Patent Grant
11788127
The systems and methods disclosed herein relate generally to the automated execution of nucleic acid amplification assays, such as Polymerase Chain Reaction (PCR), and in some instances real-time PCR, in a plurality of micro-fluidic reaction chambers in a microfluidic cartridge. The system may subsequently detect target nucleic acids, e.g., target amplicons, within each of the reaction chambers.
The medical diagnostics industry is a critical element of today's healthcare infrastructure. At present, however, in vitro diagnostic analyses, no matter how routine, have become a bottleneck in patient care. There are several reasons for this. First, many diagnostic analyses can only be done with highly specialized equipment that is both expensive and only operable by trained clinicians. Such equipment may be found in only a few locations—often just one in any given urban area. This requires hospitals to send out samples for analyses to these locations, thereby incurring shipping costs and transportation delays, and possibly even sample loss or mishandling. Second, the equipment in question is typically not available “on-demand” but instead runs in batches, thereby delaying the processing time for many samples as they must wait for a machine to reach capacity before they can be run.
Understanding that diagnostic assays on biological samples may break down into several key steps, it is often desirable to automate one or more steps. For example, a biological sample, such as those obtained from a patient, can be used in nucleic acid amplification assays, in order to amplify a target nucleic acid (e.g., DNA, RNA, or the like) of interest. Once amplified, the presence of a target nucleic acid, or amplification product of a target nucleic acid (e.g., a target amplicon) reactor can be detected, wherein the presence of a target nucleic acid and/or target amplicon is used to identify and/or quantify the presence of a target (e.g., a target microorganism or the like). Often, nucleic acid amplification assays involve multiple steps, which can include nucleic acid extraction, nucleic acid amplification, and detection. It is desirable to automate certain steps of these processes.
There is a need for a method and apparatus for carrying out molecular diagnostic assays on multiple samples in parallel, with or without amplification of target nucleic acids, and detection on a prepared biological samples. The system may be configured for high throughput, and operation in a commercial reference laboratory or at the point of care, thereby eliminating the need to send the sample out to a specialized facility.
The embodiments disclosed herein relate to methods and devices for the simultaneous testing of multiple samples. Certain embodiments contemplate an apparatus for performing real-time nucleic acid amplification and detection. The apparatus can include a detector head comprising a plurality of photodetector and light source pairs. The detector head can be mounted on a rail, wherein the detector and light source pairs are aligned in a first row and a second row. The apparatus can include a receptacle for a microfluidic cartridge that has a plurality of independent reaction chambers aligned in adjacent columns of a first row and a second row. The apparatus can also include an aperture plate that is configured to be positioned over the microfluidic cartridge when the cartridge is present in the receptacle. The aperture plate can include a plurality of apertures that are each aligned over each of the plurality of reaction chambers when the receptacle is holding the microfluidic cartridge. The detector head can be located over the aperture plate, and be moveable along the rail, such that each of the plurality of photodetector and light source pairs in the first row can be positioned over each aperture in the first row of the aperture plate, and each of the plurality of photodetector and light source pairs in the second row can be positioned over each aperture in the second row of the aperture plate.
In some embodiments, the apparatus also includes a second detector head that has a plurality of photodetector and light source pairs aligned into a first row and a second row. The second detector head can be mounted on the rail. The apparatus can also include a second receptacle for a microfluidic cartridge including a plurality of independent reaction chambers aligned in adjacent columns of a first row and a second row. The apparatus can also include a second aperture plate configured to be positioned over the second microfluidic cartridge when the second cartridge is present in the second receptacle, and which can include a plurality of apertures that are each aligned over each of the plurality of reaction chambers of the second microfluidic cartridge when the second receptacle is holding the second microfluidic cartridge. The second detector head can be located over the aperture plate, and can be moveable along the rail such that each of the plurality of photodetector and light source pairs in the first row of the second detector head can be positioned over each aperture in the first row of the second aperture plate, and each of the plurality of photodetector and light source pairs in the second row of the second detector head can be positioned over each aperture in the second row of the second aperture plate.
In some embodiments, the photodetector and light source pairs can include at least six different photodetector and light source pairs operating in six different wavelengths. In some embodiments, the six different wavelengths comprise a light source emitting a green colored light, a light source emitting a yellow colored light, a light source emitting an orange colored light, a light source emitting a red colored light, and a light source emitting a crimson colored light. In some embodiments, the detector head includes at least N rows of photodetector and light source pairs, and the detector is configured to move to at least M+N−1 positions over an aperture plate comprising M rows of apertures.
In some embodiments, the aperture plate comprises steel, aluminum, nickel, or a combination thereof. In some embodiments, the aperture plate can have a thickness of approximately 0.25 inches. In some embodiments, at least part of the aperture plate is electrochemically oxidized to be darker than when the aperture plate is not electrochemically oxidized. In some embodiments, the aperture plate provides substantially uniform pressure across the area of the microfluidic cartridge, when the cartridge is present within the receptacle. In some embodiments, the aperture plate comprises at least one of aluminum, zinc or nickel, the aperture plate further comprising a colorant.
In some embodiments, the apparatus further comprises a heater plate, wherein the heater plate is positioned underneath the microfluidic cartridge when a cartridge is present in the receptacle. In some embodiments the heater plate comprises at least one of glass or quartz. In some embodiments, the aperture plate provides substantially uniform pressure across the area of the microfluidic cartridge when a cartridge is present within the receptacle. The substantially uniform pressure can facilitate substantially uniform thermal contact between the microfluidic reaction chambers and the heater plate. As such, in some embodiments, the aperture plate provide uniform pressure that can ensure that each of the plurality of reaction chambers or reactors in the microfluidic cartridge are in uniformly thermal contact or communication with a respective a plurality of heating elements located within the heater plate.
In some embodiments, the apparatus further comprises a photodetector, the photodetector located over the aperture plate, wherein the micro-fluidic chamber is configured to receive light at a glancing angle from a light source relative to the photodetector. In some embodiments, the heater plate comprises a plurality of heating elements, wherein each of the plurality of heating elements is positioned such that when the microfluidic cartridge is present in the receptacle, the plurality of heating elements are in thermal connection with each of the plurality of reaction chambers, respectively.
Certain embodiments contemplate a method implemented on one or more computer processors for optimizing protocols, such as polymerase chain reaction (PCR) protocols or the like, for simultaneously performing a plurality of thermal cycling reactions, wherein each thermal cycling reaction comprises one or more detection steps, and wherein the thermal cycling reactions are performed in a plurality of reactors. The method can include the steps of determining or providing or accessing a detection cycle time for each of the plurality of reactors; receiving or accessing a protocol step, the step associated with a step duration, the step comprising a time for detection; and determining a first adjustment to the step such that the step duration is a multiple of the detection cycle time.
In some embodiments the method further comprises determining a second adjustment to the step, wherein the time for detection is a multiple of the detection cycle time when the step is adjusted by the first adjustment and by the second adjustment. In some embodiments the method further comprises determining a starting offset adjustment based on a position of a reaction chamber associated with the protocol. In some embodiments, the detection cycle time comprises the amount of time required for a detector head to perform a predetermined plurality of detections for a reactor. In some embodiments, the detection cycle time includes a time required for movement of the detector head to each of a plurality of reactors and movement of the detector head to the start position. In some embodiments, the method further comprises initiating the protocol.
Certain embodiments contemplate a non-transitory computer-readable medium comprising instructions, the instructions configured to cause one or more processors to perform the following steps: determining or providing or accessing a detection cycle time; receiving or accessing a protocol step, wherein the step is associated with a step duration, and the wherein step includes a time for detection; and determining a first adjustment to the step such that the step duration is a multiple of the detection cycle time.
In some embodiments, the protocol step is associated with a protocol from a plurality of protocols. Each of the plurality of protocols can be associated with at least one of a plurality of thermal cycling reactions, such as polymerase chain reaction (PCR) protocols, wherein each thermal cycling reaction comprises one or more detection steps, and wherein the determining a first adjustment is based at least in part on a timing of one or more detection steps associated with the thermal cycling reactions of at least two or more of the plurality of protocols when the two or more of the plurality of protocols are simultaneously run. In some embodiments, the method also includes the step of determining a second adjustment to the step, wherein the time for detection is a multiple of the detection cycle time when the step is adjusted by the first adjustment and by the second adjustment. In some embodiments, the method also includes the step of determining a starting offset adjustment based on a position of a reaction chamber associated with the protocol. In some embodiments, the detection cycle time includes the amount of time required for a detector head to perform a predetermined plurality of detections for a reaction chamber. In some embodiments, the detection cycle time also includes a time required for movement of the detector head to each of a plurality of reaction chamber detection positions and movement of the detector head to a start position. In some embodiments, the method further comprises initiating the protocol.
Certain embodiments contemplate a system for optimizing protocols for a plurality of reaction chambers. The system can include a processor configured to perform the following: determining or providing or accessing a detection cycle time; receiving or accessing a protocol step, wherein the step can be associated with a step duration, and wherein the step includes a time for detection; and determining a first adjustment to the step such that the step duration is a multiple of the detection cycle time.
