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WO2018152351A1 - Dosage à changement rapide de température - Google Patents

Dosage à changement rapide de température Download PDF

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Publication number
WO2018152351A1
WO2018152351A1 PCT/US2018/018405 US2018018405W WO2018152351A1 WO 2018152351 A1 WO2018152351 A1 WO 2018152351A1 US 2018018405 W US2018018405 W US 2018018405W WO 2018152351 A1 WO2018152351 A1 WO 2018152351A1
Authority
WO
WIPO (PCT)
Prior art keywords
plates
sample
prior
plate
clamp
Prior art date
Application number
PCT/US2018/018405
Other languages
English (en)
Inventor
Stephen Y. Chou
Wei Ding
Yufan ZHANG
Ji QI
Original Assignee
Essenlix Corporation
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from PCT/US2018/017307 external-priority patent/WO2018148342A1/fr
Priority claimed from PCT/US2018/017492 external-priority patent/WO2018148461A1/fr
Priority claimed from PCT/US2018/017494 external-priority patent/WO2018148463A1/fr
Priority claimed from PCT/US2018/017489 external-priority patent/WO2018148458A1/fr
Priority claimed from PCT/US2018/017502 external-priority patent/WO2018148470A1/fr
Priority claimed from PCT/US2018/017504 external-priority patent/WO2018148471A2/fr
Priority claimed from PCT/US2018/017713 external-priority patent/WO2018148607A1/fr
Priority claimed from PCT/US2018/017716 external-priority patent/WO2018148609A2/fr
Priority claimed from PCT/US2018/017712 external-priority patent/WO2018148606A1/fr
Priority claimed from PCT/US2018/018007 external-priority patent/WO2018148729A1/fr
Priority claimed from PCT/US2018/017499 external-priority patent/WO2018152005A1/fr
Priority claimed from PCT/US2018/018108 external-priority patent/WO2018148764A1/fr
Priority to CA3053295A priority Critical patent/CA3053295A1/fr
Priority to EP18753608.1A priority patent/EP3583423A4/fr
Priority to JP2019544049A priority patent/JP2020508043A/ja
Priority to US16/484,998 priority patent/US20200078792A1/en
Priority to CN201880024948.7A priority patent/CN111194409B/zh
Application filed by Essenlix Corporation filed Critical Essenlix Corporation
Priority to US16/485,347 priority patent/US10966634B2/en
Priority to CN201880025156.1A priority patent/CN111448449B/zh
Priority to PCT/US2018/018521 priority patent/WO2018152422A1/fr
Priority to CA3053301A priority patent/CA3053301A1/fr
Priority to US16/485,126 priority patent/US11523752B2/en
Priority to PCT/US2018/018520 priority patent/WO2018152421A1/fr
Priority to JP2019544634A priority patent/JP7107953B2/ja
Priority to CA3060971A priority patent/CA3060971C/fr
Priority to CN201880041351.3A priority patent/CN111771125B/zh
Priority to EP18788089.3A priority patent/EP3612841A4/fr
Priority to JP2019556963A priority patent/JP2020517266A/ja
Priority to PCT/US2018/028784 priority patent/WO2018195528A1/fr
Priority to CN202311781492.8A priority patent/CN118218039A/zh
Priority to US16/605,853 priority patent/US10926265B2/en
Priority to PCT/US2018/034230 priority patent/WO2018217953A1/fr
Priority to EP18805264.1A priority patent/EP3631000A4/fr
Priority to US16/616,680 priority patent/US12064771B2/en
Priority to JP2019565255A priority patent/JP7335816B2/ja
Priority to CN201880048466.5A priority patent/CN112218939A/zh
Priority to CA3064744A priority patent/CA3064744A1/fr
Publication of WO2018152351A1 publication Critical patent/WO2018152351A1/fr
Priority to PCT/US2018/065297 priority patent/WO2019118652A1/fr
Priority to US16/772,396 priority patent/US11648551B2/en
Priority to US17/150,730 priority patent/US11369968B2/en
Priority to JP2022109424A priority patent/JP2022125266A/ja
Priority to US17/980,400 priority patent/US20230077906A1/en
Priority to US18/121,534 priority patent/US12226769B2/en
Priority to US18/809,075 priority patent/US20250099965A1/en

