to the detection chamber (350).
[0008]
Method according to claim 6 or 7, characterized in that obtaining a scan includes: obtaining a first scan of the detection chamber (350), obtaining a second scan of the detection chamber (350) after placing a sample in the detection chamber (350), and comparing the first background scan with the second scan to determine whether a selected volume of the sample is located in the detection chamber (350).
[0009]
9. Method according to claim 8, characterized in that comparing the first background scan with the second scan to determine whether a selected sample volume is located in the detection chamber (350) includes determining whether there is a limit change between the first background scan and the second scan.
[0010]
10. Method, according to claim 9, characterized by the fact that it still comprises providing an optical module (48, 52, 56) operatively positioned in relation to the sample processing device (300) in a gantry (60), in that optically verifying the detection chamber (350) includes the optical verification of the detection chamber (350) with the optical module (48, 52, 56) in a plurality of radial positions, in relation to the axis of rotation (A).
[0011]
11. Method, according to claim 10, characterized by the fact that it still comprises: determining a radial position in which a limit change is located between the first background scan and the second scan; and use the radial position to determine the sample volume that is located in the detection chamber (350).
[0012]
12. Method for processing sample processing devices, the method comprising: providing a sample processing device (300) comprising a detection chamber (350); and rotating the sample processing device (300) about an axis of rotation; characterized by the fact that the method still comprises optically checking the detection chamber (350) to determine whether a selected volume of material is present in the detection chamber (350), while rotating the sample processing device (300).
[0013]
13. Method according to claim 1, characterized by the fact that optically checking the detection chamber (350) includes the optical checking of the detection chamber (350) in a selected position to determine whether the material is present in the selected position .
[0014]
14. Method according to claim 1 or 2, characterized in that optically checking the detection chamber (350) includes the optical checking of the detection chamber for an optical property of a sample to determine whether a selected volume of the sample is present in the detection chamber (350).
[0015]
15. Method according to any one of claims 1 to 3, characterized in that the detection chamber (350) includes an internal perimeter (351) located closer to the axis of rotation (A), and in which to verify optically the detection chamber (350) includes optical verification of the detection chamber (350) in a gantry position close to the internal perimeter (351) of the detection chamber (350).
[0016]
16. Method according to any one of claims 2 to 4, characterized by the fact that optically checking the detection chamber (350) includes the optical checking of the detection chamber (350) for a meniscus.
[0017]
17. Method according to any one of claims 2 to 5, characterized by the fact that optically verifying the detection chamber (350) includes emitting an electromagnetic signal (49) to the detection chamber (350), and obtaining a scan by detecting backscattered reflection of the electromagnetic signal (49), after sending the electromagnetic signal (49) to the detection chamber (350).
[0018]
18. Method according to any of claims 2 to 5, characterized by the fact that optically verifying the detection chamber (350) includes emitting an electromagnetic signal (49) to the detection chamber (350), and obtaining a scan by detecting the fluorescence emitted by a material in the detection chamber (350), after emitting the electromagnetic signal (49) to the detection chamber (350).
[0019]
19. Method according to claim 6 or 7, characterized in that obtaining a scan includes: obtaining a first scan of the detection chamber (350), obtaining a second scan of the detection chamber (350) after placing a sample in the detection chamber (350), and comparing the first background scan with the second scan to determine whether a selected volume of the sample is located in the detection chamber (350).
[0020]
20. Method according to claim 8, characterized in that comparing the first background scan with the second scan to determine whether a selected sample volume is located in the detection chamber (350) includes determining whether there is a limit change between the first background scan and the second scan.
[0021]
21. Method, according to claim 9, characterized by the fact that it also comprises providing an optical module (48, 52, 56) operatively positioned in relation to the sample processing device (300) in a gantry (60), in that optically verifying the detection chamber (350) includes the optical verification of the detection chamber (350) with the optical module (48, 52, 56) in a plurality of radial positions, in relation to the axis of rotation (A).
[0022]
22. Method, according to claim 10, characterized by the fact that it still comprises: determining a radial position in which a limit change is located between the first background scan and the second scan; and use the radial position to determine the sample volume that is located in the detection chamber (350).
[0023]
23. Method according to any one of claims 2-10, characterized in that it further comprises providing an optical module (48, 52, 56) operatively positioned in relation to the sample processing device (300) in a gantry ( 60), and wherein optically verifying the detection chamber includes optical verification of the detection chamber (350) with the optical module (48, 52, 56) in a plurality of gantry positions.
[0024]
24. Method according to claim 12, characterized by the fact that each position of the plurality of gantry positions is associated with a quantity of material, and further comprises: detecting a limit signal in a gantry position; and correlating the gantry position to an amount of material that is present in the detection chamber (350).
[0025]
25. Method according to claim 12 or 13, characterized in that the plurality of gantry positions includes different radial positions in the detection chamber (350), in relation to the axis of rotation (A).
[0026]
26. System for processing sample processing devices, the system comprising: a sample processing device (300) comprising a detection chamber (350); a motor (126) configured to rotate the sample processing device (300) about an axis of rotation (A); characterized by an optical module (48) operatively positioned in relation to the sample processing device (300) and configured to optically check the detection chamber (350) to determine whether a selected volume of material is present in the detection chamber (350) of the sample processing device (300), while rotating the sample processing device (300).

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引用文献:

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公开号 | 申请日 | 公开日 | 申请人 | 专利标题

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法律状态:
2017-10-31| B25A| Requested transfer of rights approved|Owner name: FOCUS DIAGNOSTICS, INC. (US) , QUEST DIAGNOSTICS I |

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2017-11-21| B25A| Requested transfer of rights approved|Owner name: FOCUS DIAGNOSTICS, INC. (US) , DIASORIN S.P.A. (IT |

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2018-04-03| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]|

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2019-07-23| B06U| Preliminary requirement: requests with searches performed by other patent offices: procedure suspended [chapter 6.21 patent gazette]|

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2020-06-09| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|

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2020-11-03| B16A| Patent or certificate of addition of invention granted [chapter 16.1 patent gazette]|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 18/05/2012, OBSERVADAS AS CONDICOES LEGAIS. |

优先权:

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申请号 | 申请日 | 专利标题

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US201161487618P| true| 2011-05-18|2011-05-18|

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US61/487,618|2011-05-18|

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PCT/US2012/038498|WO2012158997A1|2011-05-18|2012-05-18|Systems and methods for detecting the presence of a selected volume of material in a sample processing device|

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