In some embodiments, the protocol step is associated with a protocol from a plurality of protocols. Each of the plurality of protocols can be associated with at least one of a plurality of thermal cycling reactions, such as a polymerase chain reaction (PCR) protocol, wherein each thermal cycling reaction comprises one or more detection steps, and wherein the determining a first adjustment is based at least in part on a timing of one or more detection steps associated with the thermal cycling reactions of at least two or more of the plurality of protocols when the two or more of the plurality of protocols are simultaneously run. In some embodiments, the processor is also configured to determine a second adjustment to the step, wherein the time for detection is a multiple of the detection cycle time when the step is adjusted by the first adjustment and by the second adjustment. In some embodiments, the processor is also configured to determine a starting offset adjustment based on a position of a reaction chamber associated with the protocol. In some embodiments, the detection cycle time includes the amount of time required for a detector head to perform a predetermined plurality of detections for a reaction chamber. In some embodiments, the detection cycle time also includes a time required for movement of the detector head to each of a plurality of reaction chamber detection positions and movement of the detector head to the start position. In some embodiments, the processor is further configured to initiate the protocol.
Certain embodiments contemplate a method for simultaneously performing real-time PCR in a plurality of PCR reaction chambers, comprising: (a) providing a scan time sufficient for a detector assembly to perform a scan cycle during which it can scan each of the plurality of PCR reaction chambers for at least one detectable signal and become ready to repeat the scan; (b) providing a reaction protocol for each of the PCR reaction chambers that includes multiple cycles, each cycle comprising a cycle time that includes at least one heating step, at least one cooling step, and at least one temperature plateau that includes a reading cycle period during which the detector assembly is to scan the reaction chamber for at least one detectable signal; (c) determining, using a processor, whether the cycle time for that reaction chamber is the same as or an integer multiple of the scan time, and if not, adjusting the scan time or the cycle time so that the cycle time is the same as or an integer multiple of the scan time; (d) performing at least steps (b) and (c) for the reaction protocol for each of the plurality of PCR reaction chambers so that the cycle time for each reaction protocol is the same as or an integer multiple of the scan time; and (e) under direction of a processor, performing real time PCR on each of the reaction chambers using the reaction protocol for each of the reaction chambers, including performing multiple scan cycles with the detector assembly, wherein each PCR reaction chamber is scanned by the detector assembly during each reading cycle period for that reaction chamber.
In some embodiments the method further comprises phase adjusting the cycle time of the reaction protocol for at least one of the reaction chambers. In some embodiments, at least one said reaction protocol is different from another said reaction protocol. In some embodiments, at least one cycle time in one reaction protocol is different from the cycle time in another reaction protocol.
Certain of the present embodiments contemplate an apparatus, referred to herein as a thermocycler, which may consistently heat and analyze microfluidic chambers. Polynucleotide amplification, such as by real-time PCR, can be performed within the microfluidic chambers. In some embodiments, the thermocycler can be configured to perform individual thermocycling and detection protocols in a plurality of microfluidic reaction chambers within a microfluidic cartridge. The thermocycling can be used to amplify nucleic acids, e.g., DNA, RNA or the like, e.g., by real-time PCR or other nucleic acid amplification protocols described herein, within the microfluidic reaction chambers. The thermocycler may comprise a detector head, comprising a plurality of detector pairs, e.g., six or more detector head pairs, wherein each detector pair comprises a light-emitting source, e.g., an LED or the like, and a cognate photodiode. In some embodiments, each individual detector pair is configured to generate and detect light emitted from a fluorescent moiety, e.g., a fluorescent probe, to indicate the presence of a target polynucleotide.
As used herein, the term “microfluidic” refers to volumes of less than 1 ml, preferably less than 0.9 ml, e.g., 0.8 ml, 0.7 ml, 0.6 ml, 0.5 ml, 0.4 ml, 0.3 ml, 0.2 ml, 0.1 ml, 90 μl, 80 μl, 70 μl, 60 μl, 50 μl, 40 μl, 30 μl, 20 μl, 10 μl, 5 μl, 4 μl, 3 μl, 2 μl, 1 μl, or less, or any amount in between. It is to be understood that, unless specifically made clear to the contrary, where the term PCR is used herein, any variant of PCR including but not limited to real-time and quantitative PCR, and any other form of polynucleotide amplification is intended to be encompassed.
The detection process used in the assay may also be multiplexed to permit multiple concurrent measurements on multiple reactions concurrently. In some embodiments, these measurements may be taken from separate reaction chambers. Certain of these embodiments perform a plurality of PCR reactions simultaneously in a single PCR reaction chamber, e.g., multiplex PCR. A PCR protocol may comprise guidelines for performing the successive annealing and denaturing of the polynucleotides in the reaction chamber prior to detection. Such guidelines, comprising a time profile for heating the chamber, may be referred to as a “protocol”. Certain of the disclosed embodiments facilitate consistent heating and/or cooling across a plurality of reaction chambers performing PCR, while facilitating detection using a sensor array. In certain embodiments, the apparatus may comprise an aperture plate which facilitates consistent heating and cooling of the reaction chambers by applying pressure to a cartridge containing a plurality of PCR reaction chambers. Certain details and methods for processing polynucleotides may be found in e.g., U.S. Patent Application Publication 2009-0131650 and U.S. Patent Application Publication 2010-0009351, incorporated herein by reference.
The skilled artisan will appreciate that the embodiments disclosed herein are useful for various types of nucleic acid amplification reactions. For example, methods of nucleic acid amplification in connection with the embodiments disclosed herein can include, but are not limited to: polymerase chain reaction (PCR), strand displacement amplification (SDA), for example multiple displacement amplification (MDA), loop-mediated isothermal amplification (LAMP), ligase chain reaction (LCR), immuno-amplification, and a variety of transcription-based amplification procedures, including transcription-mediated amplification (TMA), nucleic acid sequence based amplification (NASBA), self-sustained sequence replication (3SR), and rolling circle amplification. See, e.g., Mullis, “Process for Amplifying, Detecting, and/or Cloning Nucleic Acid Sequences,” U.S. Pat. No. 4,683,195; Walker, “Strand Displacement Amplification,” U.S. Pat. No. 5,455,166; Dean et al, “Multiple displacement amplification,” U.S. Pat. No. 6,977,148; Notomi et al., “Process for Synthesizing Nucleic Acid,” U.S. Pat. No. 6,410,278; Landegren et al. U.S. Pat. No. 4,988,617 “Method of detecting a nucleotide change in nucleic acids”; Birkenmeyer, “Amplification of Target Nucleic Acids Using Gap Filling Ligase Chain Reaction,” U.S. Pat. No. 5,427,930; Cashman, “Blocked-Polymerase Polynucleotide Immunoassay Method and Kit,” U.S. Pat. No. 5,849,478; Kacian et al., “Nucleic Acid Sequence Amplification Methods,” U.S. Pat. No. 5,399,491; Malek et al., “Enhanced Nucleic Acid Amplification Process,” U.S. Pat. No. 5,130,238; Lizardi et al., BioTechnology, 6:1197 (1988); Lizardi et al., U.S. Pat. No. 5,854,033 “Rolling circle replication reporter systems.”
In some embodiments disclosed herein, the target nucleic acid, e.g., target amplicon, can be detected using an oligonucleotide probe. Preferably, the probes include one or more detectable moieties that can be detected by the systems disclosed herein. The skilled artisan will appreciate that several probe technologies are useful in the embodiments described herein. By way of example, the embodiments disclosed herein can be used with TAQMAN® probes, molecular beacon probes, SCORPION™ probes, and the like.
TaqMan® assays are homogenous assays for detecting polynucleotides (see U.S. Pat. No. 5,723,591). In TAQMAN® assays, two PCR primers flank a central TAQMAN® probe oligonucleotide. The probe oligonucleotide contains a fluorophore and quencher. During the polymerization step of the PCR process, the 5′ nuclease activity of the polymerase cleaves the probe oligonucleotide, causing the fluorophore moiety to become physically separated from the quencher, which increases fluorescence emission. As more PCR product is created, the intensity of emission at the novel wavelength increases.
Molecular beacons are an alternative to TAQMAN® probes for the detection of polynucleotides, and are described in, e.g., U.S. Pat. Nos. 6,277,607; 6,150,097; and 6,037,130. Molecular beacons are oligonucleotide hairpins which undergo a conformational change upon binding to a perfectly matched template. The conformational change of the oligonucleotide increases the physical distance between a fluorophore moiety and a quencher moiety present on the oligonucleotide. This increase in physical distance causes the effect of the quencher to be diminished, thus increasing the signal derived from the fluorophore.
The adjacent probes method amplifies the target sequence by polymerase chain reaction in the presence of two nucleic acid probes that hybridize to adjacent regions of the target sequence, one of the probes being labeled with an acceptor fluorophore and the other probe labeled with a donor fluorophore of a fluorescence energy transfer pair. Upon hybridization of the two probes with the target sequence, the donor fluorophore interacts with the acceptor fluorophore to generate a detectable signal. The sample is then excited with light at a wavelength absorbed by the donor fluorophore and the fluorescent emission from the fluorescence energy transfer pair is detected for the determination of that target amount. U.S. Pat. No. 6,174,670 discloses such methods.
Sunrise primers utilize a hairpin structure similar to molecular beacons, but attached to a target binding sequence which serves as a primer. When the primer's complementary strand is synthesized, the hairpin structure is disrupted, thereby eliminating quenching. These primers detect amplified product and do not require the use of a polymerase with a 5′ exonuclease activity. Sunrise primers are described by Nazarenko et al. (Nucleic Acids Res. 25:2516-21 (1997) and in U.S. Pat. No. 5,866,336.