Links

Classifications

    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L7/00—Heating or cooling apparatus; Heat insulating devices
    • B01L7/52—Heating or cooling apparatus; Heat insulating devices with provision for submitting samples to a predetermined sequence of different temperatures, e.g. for treating nucleic acid samples
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
    • B01L3/508—Containers for the purpose of retaining a material to be analysed, e.g. test tubes rigid containers not provided for above
    • B01L3/5085—Containers for the purpose of retaining a material to be analysed, e.g. test tubes rigid containers not provided for above for multiple samples, e.g. microtitration plates
    • B01L3/50851—Containers for the purpose of retaining a material to be analysed, e.g. test tubes rigid containers not provided for above for multiple samples, e.g. microtitration plates specially adapted for heating or cooling samples
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2200/00—Solutions for specific problems relating to chemical or physical laboratory apparatus
    • B01L2200/14—Process control and prevention of errors
    • B01L2200/143—Quality control, feedback systems
    • B01L2200/147—Employing temperature sensors
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/08—Geometry, shape and general structure
    • B01L2300/0809—Geometry, shape and general structure rectangular shaped
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/08—Geometry, shape and general structure
    • B01L2300/0893—Geometry, shape and general structure having a very large number of wells, microfabricated wells
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/18—Means for temperature control
    • B01L2300/1805—Conductive heating, heat from thermostatted solids is conducted to receptacles, e.g. heating plates, blocks
    • B01L2300/1811—Conductive heating, heat from thermostatted solids is conducted to receptacles, e.g. heating plates, blocks using electromagnetic induction heating
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6844—Nucleic acid amplification reactions
    • C12Q1/686—Polymerase chain reaction [PCR]