SCORPION™ probes combine a primer with an added hairpin structure, similar to Sunrise primers. However, the hairpin structure of SCORPION™ probes is not opened by synthesis of the complementary strand, but by hybridization of part of the hairpin structure with a portion of the target which is downstream from the portion which hybridizes to the primer.
DzyNA-PCR involves a primer containing the antisense sequence of a DNAzyme, an oligonucleotide capable of cleaving specific RNA phosphodiester bonds. The primer binds to a target sequence and drives an amplification reaction producing an amplicon which contains the active DNAzyme. The active DNAzyme then cleaves a generic reporter substrate in the reaction mixture. The reporter substrate contains a fluorophore-quencher pair, and cleavage of the substrate produces a fluorescence signal which increases with the amplification of the target sequence. DNAzy-PCR is described in Todd et al., Clin. Chem. 46:625-30 (2000), and in U.S. Pat. No. 6,140,055.
Fiandaca et al. describes a fluorogenic method for PCR analysis utilizing a quencher-labeled peptide nucleic acid (Q-PNA) probe and a fluorophore-labeled oligonucleotide primer. Fiandaca et al. Genome Research. 11:609-613 (2001). The Q-PNA hybridizes to a tag sequence at the 5′ end of the primer.
Li et al. describes a double stranded probe having a quencher and fluorophore on opposite oligonucleotide strands. Li et al. Nucleic Acids Research. 30(2): e5, 1-9 (2002). When not bound to the target, the strands hybridize to each other and the probe is quenched. However, when a target is present at least one strand hybridizes to the target resulting in a fluorescent signal.
Fluorophore labels and moieties useful in the embodiments disclosed herein include, but are not limited to, dyes of the fluorescein family, the carboxyrhodamine family, the cyanine family, and the rhodamine family. Other families of dyes that can be used in the invention include, e.g., polyhalofluorescein-family dyes, hexachlorofluorescein-family dyes, coumarin-family dyes, oxazine-family dyes, thiazine-family dyes, squaraine-family dyes, chelated lanthanide-family dyes, the family of dyes available under the trade designation Alexa Fluor J, from Molecular Probes, and the family of dyes available under the trade designation Bodipy J, from Invitrogen (Carlsbad, Calif.). Dyes of the fluorescein family include, e.g., 6-carboxyfluorescein (FAM), 2′,4′,1,4,-tetrachlorofluorescein (TET), 2′,4′,5′,7′,1,4-hexachlorofluorescein (HEX), 2′,7′-dimethoxy-4′,5′-dichloro-6-carboxyrhodamine (JOE), 2′-chloro-5′-fluoro-7′,8′-fused phenyl-1,4-dichloro-6-carboxyfluorescein (NED), 2′-chloro-7′-phenyl-1,4-dichloro-6-carboxyfluorescein (VIC), 6-carboxy-X-rhodamine (ROX), and 2′,4′,5′,7′-tetrachloro-5-carboxy-fluorescein (ZOE). Dyes of the carboxyrhodamine family include tetramethyl-6-carboxyrhodamine (TAMRA), tetrapropano-6-carboxyrhodamine (ROX), Texas Red, R110, and R6G. Dyes of the cyanine family include Cy2, Cy3, Cy3.5, Cy5, Cy5.5, and Cy7. Fluorophores are readily available commercially from, for instance, Perkin-Elmer (Foster City, Calif.), Molecular Probes, Inc. (Eugene, Oreg.), and Amersham GE Healthcare (Piscataway, N.J.).
As discussed above, in some embodiments, the probes useful in the embodiments disclosed herein can comprise a quencher. Quenchers may be fluorescent quenchers or non-fluorescent quenchers. Fluorescent quenchers include, but are not limited to, TAMRA, ROX, DABCYL, DABSYL, cyanine dyes including nitrothiazole blue (NTB), anthraquinone, malachite green, nitrothiazole, and nitroimidazole compounds. Exemplary non-fluorescent quenchers that dissipate energy absorbed from a fluorophore include those available under the trade designation Black Hole™ from Biosearch Technologies, Inc. (Novato, Calif.), those available under the trade designation Eclipse™. Dark, from Epoch Biosciences (Bothell, Wash.), those available under the trade designation Qx1J, from Anaspec, Inc. (San Jose, Calif.), and those available under the trade designation Iowa Black™ from Integrated DNA Technologies (Coralville, Iowa).
In some embodiments discussed above, a fluorophore and a quencher are used together, and may be on the same or different oligonucleotides. When paired together, a fluorophore and fluorescent quencher can be referred to as a donor fluorophore and acceptor fluorophore, respectively. A number of convenient fluorophore/quencher pairs are known in the art (see, for example, Glazer et al, Current Opinion in Biotechnology, 1997; 8:94-102; Tyagi et al., 1998, Nat. Biotechnol., 16:49-53) and are readily available commercially from, for instance, Molecular Probes (Junction City, Oreg.), and Applied Biosystems (Foster City, Calif.). Examples of donor fluorophores that can be used with various acceptor fluorophores include, but are not limited to, fluorescein, Lucifer Yellow, B-phycoerythrin, 9-acridineisothiocyanate, Lucifer Yellow VS, 4-acetamido-4′-isothio-cyanatostilbene-2,2′-disulfonic acid, 7-di ethyl amino-3-(4′-isothiocyanatophenyl)-4-methylcoumarin, succinimdyl 1-pyrenebutyrate, and 4-acetamido-4′-isothiocyanatostilbene-2-,2′-disulfonic acid derivatives. Acceptor fluorophores typically depend upon the donor fluorophore used. Examples of acceptor fluorophores include, but are not limited to, LC-Red 640, LC-Red 705, Cy5, Cy5.5, Lissamine rhodamine B sulfonyl chloride, tetramethyl rhodamine isothiocyanate, rhodamine×isothiocyanate, erythrosine isothiocyanate, fluorescein, diethylenetriamine pentaacetate or other chelates of Lanthanide ions (e.g., Europium, or Terbium). Donor and acceptor fluorophores are readily available commercially from, for instance, Molecular Probes or Sigma Chemical Co. (St. Louis, Mo.). Flourophore/quencher pairs useful in the compositions and methods disclosed herein are well-known in the art, and can be found, e.g., described in S. Marras, “Selection of Fluorophore and Quencher Pairs for Fluorescent Nucleic Acid Hybridization Probes” available at the world wide web site molecular-beacons.org/download/marras,mmb06%28335%293.pdf (as of Apr. 11, 2012).
The detection process used in the assays disclosed herein advantageously permits multiple concurrent measurements of multiple detectable moieties, e.g., a plurality of probes containing different detectable moieties, etc. In some embodiments, these measurements may be taken from separate reaction chambers within a microfluidic cartridge, e.g., comprising a chamber layer (the chamber layer referring herein to that portion of the microfluidic cartridge containing the reaction chambers). Certain of these embodiments perform a plurality of amplification reactions simultaneously in a single reaction chamber, e.g., multiplex PCR. A PCR protocol may comprise guidelines for performing the successive annealing and denaturing of the polynucleotides in the reaction chamber prior to detection. In certain embodiments, the apparatus is configured to facilitate consistent heating and/or cooling across a plurality of reaction chambers to perform nucleic acid amplification, and to facilitate detection of target amplicons in individual reaction chambers, e.g., by detecting fluorescent emissions, using a sensor array.
In certain embodiments, the apparatus may comprise an aperture plate which facilitates consistent heating and cooling of the reaction chambers by applying pressure to a cartridge containing a plurality of reaction chambers via multiple, independent optical pairs. The aperture plate is preferably configured to enable and facilitate the generation and detection of fluorescent signals from probes within multiple, independent reaction chambers. In some embodiments, the aperture plate is configured such that there is an individual aperture (or windows), positioned over each of the individual reaction chambers in the microfluidic cartridge.
Diagnostic Apparatus
As seen in the embodiments of
In some embodiments, each specimen rack 24a, 24b may include multiple holders 26. The holders 26 may include receptacles for holding diagnostic reagents, such as reagents for nucleic acid amplification, e.g., PCR reagents or the like. The racks 24 may also include specimen tubes (not shown) and mixing tubes (not shown) for preparing diagnostic-ready samples, such as amplification-ready samples. The apparatus may prepare the desired reagents in the racks 24a, 24b using the dispenser 400. Further description of various fluid dispensers may be found in e.g., U.S. Patent Application Publication 2009-0130719 and U.S. Patent Application Publication 2009-0155123, incorporated herein by reference.
In some embodiments, the reaction chambers within the microfluidic cartridge(s) includes one or more reagents, buffers, etc., used in the nucleic amplification assay. For example, in some embodiments, the reaction chambers of the microfluidic cartridge can include, e.g., amplification primers, probes, nucleotides, enzymes such as polymerase, buffering agents, or the like. By way of example, in some embodiments, the reaction chambers can include lyophilized reagents, to which processed biological sample (e.g., a solution of extracted nucleic acids) is added. The prepared fluids may then be transferred to a microfluidic cartridge and be inserted into heater/optical modules 500a, 500b for processing and analysis.
Also shown in
As will be described in more detail below, the diagnostic apparatus 10 may be capable of conducting real-time diagnostics on one or more samples. The sample to be tested may first be placed in a specimen tube (not shown) on the rack 24a or 24b. Diagnostic reagents may be located in the holders 26 on the rack 24a inside the diagnostic apparatus 10. The fluid dispenser 400 may mix and prepare the sample for diagnostic testing and may then deliver the prepared sample to the microfluidic cartridge 200 for thermal cycling and analyte detection in the heater/optical modules 500a, 500b. Alternatively, the fluid dispenser 400 may deliver nucleic acid samples to the reaction chambers of the microfluidic cartridge, wherein the reaction chambers of the microfluidic cartridge already contain reagents for an amplification reaction.
Receiving Tray
As illustrated in
The receiving tray 520 may be aligned so that various components of the apparatus that can operate on the microfluidic cartridge 200 (such as, heat sources, detectors, force members, and the like) are positioned to properly operate on the microfluidic cartridge 200 while the cartridge 200 is received in the recessed bay 524 of the receiving tray 520. For example, contact heat sources on the heater substrate 600 may be positioned in the recessed bay 524 such that the heat sources can be thermally coupled to distinct locations on the microfluidic cartridge 200 that is received in the receiving tray 520.
Microfluidic Cartridge
Certain embodiments contemplate a microfluidic cartridge configured to carry out amplification, such as by PCR, of one or more polynucleotides from one or more samples. By cartridge is meant a unit that may be disposable, or reusable in whole or in part, and that may be configured to be used in conjunction with some other apparatus that has been suitably and complementarily configured to receive and operate on (such as deliver energy to) the cartridge.
By microfluidic, as used herein, is meant that volumes of sample, and/or reagent, and/or amplified polynucleotide are from about 0.1 μl to about 999 μl, such as from 1-100 μl, or from 2-25 μl, as defined above. Similarly, as applied to a cartridge, the term microfluidic means that various components and channels of the cartridge, as further described herein, are configured to accept, and/or retain, and/or facilitate passage of microfluidic volumes of sample, reagent, or amplified polynucleotide. Certain embodiments herein can also function with nanoliter volumes (in the range of 10-500 nanoliters, such as 100 nanoliters).
The microfluidic cartridge 200 may include a registration member 202, for example, a cutout, which corresponds to a complementary edge in the recessed bay 524 of the receiving tray 520a,b of the heater/optical modules 500a, 500b. The registration member 202 and the complementary edge 526 may allow for secure and correct placement of the microfluidic cartridge 200 in the receiving tray 520a, b.
In various embodiments, the components of a microfluidic networks in the sample lanes 1706 of the cartridge 200 may be heated by thermally coupling them with the heaters in a heater substrate 600. The heater substrate 600 may be configured to heat a sample mixture comprising amplification reagents and an amplification-ready polynucleotide sample and cause it to undergo thermal cycling conditions suitable for creating amplicons from the amplification-ready sample. The heater substrate 600 may be located on the cartridge 200 in some embodiments or in the recessed bay 524.
The microfluidic network in each lane may be configured to carry out nucleic acid amplification, such as by PCR, on an amplification-ready sample, such as one containing nucleic acid extracted from a sample. An amplification-ready sample may comprise a mixture of amplification reagents and the extracted polynucleotide sample. The mixture may be suitable for subjecting to thermal cycling conditions to create amplicons from the extracted polynucleotide sample. For example, an amplification-ready sample, such as a PCR-ready sample, may include a PCR reagent mixture comprising a polymerase enzyme, a positive control nucleic acid, a fluorogenic hybridization probe selective for at least a portion of the positive control nucleic acid and a plurality of nucleotides, and at least one probe that is selective for a target polynucleotide sequence. The microfluidic network may be configured to couple heat from an external heat source with the mixture comprising the PCR reagent and the extracted polynucleotide sample under thermal cycling conditions suitable for creating PCR amplicons from the extracted polynucleotide sample.
In various embodiments, the reagent mixture may comprise fluorescent or other optically-detectable labels for the detection of the generation of a desired amplicon. In some embodiments, multiple sets of primers and multiple labels can be used in a multiplex assay format, e.g., multiplexed PCR, where each of a plurality of different amplicons can be detected in a single reaction chamber, if present. For example, one assay chamber could include template nucleic acids from a test sample, positive control template nucleic acids, one or more primer pairs for the amplification of specific target sequences, one or more probes for the detection of target amplicons, and one or more primer pairs and a probe for the detection of positive control amplicons. Additionally, the skilled artisan will appreciate that in some embodiments, the microfluidic cartridge accommodates a negative control polynucleotide that will not produce an amplicon with primer pairs used to amplify target or positive control sequences.
In certain of the illustrated embodiments, the chambers 1703a-c respectively associated with each lane 1706a-c of a multi-lane cartridge 200 may perform independent amplification reactions. The results of the reactions for the first column of chambers (1703a, 1703b) for the first two lanes (1706a,1706b) may then be simultaneously and independently measured using a detector head which comprises a “left” and a “right” light source-photodetector pair. That is each chamber 1703a-b of each lane 1706a-b may receive light from a separate light source and be observed by a separate photodetector simultaneously. In this manner, a variety of combinations of reactions may be performed in the cartridge efficiently. For example, in some embodiments, a plurality of amplification assays for the detection of a plurality target nucleic acids can be performed in one lane, a positive control and a negative control in two other lanes; or one or more amplification assays for the detection of one or more target nucleic acids, respectively, in combination with an internal positive control in one lane, with a negative control in a separate lane. In one particular embodiment, 2, 3, 4, 5, 6, or more assays are multiplexed in a single lane, with at least that number of fluorescently distinct fluorophores in the reaction chamber.
A microfluidic cartridge 200 may be constructed from a number of layers. Accordingly, one aspect of the present technology relates to a micro fluidic cartridge that comprises a first, second, third, fourth, and fifth layers wherein one or more layers define a plurality of microfluidic networks, each network having various components configured to carry out PCR on a sample in which the presence or absence of one or more polynucleotides is to be determined. In another embodiment, the microfluidic cartridge 200 can comprise a plurality of lanes, each including a reaction chamber, etched or molded in a single plane, such as in a molded plastic substrate, with each lane being closed by a cover layer, such as an adhesive plastic film layer. Embodiments with 8, 10, 12, 14, 16, 18, 20, 22, 24, 28, 30, or more lanes per cartridge are contemplated. For example, one suitable design is a single cartridge 200 having 24 reaction chambers, arranged in two rows of 12 reaction chambers, optionally having relatively aligned inlet ports. Further description of various cartridges and their components may be found in e.g., U.S. Patent Application Publication 2008-0182301 and U.S. Patent Application Publication 2009-0130719, incorporated herein by reference.
Heater Substrate
Shown in
The heater substrate 600 may be organized into “lanes” 1605a, b paralleling the structure of the lanes 1706a-c of the cartridge 200. In some embodiments, the heater substrate 600 may include 24 heater lanes 1605a, 1605b corresponding to the sample lanes 1706 of cartridge 200. When the microfluidic cartridge 200 is placed in the recessed bay 524 of the receiving tray 520a,b, the components of the cartridge 200 may be aligned adjacent to, and above, the corresponding heaters in the heater substrate 600. When the microfluidic cartridge 200 is placed in the recessed bay 524, the heaters may be in physical contact with the respective components. In some embodiments the heaters remain thermally coupled to their respective components, e.g., through one or more intermediate layers or materials, though not in direct physical contact. Further description of lanes may be found e.g., in U.S. Patent Application Publication 2009-0130719, herein incorporated by reference.
In some embodiments, multiple heaters may be configured to simultaneously and uniformly activate to heat their respective adjacent cartridge components of the microfluidic network in the microfluidic cartridge 200. Each heater may be independently controlled by a processor and/or control circuitry used in conjunction with the apparatus described herein. Generally, the heating of microfluidic components (gates, valves, chambers, etc.) in the microfluidic cartridge 200, is controlled by passing currents through suitably configured micro-fabricated heaters. Under control of suitable circuitry, the lanes 1706 of a multi-lane cartridge can then be heated independently, and thereby controlled independently, of one another. Furthermore, as is described in more detail below, the individual heaters 1601-1604 can be heated independently, and thereby controlled independently, of one another. This can lead to a greater energy efficiency and control of the apparatus, because not all heaters are heating at the same time, and a given heater is receiving current for only that fraction of the time when it is required to heat.
The heater substrate 600 may also include one or more heat sensors. In order to reduce the number of sensor or heaters required to control the heaters in a heater lanes 1605a, 1605b, the heaters may be used to sense temperature as well as heat, and thereby obviate the need to have a separate dedicated sensor for each heater. For example, the impedance and/or resistance of some materials change with the surrounding temperature. Accordingly, the resistance of heater/sensors 1601-1604 may be used as an indication of temperature when the sensors are not being actively heated.
In some embodiments, the heaters in the heater substrate 600 may be designed to have sufficient wattage to allow the heaters to be grouped in series or in parallel to reduce the number of electronically-controllable elements, thereby reducing the burden on the associated electronic circuitry. Heaters that are grouped together in this manner would be operated under synchronized and substantially simultaneous control.
In some embodiments, the reaction chamber heaters on opposite sides of the second stage heaters can be grouped and configured to operate under synchronized control. For example, in some embodiments, the PCR/amplification heaters 1601-1602 can be grouped and configured to operate under synchronized control. Alternative groupings and configurations can be applied to other heater groups of the PCR/amplification heaters 1601-1604. The PCR/amplification heaters 1601-1604 may be configured to operate individually and independently or they can be configured to operate in groups of two (pairs), three (thirds), four, five or six.
In some embodiments, the heating may be controlled by periodically turning the current on and off to a respective heater with varying pulse width modulation (PWM), wherein pulse width modulation refers to the on-time/off-time ratio for the current. The current can be supplied by connecting a micro fabricated heater to a high voltage source (for example, 30V), which can be gated by the PWM signal. In some embodiments, the device may include 48 PWM signal generators. In some embodiments there will be two PWM signal generators associated with each reaction chamber. Operation of a PWM generator may include generating a signal with a chosen, programmable period (the end count) and granularity. For instance, the signal can be 4000 us (micro-seconds) with a granularity of 1 us, in which case the PWM generator can maintain a counter beginning at zero and advancing in increments of 1 us until it reaches 4000 us, when it returns to zero. Thus, the amount of heat produced can be adjusted by adjusting the end count. A high end count corresponds to a greater length of time during which the micro fabricated heater receives current and therefore a greater amount of heat produced.
In various embodiments, the operation of a PWM generator may also include a programmable start count in addition to the aforementioned end count and granularity. In such embodiments, multiple PWM generators can produce signals that can be selectively non-overlapping (e.g., by multiplexing the on-time of the various heaters) such that the current capacity of the high voltage power is not exceeded.
Multiple heaters can be controlled by different PWM signal generators with varying start and end counts. The heaters can be divided into banks, whereby a bank defines a group of heaters of the same start count. Control of heating elements, and cooling elements, if present, in certain embodiments is discussed in further detail below.
Optical Module
As shown in
Detector Head
In some embodiments, each one of the plurality of detector pairs may be arranged along the length of the detector head 700 in rows. That is, behind the pairs 726 and 727 illustrated in
Each light source, such as for example light source 726a, may be configured to produce light of a wavelength specific to a specific fluorescent moiety associated with, e.g., a probe, contained in the reaction chambers. Each light detector, such as for example 726b, may be configured to detect the light emitted from the fluorescent probes associated with the light produced by the light emitter in the detector pair. The detector pairs may be configured to independently detect a plurality of fluorescent moieties, e.g., different fluorescent probes, having different fluorescent emission spectra, wherein in each reaction chamber, emission from each fluorescent probe is indicative of the presence or absence of one particular target polynucleotide or a fragment thereof. Although folded light paths can be used, one embodiment utilizes a detector and emitter pair where each is in direct optical contact with the reaction chamber, preferably simultaneously in such contact. Optionally, the detector and emitter of a pair are aligned with the reaction chamber along lines that substantially intersect at an acute angle at the reaction chamber. The angle can be, for example, between about 5 and 70 degrees, preferably between about 8 and 60 degrees, more preferably between about 10 and 50 degrees.
In some embodiments, the detector head includes two rows of photodetector and light source pairs that correspond to two rows of reaction chambers of microfluidic cartridges, when present in the apparatus. For example, the detector head can include a first or top row of six photodetector and light source pairs, and a second, or bottom row of photodetector and light source pairs, that are configured to query first and second rows of reaction chambers within a microfluidic cartridge, respectively.
The exemplary arrangement of photodetectors and light sources depicted in
The light-emitter and photodetector pairs of each column may be calibrated using the normalizer plate. After calibration, the detector head may be moved to a position such that a first column of light-emitter and photodetector pairs is located over a first group of lanes such that each light-emitter and photodetector pair has access to a reaction chamber of the lanes. Detection of the reaction chambers in the first group of lanes will then be performed using the first column of emitters/detectors. Then, the detector head may be moved to a second position such that the first column is over a second group of lanes and the second column is over the first group of lanes. Detection of the reaction chambers in the second group of lanes will then be performed using the first column of emitters/detectors and detection of the reaction chambers in the first group of lanes will then be performed using the second column of emitters/detectors. The process may continue until each column has passed over each lane. Thus, for N columns of detectors and M columns of chambers, the detector will perform detections at least M+N−1 positions. For example, in the embodiments of
Chamber Plate
Certain of the present embodiments relate to the plating surrounding and including the chamber layer. Particularly, certain embodiments contemplate the manufacture of an aperture layer comprising characteristics that advantageously facilitate consistent results across trials of the heating/detection module, as discussed in further detail below.
In this manner, each thermal unit may be associated with one or more reaction chambers 1703a-d, separately from the remaining reaction chambers. In agreement with the protocol specified for each reaction chamber, the thermal units may successively heat and/or cool their corresponding chamber appropriately. For example, thermal unit 1605c may cool and/or heat chamber 1703a such that the temperature of chamber 1703a is substantially independent of the cooling and thermal state of the chamber 1703a. While heating may be accomplished by running current through a microfluidic or electronic circuit, cooling may be “passive” in that only convection between the microfluidic chamber and is used to reduce the chamber's temperature. The thermal units 1605a, 1605b, 1605c may be controlled using a closed loop control system.
In some embodiments, aperture plate 540 may be located over the chamber layer 200 and can provide pressure to chamber layer 200 to facilitate heating and cooling of the microfluidic cartridge, e.g., the chamber layer, by thermal layer 600. The aperture plate can include a plurality of apertures 557a-d to facilitate each photodetector's 726b observation of an individual reaction chambers 1703a-d. In the absence of aperture plate 540, and depending on the configuration of the thermal layer 600 and chamber layer 200, chamber layer 200 may “warp” and/or be sufficiently flexible that the thermal communication between chambers and the respective thermal units is inconsistent. Inconsistent heating and cooling can lead to less accurate execution of the protocols and less precise and accurate results. As described above, significant warping may restrict the optical head from lateral movement. Thus, the thickness of the aperture plate must be appropriately selected to facilitate a proper light path between each reaction chamber and the light sources and photodetectors while still ensuring proper heating and cooling of the chamber layer. If the aperture layer is too thick, the distance from the photodetector 726b to the chamber may be too great, undesirably attenuating the fluorescence reading from the reaction chamber. In addition to increasing the distance to the reaction chamber, an aperture layer 540 which is too thick or too heavy will place too much pressure on the reaction chamber, causing convection to be too great. Conversely, if the aperture layer 540 is too thin it may not prevent the chamber layer 200 from bending and warping, and the aperture layer 540 may bend and warp itself. Warping of apertures 557a-d or the chambers 1703a-d may deflect light from the light source 726a and prevent accurate readings by photodetector 726b.
Accordingly, the embodiments described herein provide aperture layers that advantageously avoid the drawbacks described above. In certain embodiments, the aperture layer 540 is made, at least in part, of steel. In these embodiments, steel provides the appropriate strength, density and resistance to deflection desired for operation. Furthermore, the steel may provide low self-fluorescence and is therefore less likely to adversely affect the reading of photodetector 726b. The steel may also be electrochemically treated to diminish its self-fluorescence and thereby be less likely to adversely affect the reading of the photodetector. In certain embodiments, the aperture layer may instead comprise black nickel (Ni), i.e. Ni with a colorant added to it to reduce self-fluorescence. Certain embodiments contemplate combinations of these different materials and electrochemical treatments. In certain embodiments, the aperture layer 540 is made of aluminum and when secured by the adjoining support panels 500, 506, and 546, provide the appropriate strength. The aluminum may be electrochemically plated with an anodic oxide finish, e.g., with a black colorant added to reduce self-fluorescence.
The illumination optics may be designed so that the excitation light falling on the reaction chamber, or reactor, is incident along an area that is similar to the shape of the reactor. As the reactor may be long and narrow, the illumination spot may also be long and narrow, i.e., extended, as well. Thus the shape of apertures 557a-d may be designed with consideration both to the dimensions of the reaction chamber underneath, as well as to the relative positions of the corresponding light emitter and photodetector. The length of the spot may be adjusted by altering a number of factors, including: the diameter of the bore where the photodetector 726b is placed (the tube that holds the filter and lens may have an aperturing effect); the distance of the photodetector 726b from the PCR reactor; and the use of proper lens in photodetector 726b.
Force Member
In certain embodiments, the receiving tray 520 places the chamber layer 200 in proximity to the thermal layer 600 or aperture layer 540, but does not mechanically couple and/or thereby place the layers in contact with one another. In this manner, the chamber layer 200 may be thermally, but not mechanically, coupled to the thermal layer 600. In other embodiments, the receiving tray places the thermal layer 600 in both mechanical and thermal contact with the chamber layer 200 and the chamber layer in mechanical contact with the aperture layer 540. In various embodiments, the apparatus may include one or more force members (not shown) that are configured to apply pressure to the receiving tray 520 in order to thermally couple the heat sources to the microfluidic cartridge 200 positioned in the receiving tray 520. The application of pressure may be important to ensure consistent thermal contact between the heater substrate and the reaction chambers, gates, and valves, etc., in the microfluidic cartridge 200. When the receiving tray 520 is in a closed position, thereby being positioned under the aperture plate 540 of the optical module 502, the force member, such as a motor assembly, below the receiving tray 520 may begin traveling upwards towards the optical module 502, thereby bringing the receiving tray 520 closer to the optical module 502. As the receiving tray 520 travels upwards towards the optical module 502, the cartridge 200 may begin to come in contact with a bottom surface of the aperture plate 540. The cartridge 200 may continue traveling upward until sufficient pressure is received on the cartridge 200. As discussed above, the aperture plate 540 may apply an equal pressure across all points of the top of the cartridge 200 and thus, presses the cartridge 200 against the heater substrate 600 with uniform pressure. As discussed, the aperture layer may be selected to possess properties which facilitate this operation. For example, the material selection of the aperture plate 540 may provide very little deflection of the cartridge 200, when pressed against it.
The application of uniform pressure of the cartridge 200 against the heater substrate 600 may allow for uniform heating for each of the components of the cartridge when desirable. Although uniform pressure and contact may be obtained between the heaters in the heater substrate 600 and the components (valves, gates, chambers, etc.) of the microfluidic networks in the cartridge 200, the heaters are not necessarily activated simultaneously, as discussed above. In certain embodiments, application of even pressure does not necessarily result in equal heating of different components of the cartridge 200. In some embodiments, both the activation of a specific heater in the heater substrate 600 along with the pressure applied by the aperture plate 540 to the cartridge 200 activate a particular component of cartridge 200.
In the embodiment shown in
In general the dimensions of the aperture plate 540 are selected such that in combination with the properties of the materials constituting the aperture plate 540, the plate 540 provides sufficient pressure to the underlying chamber plate to facilitate proper heating and cooling as well as sufficient rigidity to prevent warping or deformation of the chamber plate. Such deformation may result in obstructions to the light source and photodetector optical path to the reaction chamber. Simultaneously, the dimensions of the plate should not impose an unfavorable distance from the reaction chamber of the chamber layer to the light-source and photodetector pair through the apertures 557. Neither should the aperture plate's dimensions 540 obstruct the optical path from the light-source and photodetector pair to the contents of the chamber reactor.
In some embodiments the normalizer plate 546 may be attached to the aperture plate by inserting screws at positions 9001 or other fixation means through an aperture. In other embodiments, these positions may facilitate broader calibration techniques via the apertures over the normalizer plates than with regard to the remaining apertures.
Diagnostic Analysis Consistency
Certain of the present embodiments contemplate methods for ensuring consistent diagnostic analyses across trials within the same heater/detector and across different heater/detectors. Particularly, embodiments of a system and process for determining the duration and offsets for a plurality of PCR protocols so as to synchronize detection therebetween are disclosed. Additionally, methods for adjusting the reactor cooling time to ensure more consistent results are discussed.
In certain embodiments the thermal trajectory for both heating and cooling may be determined for the entirety of the reaction prior to the start of the run. In some systems, the contour of temperature versus time is monitored and adjusted throughout the reaction in order to minimize transition temperatures, and taking into account the variations in efficiencies of different heating elements. In other words, some systems utilize feedback control loops to drive to a target temperature, wherein the actual contour of the temperature time relationship can vary from cycle to cycle. Such adjustments can result in different overall reaction times, and, more importantly, different overall reaction efficiencies. Accordingly, in some embodiments, the systems and methods described herein advantageously provide systems wherein the contour of the temperature versus time relationship of the complete reaction for each independent reaction chamber (or group of chambers) is predetermined set prior to the start of the run. Not only does this advantageously allow for synchronization of the multiple detection steps across a plurality of different reactors, but it also enables for stricter control over parameters that minimize differences in reaction efficiencies that may arise as a result of different temperature/time contours. In some embodiments, the systems and methods provided herein provide for the report of errors at the end of a reaction if the measured temperature is different from the expected value when a run is completed.
At various points in the protocol temperature profile 2000, the user or recipe may specify that a detection occur. For example, for some protocols a detection may be requested at the end of segment 2000D. Were detections arbitrarily specified in each protocol, the detector head would need to travel between positions in an inefficient manner and may even find it impossible to perform detections at the requested times. That is, were each of a plurality of protocols to be initiated simultaneously and run in parallel simultaneously across each of the reaction chambers in the cartridge, it would be very inefficient for the detector to meet each protocol's detection requests. Particularly, once calibration was complete the detector would need to first travel to positions suitable to perform detections for each light source-detector pair in its array for the first profile. By the time the detector finished, however, each of the remaining protocols would be entering a period when detection is not to be performed. There will therefore be a “dead time” period when the detector cannot perform any detections and must instead simply sit idle waiting for the opportunity to perform the next detection. This “dead time” is inefficient and unnecessarily prolongs the diagnostic process. Furthermore, where successive detections are to be performed, the “dead time” may generate irregular and aperiodic detections of the same chamber, possibly introducing inconsistent readings.
Certain of the present embodiments contemplate automated adjustments to portions of the profile 2000 to facilitate efficient detection across multiple protocols. This may be accomplished by allowing the user to edit, or the system may edit automatically, the length of segment 2000B or 2000D.
It should be understood that so long as at least a minimum plateau time occurs, some minor extension of plateau times can be accommodated in most amplification protocols. This flexibility is utilized to all efficient accommodation of different assays being performed simultaneously, while performing real-time monitoring of amplification by reading the various assays using a scanning detector head.
If detection were to be performed during segment 2000B, for example, the system or the user may extend the duration of segment 2000B as necessary to accommodate detector head movement and to coordinate the reading of a plurality of assays being performed simultaneously. The duration of segments 2000A and 2000C may be calculated using a predetermined standard cooling rate from the preceding temperatures and incorporated into the analysis. Some embodiments do not allow the user to edit these segments and they are instead accounted for by the system internally.
In certain embodiments, the protocol adjustments determined by the system may comprise at least three separate forms. The first adjustment may comprise an “intra-cycle adjustment” wherein plateaus such as 2000B and 2000D of the protocol are extended such that the entire step cycle 2000A-D achieves a desired duration, in some instances an integer multiple of a detection cycle time. This adjustment is described with respect to
Protocol Adjustment Overview
In some embodiments, the process may first determine a plurality of “intra-cycle adjustments” for one or more of the protocols 4003. As discussed below with respect to
Thus, intra-cycle adjustments ensure that the cycle of the protocol is an integer multiple of the detection cycle time. However, a detection may be requested at any point within a cycle. If the detection cycle time is 10 seconds, then the very earliest that a detection may be performed is at 10 seconds after the protocol initiates. Detections may then be performed at integer multiples after that time (20, 30, 40 seconds, etc.).
Thus, a further adjustment, an “inter-cycle” adjustment 4004, may then be determined to ensure that the requested detection occurs at the appropriate time. These “inter-cycle adjustments” may be incorporated into the protocol as additional delays between protocol steps or substeps. Phrased differently, a PCR protocol once subjected to “intra-cycle” adjustments may comprise “valid” cycle steps. The PCR protocol may then be generated by chaining together each of the steps and adding transitions from step to step. The “inter-cycle adjustments” 4004 ensure that the detection times occur at the desired integer multiples of the detection cycle time after the cycles have been chained together.
For example, for a system having a detection cycle time of 10 seconds a protocol may comprise a step having its first detection at 18 seconds into a cycle. The cycle duration (the duration of the entire step) may last for 30 seconds (perhaps after an “intra-cycle” adjustment). Thus, while the cycle time as a whole is properly aligned with the 10 second detection cycle time (3×10=30 seconds) the first detection is itself not properly aligned with the detection (18 second is not a multiple of 10 seconds). The system will add 2 seconds of “inter-cycle” adjustment to the very first detection run so that the first detection occurs 20 seconds after the start of the protocol. This may be done by extending the previous step's final hold temperature for an additional 2 seconds via a “padding adjustment”. If there is no previous step, the system would insert a 2 second hold at ambient temperature to the beginning of the first run of the cycle. Thus, if the system begins operation at T0, the first detection will occur at T0+20 seconds, the second detection at T0+50 seconds, and so forth.
Because of the inter and intra-cycle adjustments, the protocol is now in a form such that detections will only be requested at times convenient for the detector head to move to the reaction chamber performing the protocol. Were all protocols performed in reaction chambers located in the first column of the cartridge (and sufficient number of detectors present in the detector head) intra and inter-cycle adjustments alone would suffice to properly modify the protocol for efficient detection (a first column here referring to a column of lanes such as lanes 1706a and 1706b with associated chambers 1703a and 1703b in
Thus “starting adjustment offsets” are added to the protocol based on the location of the chamber in which the protocol is performed. These “starting adjustment offsets” 4005 are described in greater detail with respect to
Although described in the order of steps 4003, 4005, and 4004, one will readily recognize that these steps may be arranged into any other suitable order, and neither need the system perform each step successively. In some embodiments, however, such as that described above, it may be necessary to perform inter-cycle adjustments after performing intra-cycle adjustments, as the inter-cycle adjustment depends on the intra-cycle modification. In contrast, the starting-offset adjustment 4005 may not depend on any previous determination. That is, in some embodiments the starting offset 4005 need be determined only once at run time, whereas the intra-cycle adjustments 4003 and inter-cycle adjustments 4004 may be performed for each cycle step in the protocols.
In some embodiments, once the protocol times have been properly adjusted, the process may then initiate the protocols 4006. In some embodiments a processor may simply place the offsets in a memory location for retrieval by a separate dedicated component of the system which itself initiates each protocol.
Intra-Cycle Adjustment
“Intra-cycle adjustments” comprise adjustments to step or substep intervals, as may have been specified by a user or received from a database, so that the step as a whole is an integer multiple of a predetermined duration. With reference to
In the example of
In the example illustrated in
Thus, the total duration for the step as a whole is:
4.25 (heat)+2.0 (denature)+7.05 (cool)+10.2 (anneal)+2.2 (detection)=25.7 seconds.
As 25.7 seconds is not a multiple of the 10 second detection time, adjustment will be necessary. As indicated 5003b, the system informs the user that they may either remove 5.7 seconds from the step duration or add an additional 4.3 seconds to achieve a multiple of the detection cycle time (i.e., a multiple of 10 seconds). These “intra-cycle step adjustments” will be incorporated into the protocol after the user's selection.
One will recognize that the system may consider a plurality of other factors not indicated in this example when providing the user with an adjustment range. For example, additional delays to motor movement or incubation preparation may be factored in to the system's analysis.
Inter-Cycle Adjustments
As mentioned above, “inter-cycle adjustments” comprise adjustments to the first cycle of a substep so as to create a delay between cycle steps. “Inter-cycle adjustments” may depend on the timing of the preceding steps and the end temperature of the immediately preceding step (if one exists). With reference to
In some embodiments the adjustment 6005 is determined by first determining the time required to heat or cool the temperature from the end of the previous step to the first substep temperature of the next step. If any additional time is necessary for alignment, the temperature from the end of the previous step may be maintained for this time. An example of alignment between the end temperature of a hold step at 75° C. to the first substep temperature of 95° C. is shown in
Starting Offset Adjustments
The second protocol 3005 includes a different profile from 3001. The profile 3005 comprises an initialization step lasting from 0 to 30 seconds. The profile 3005 is then followed by a plurality of 50 second cycles, with the first detection at 40 seconds. These cycles represent a 3-Temperature PCR, which includes a denature at a high temperature, the anneal and detection at the low temperature, and then an extension at a middle temperature. As before, the first initialization cycle may include a small inter-cycle delay at the beginning for alignment. One will recognize that his inter-cycle delay may be inserted at a variety of positions about the initialization step to ensure detection alignment.
Thus, with properly selected “starting adjustments” the system can ensure consistent detection times across each of the reactors. As illustrated in
Active Cooling
In certain of the embodiments while heating of the reactor chamber is active, that is, heaters are actively applied to the chamber, cooling of the reactor chamber may passive, where convection alone is used to cool the reactor contents. In order to further provide for consistent diagnostic performance, certain of the embodiments contemplate active participation in the reactor's cooling process to ensure consistent behavior.
The ambient temperature in the location where the heating/detection unit is located may not be the same. That is, a system operating in southern Arizona may not be subjected to the same ambient temperatures as a system operating in northern Alaska. Thus, in the hottest ambient temperature in which the system is expected to be operated, the profile 7001 may have a cooling curve 7003. In a cooler environment, the cooling profile 7002 may instead result. To compensate for the difference, certain embodiments contemplate monitoring the reactor cooling profile via the temperature sensors, possibly those discussed with regard to
Certain of these embodiments apply Newton's law of cooling to determine when to apply the heaters:
T(t)=Ta+(T(0)−Ta)e−rt
Where: T(t) is the temperature at time t, T(0) is the initial temperature, Ta is the ambient temperature parameter, r is the decay constant parameter, and t is time. In some embodiments 50.2 degrees Celsius and 0.098 may be used as the ambient temperature parameter and decay constant parameter, respectively. In this embodiment, the ambient temperature parameter is selected to be higher than any expected ambient operating temperature, thus allowing full control over the cooling cycle by applying at least some small amount of heat during each cooling cycle, regardless of ambient temperature, in order to match the actual cooling to the cooling curve of the maximal profile 7003 in each instance.
As used herein, an “input” can be, for example, data received from a keyboard, rollerball, mouse, voice recognition system or other device capable of transmitting information from a user to a computer. The input device can also be a touch screen associated with the display, in which case the user responds to prompts on the display by touching the screen. The user may enter textual information through the input device such as the keyboard or the touch-screen.
The invention is operational with numerous other general purpose or special purpose computing system environments or configurations. Examples of well-known computing systems, environments, and/or configurations that may be suitable for use with the invention include, but are not limited to, microcontrollers, personal computers, server computers, hand-held or laptop devices, multiprocessor systems, microprocessor-based systems, programmable consumer electronics, network PCs, minicomputers, mainframe computers, distributed computing environments that include any of the above systems or devices.
As used herein, “instructions” refer to computer-implemented steps for processing information in the system. Instructions can be implemented in software, firmware or hardware and include any type of programmed step undertaken by components of the system.
A “microprocessor” or “processor” may be any conventional general purpose single- or multi-core microprocessor such as a Pentium® processor, Intel® Core™, a 8051 processor, a MIPS® processor, or an ALPHA® processor. In addition, the microprocessor may be any conventional special purpose microprocessor such as a digital signal processor or a graphics processor. A “processor” may also refer to, but is not limited to, microcontrollers, field programmable gate arrays (FPGAs), application-specific integrated circuits (ASICs), complex programmable logic devices (CPLDs), programmable logic arrays (PLAs), microprocessors, or other similar processing devices.
The system is comprised of various modules as discussed in detail below. As can be appreciated by one of ordinary skill in the art, each of the modules comprises various sub-routines, procedures, definitional statements and macros. Each of the modules are typically separately compiled and linked into a single executable program. Therefore, the following description of each of the modules is used for convenience to describe the functionality of the preferred system. Thus, the processes that are undergone by each of the modules may be arbitrarily redistributed to one of the other modules, combined together in a single module, or made available in, for example, a shareable dynamic link library.
Certain embodiments of the system may be used in connection with various operating systems such as SNOW LEOPARD®, iOS®, LINUX, UNIX or MICROSOFT WINDOWS®, or any other suitable operating system.
Certain embodiments of the system may be written in any conventional programming language such as assembly, C, C++, BASIC, Pascal, or Java, and run under a conventional operating system, or the like, or any other suitable programming language.
In addition, the modules or instructions may be stored onto one or more programmable storage devices, such as FLASH drives, CD-ROMs, hard disks, and DVDs. One embodiment includes a programmable storage device having instructions stored thereon.
While the above processes and methods are described above as including certain steps and are described in a particular order, it should be recognized that these processes and methods may include additional steps or may omit some of the steps described. Further, each of the steps of the processes does not necessarily need to be performed in the order it is described.
While the above description has shown, described, and pointed out novel features of the invention as applied to various embodiments, it will be understood that various omissions, substitutions, and changes in the form and details of the system or process illustrated may be made by those skilled in the art without departing from the spirit of the invention. As will be recognized, the present invention may be embodied within a form that does not provide all of the features and benefits set forth herein, as some features may be used or practiced separately from others.
The steps of a method or algorithm described in connection with the embodiments disclosed herein may be embodied directly in hardware, in a software module executed by a processor, or in a combination of the two. A software module may reside in RAM memory, flash memory, ROM memory, EPROM memory, EEPROM memory, registers, hard disk, a removable disk, a CD-ROM, or any other form of storage medium known in the art. An exemplary storage medium may be coupled to the processor such the processor can read information from, and write information to, the storage medium. In the alternative, the storage medium may be integral to the processor. The processor and the storage medium may reside in an ASIC. The ASIC may reside in a user terminal. In the alternative, the processor and the storage medium may reside as discrete components in a user terminal.
This application is a divisional of U.S. application Ser. No. 15/706,313, filed Sep. 15, 2017 and scheduled to issue as U.S. Pat. No. 10,781,482 on Sep. 22, 2020, which is a divisional of U.S. application Ser. No. 14/054,397, filed Oct. 15, 2013 and issued as U.S. Pat. No. 9,765,389, on Sep. 19, 2017, which is a continuation of International Patent Application No. PCT/US2012/033667, filed Apr. 13, 2012, entitled “SYNCHRONIZED THERMOCYCLING AND SCANNING OPTICAL DETECTION,” which claims the benefit of priority to U.S. Provisional Patent Application Ser. No. 61/476,175, filed on Apr. 15, 2011, entitled “SOFTWARE CONTROL PROCESS TO SYNCHRONIZE THERMOCYCLING AND SCANNING OPTICAL DETECTION” and U.S. Provisional Patent Application Ser. No. 61/476,167, filed on Apr. 15, 2011, entitled “6-COLOR SCANNING REAL-TIME MICROFLUIDIC THERMOCYCLER.” Each of the aforementioned applications is incorporated by reference herein in its entirety.
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| Record of Oral Hearing in IPR2019-00488 and IPR2019-00490 held Apr. 21, 2020 in 80 pages; Petitioner's Demonstratives for Oral Hearing in IPR2019-00488 and IPR2019-00490 held Apr. 21, 2020 in 72 pages; Patent Owner's Demonstratives for Oral Hearing in IPR2019-0488 and IPR2019-00490 held Apr. 21, 2020 in 88 pages; Patent Owner's Objections to Petitioner's Oral Hearing Demonstratives in IPR2019-00488 and IPR2019-00490 dated Apr. 16, 2020 (4 pages). |
| Petition for Inter Partes Review of U.S. Pat. No. 8,273,308 (Paper 2 in IPR2020-01083) dated Jun. 12, 2020 (104 pages). |
| Petition for Inter Partes Review of U.S. Pat. No. 8,273,308 (Paper 2 in IPR2020-01091) dated Jun. 12, 2020 (105 pages). |
| Petition for Inter Partes Review of U.S. Pat. No. 8,803,069 (Paper 2 in IPR2020-01095) dated Jun. 12, 2020 (84 pages). |
| Petition for Inter Partes Review of U.S. Pat. No. 8,803,069 (Paper 3 in IPR2020-01100) dated Jun. 12, 2020 (83 pages). |
| Petition for Inter Partes Review of U.S. Pat. No. 8,709,787 (Paper 2 in IPR2020-01132) dated Jun. 18, 2020 (96 pages). |
| Petition for Inter Partes Review of U.S. Pat. No. 8,415,103 (Paper 2 in IPR2020-01133) dated Jun. 18, 2020 (96 pages). |
| Petition for Inter Partes Review of U.S. Pat. No. 8,709,787 (Paper 2 in IPR2020-01137) dated Jun. 19, 2020 (86 pages). |
| Petition for Inter Partes Review of U.S. Pat. No. 8,415,103 (Paper 2 in IPR2020-01136) dated Jun. 19, 2020 (85 pages). |
| Declaration of Mark A. Burns, Ph.D. (Exhibit N1101 in IPR2020-01132 and IPR2020-01133) dated Jun. 17, 2020 (253 pages). |
| Declaration of Mark A. Burns, Ph.D. (Exhibit N1201 in IPR2020-01136 and IPR2020-01137) dated Jun. 19, 2020 (205 pages). |
| Judgment/Final Written Decision in Inter Partes Review of U.S. Pat. No. 7,998,708 (Paper No. 52 in IPR2019-00488) dated Jul. 14, 2020 (43 pages). |
| Judgment/Final Written Decision in Inter Partes Review of U.S. Pat. No. 8,323,900 (Paper No. 51 in IPR2019-00490) dated Jul. 14, 2020 (43 pages). |
| First Amended and Supplemental Complaint filed by Becton, Dickinson and Company et al. on Jun. 25, 2020 in U.S. District Court, Delaware, Case #1:19-cv-01126-LPS, Infringement Action involving U.S. Pat. Nos. 7,998,708; 8,273,308; 8,323,900; 8,415,103; 8,703,069; 8,709,787; 10,494,663; 10,364,456; 10,443,088; 10,604,788; 10,625,261; 10,625,262; and 10,632,466 (55 pages). |
| Answer to Amended and Supplemental Complaint filed by NeuModx Molecular, Inc. on Jul. 16, 2020 in U.S. District Court, Delaware, Case #1:19-cv-01126-LPS (42 pages). |
| Petitioner's Notice of Appeal in Inter Partes Review of U.S. Pat. No. 7,998,708 (Paper No. 54 in IPR2019-00488) dated Sep. 9, 2020 (48 pages). |
| Petitioner's Notice of Appeal in Inter Partes Review of U.S. Pat. No. 8,323,900 (Paper No. 53 in IPR2019-00490) dated Sep. 9, 2020 (48 pages). |
| Patent Owner Preliminary Response to Petition for Inter Partes Review of U.S. Pat. No. 8,703,069 (Paper 13 in IPR2020-01095) dated Sep. 17, 2020 (77 pages). |
| Patent Owner Preliminary Response to Petition for Inter Partes Review of U.S. Pat. No. 8,273,308 (Paper 13 in IPR2020-01091) dated Sep. 17, 2020 (70 pages). |
| Patent Owner Preliminary Response to Petition for Inter Partes Review of U.S. Pat. No. 8,703,069 (Paper 14 in IPR2020-01100) dated Sep. 17, 2020 (59 pages). |
| Declaration of M. Allen Northrup, Ph.D. in Support of Patent Owner Preliminary Responses in IPR2020-01091, IPR2020-01095 and IPR2020-01100 (Exhibit H2003) dated Sep. 16, 2020 (137 pages). |
| Patent Owner Preliminary Response to Petition for Inter Partes Review of U.S. Pat. No. 8,273,308 (Paper 13 in IPR2020-01083) dated Oct. 22, 2020 (88 pages). |
| Declaration of M. Allen Northrup, Ph.D. in support of Patent Owner Preliminary Responses in IPR2020-01083, IPR2020-01091, IPR2020-01095 and IPR2020-01100 (Exhibit H2003) dated Oct. 21, 2020 (171 pages). |
| Defendant NeuModx's Initial Invalidity Contentions filed Sep. 30, 2020 in U.S. District Court, Delaware, Case #1:19-cv-01126-LPS (47 pages). |
| Petition for Inter Partes Review of U.S. Pat. No. 10,625,262 (Paper 2 in IPR2021-00250) dated Nov. 25, 2020 (107 pages). |
| Petition for Inter Partes Review of U.S. Pat. No. 10,625,261 (Paper 2 in IPR2021 -00251) dated Nov. 25, 2020 (117 pages). |
| Petition for Inter Partes Review of U.S. Pat. No. 10,632,466 (Paper 2 in IPR2021-00253) dated Nov. 25, 2020 (121 pages). |
| Declaration of Mark A. Burns, Ph.D. (Exhibit N1001 in IPR2021-00250, IPR2021-00251 and IPR2021-00253) dated Nov. 24, 2020 (311 pages). |
| Declaration of James L. Mullins, Ph.D. (Exhibit N1029 in IPR2021-00250, IPR2021-00251, and IPR2021-00253) dated Nov. 18, 2020 (54 pages). |
| Decision Denying Institution of Inter Partes Review of U.S. Pat. No. 8,273,308 (Paper 14 in IPR2020-01091) dated Dec. 4, 2020 (21 pages). |
| Decision Denying Institution of Inter Partes Review of U.S. Pat. No. 8,703,069 (Paper 14 in IPR2020-01095) dated Dec. 4, 2020 (22 pages). |
| Decision Denying Institution of Inter Partes Review of U.S. Pat. No. 8,703,069 (Paper 15 in IPR2020-01100) dated Dec. 4, 2020 (19 pages). |
| Defendant NeuModx's Joint Claim Construction Chart filed Oct. 21, 2020 in U.S. District Court, Delaware, Case #1:19-cv-01126-LPS (25 pages). |
| Defendant NeuModx's Initial Amended Answer, Affirmative Defenses, and Counterclaims to Plaintiffs' First Amended and Supplemental Complaint filed Nov. 23, 2020 in U.S. District Court, Delaware, Case #1:19-cv-01126-LPS (97 pages). |
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| Brief for Appellee HandyLab, Inc. in Appeals from the USPTO, PTAB, in Nos. IPR2019-00488, IPR2019-00490, IPR2019-01493 and IPR2019-01494 filed May 24, 2021 in U.S. Court of Appeals for the Federal Circuit Case Nos. 20-2249, 20-2250, 20-2273 and 20-2276 (74 pages). |
| Reply Brief of Appellants Qiagen North American Holdings, Inc. and NeuMoDx Molecular, Inc. in Appeals from the USPTO, PTAB, in Nos. IPR2019-00488, IPR2019-00490, IPR2019-01493 and IPR2019-01494 filed Jun. 21, 2021 in U.S. Court of Appeals for the Federal Circuit Case Nos. 20-2249, 20-2250, 20-2273 and 20-2276 (44 pages). |
| Decision Denying Institution of Inter Partes Review of U.S. Pat. No. 10,625,262 (Paper 7 in IPR2021-00250) dated Jul. 15, 2021 (15 pages). |
| Decision Denying Institution of Inter Partes Review of U.S. Pat. No. 10,632,466 (Paper 7 in IPR2021-00253) dated Jul. 15, 2021 (22 pages). |
| Decision Denying Institution of Inter Partes Review of U.S. Pat. No. 10,625,261 (Paper 7 in IPR2021-00251) dated Jul. 15, 2021 (24 pages). |
| Patent Owner's Response in Inter Partes Review of U.S. Pat. No. 8,709,787 and Exhibit List (Paper 29 in IPR 2020-01132) dated Jul. 15, 2021 (87 pages). |
| Decision Granting Institution of Inter Partes Review of U.S. Pat. No. 8,415,103 on Rehearing (Paper 23 in IPR2020-01133) dated Aug. 6, 2021 (20 pages). |
| Decision of U.S. Court of Appeal for the Federal Circuit Affirming Inter Partes Review Final Written Decisions Determining No Challenged Claims of United States Patent Nos. 7,998,708 and 8,323,900 are Unpatentable (IPR2019-00488, IPR2019-00490, IPR2019-01493, and IPR2019-01494) dated Oct. 29, 2021 (12 pages). |
| Joint Motion to Terminate Inter Partes Review of U.S. Pat. No. 8,709,787 (Paper 37 in IPR 2020-01132) dated Nov. 15, 2021 (8 pages). |
| Joint Motion to Terminate Inter Partes Review of U.S. Pat. No. 8,415,103 (Paper 35 in IPR 2020-01133) dated Nov. 15, 2021 (8 pages). |
| Stipulation of Dismissal filed by Plaintiffs Becton, Dickinson and Company, Geneohm Sciences Canada, Inc. and HandyLab, Inc. and Defendants NeuMoDx Molecular, Inc., Qiagen GmbH, and Qiagen North American Holdings, Inc. on Nov. 12, 2021 in U.S. District Court, Delaware, Case #1:19-cv-01226-LPS (3 pages). |
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| Number | Date | Country | |
|---|---|---|---|
| 20210071234 A1 | Mar 2021 | US |
| Number | Date | Country | |
|---|---|---|---|
| 61476175 | Apr 2011 | US | |
| 61476167 | Apr 2011 | US |
| Number | Date | Country | |
|---|---|---|---|
| Parent | 15706313 | Sep 2017 | US |
| Child | 17026653 | US | |
| Parent | 14054397 | Oct 2013 | US |
| Child | 15706313 | US |
| Number | Date | Country | |
|---|---|---|---|
| Parent | PCT/US2012/033667 | Apr 2012 | US |
| Child | 14054397 | US |