Definitions

  • PCT/US18/17504 filed on 2/8/2018 (18F02), PCT Application No. PCT/US18/17499, filed on 2/8/2018 (18F17), PCT Application No. PCT/US18/17489, filed on 2/8/2018 (18F18), PCT Application No. PCT/US18/17492, filed on 2/8/2018 (18F10), PCT Application No. PCT/US18/17494, filed on 2/8/2018 (18F02), PCT Application No. PCT/US18/17502, filed on 2/8/2018 (18F09), and PCT Application No. PCT/US18/17307, filed on 2/7/2018 (18F15A), each of which is incorporated herein by reference in its entirety for all purposes.
  • PCR polymerase chain reaction
  • the present invention provides devices, systems, and methods for rapid sample thermal cycle changes for the facilitation of reactions such as but not limited to PCR.
  • One aspect of the present invention is to use two movable thin plates to compress a liquid sample into a uniform thin layer.
  • Another aspect of the present invention is to speed up sample temperature ramping speed, one of the plates of the QMAX assay is reduced to 100 urn (micron) thick or less.
  • Another aspect of the present invention is to provide solutions to the problems associated to a very thin plate in a QMAX card under a rapid temperature change or cycling.
  • the problem includes large deformation of the plate, the sample thickness changes, air bubble formation and other, that each of them can lead to failure of a PRC or isothermal nucleic acid amplification.
  • one of the solutions comprises a use of clamp with certain design to hold the two plates fixed together during the temperature changes.
  • the clamps in the present innovation can be used for the QMAX card that do not need to change the sample temperature.
  • the present invention provides the devices and methods for changing temperature of a sample quickly through making a sample into a uniform ultrathin thin over an area (or a relevant area), low thermal absorption and low thermal capacity of a sample holder, and an area heater elements.
  • PCR polymerase chain reaction
  • the present invention provides devices and methods for rapid thermal cycle changes and the devices and methods herein disclosed are suitable for the facilitation of reactions such as but not limited to PCR.
  • Fig. 1 shows perspective and sectional views of an embodiment of the device of the present invention
  • panel (A) illustrates an embodiment of the device in an open
  • panel (B) illustrates an embodiment of the device when the sample unit is in a closed configuration, where the temperature of a sample that is compressed into a thin layer between two plates is rapidly changed by a radiation source that is positioned to project electromagnetic waves onto the sample.
  • Fig. 2 shows perspective and sectional views of an embodiment of the system of the present invention
  • panel (A) illustrates the perspective view of the system when the device (sample unit of the system) is in an open configuration
  • panel (B) illustrates the sectional view of the system when the sample unit is in a closed configuration.
  • Fig. 3 shows a sectional view of an embodiment of the system of the present invention, demonstrating the system and showing additional elements that facilitate temperature change and control.
  • Fig. 4 shows perspective views of another embodiment of the present invention, where there are multiple sample contact areas on the plates, allowing the processing and analysis of multiple samples.
  • Fig. 5 shows a sectional view of an exemplary embodiment of the present invention, demonstrating how the sample is added and compressed.
  • Fig. 6 shows a sectional view of an exemplary embodiment of the present invention, demonstrating a PCR process.
  • CROF Card or card
  • COF Card or card
  • COF Card QMAX-Card
  • Q-Card CROF device
  • COF device COF device
  • QMAX-device CROF plates
  • COF plates COF plates
  • QMAX-plates are interchangeable, except that in some embodiments, the COF card does not comprise spacers; and the terms refer to a device that comprises a first plate and a second plate that are movable relative to each other into different configurations (including an open configuration and a closed configuration), and that comprises spacers (except some embodiments of the COF) that regulate the spacing between the plates.
  • X-plate refers to one of the two plates in a CROF card, wherein the spacers are fixed to this plate. More descriptions of the COF Card, CROF Card, and X-plate are described in the provisional application serial nos. 62/456065, filed on February 7, 2017, which is
  • Fig. 1 shows perspective and sectional views of an embodiment of the device of the present invention.
  • Panel (A) illustrates the device (also termed “sample unit" of the system) 100 in an open configuration.
  • the sample unit 100 comprises a first plate 10, a second plate 20, and a spacing mechanism (not shown).
  • the first plate 10 and second plate 20 respectively comprise an outer surface (1 1 and 21 , respectively) and an inner surface (12 and 22, respectively).
  • Each inner surface has a sample contact area (not indicated) for contacting a fluidic sample to be processed and/or analyzed by the device.
  • the first plate 10 and the second plate 20 are movable relative to each other into different configurations.
  • One of the configurations is the open configuration, in which, as shown in Fig. 1 panel (A), the first plate 10 and the second plate 20 are partially or entirely separated apart, and the spacing between the first plate 10 and the second plate 20 (i.e. the distance between the first plate inner surface 11 and the second plate inner surface 21) is not regulated by the spacing mechanism.
  • the open configuration allows a sample to be deposited on the first plate, the second plate, or both, in the sample contact area.
  • the first plate 10 further comprises a radiation absorbing layer 112 in the sample contact area.
  • the second plate 20 alternatively or additionally comprise the radiation absorbing layer 1 12.
  • the radiation absorbing layer 112 is configured to efficiently absorb radiation (e.g. electromagnetic waves) shed on it.
  • the absorption percentage is 50% or more, 60% or more, 70% or more, 80% or more, 90% or more, 95% or more, 99% or more, 100% or less, 85% or less, 75% or less, 65% or less, or 55% or less, or in a range between any of the two values.
  • the radiation absorbing layer 112 is further configured to convert at least a substantial portion of the absorbed radiation energy into heat (thermal energy).
  • the radiation absorbing layer 112 is configured to emit radiation in the form of heat after absorbing the energy from electromagnetic waves.
  • the term “substantial portion” or “substantially” as used herein refers to a percentage that is 50% or more, 60% or more, 70% or more, 80% or more, 90% or more, 95% or more, 99% or more, 99% or more, or 99.9% or more.
  • the radiation absorbing layer 112 comprise
  • the radiation absorbing layer 112 comprise carbon nanotube.
  • the radiation absorbing layer comprise a dot-coupled-dots-on- pillar antenna (D2PA) array, such as, but not limited to the D2PA array described in U.S. Provisional Patent Application No. 61/347, 178, which was filed on May 21 , 2010, U.S.
  • D2PA dot-coupled-dots-on- pillar antenna
  • Panel (B) of Fig. 1 shows perspective and sectional views of the sample unit 100 when it is in a closed configuration.
  • the sectional view illustrates part of the device without showing the entirety of the sample unit 100 or the spacing mechanism.
  • the sample unit 100 comprises a first plate 10, a second plate 20, and a spacing mechanism (not shown).
  • the first plate 10 and the second plate 20 are in a closed configuration.
  • the inner surfaces of the two plates 11 and 21 face each other, and the spacing between the two plates 102 is regulated by the spacing mechanism. Consequently, as shown in the figure, the two plates compress a fluidic sample 90 that is deposited on one or both of the plates into a layer, and the thickness of the layer is regulated by the spacing mechanism (not illustrated).
  • a device for rapidly changing temperature of a thin fluidic sample layer comprising: a first plate, and a second plate, wherein:
  • each of the plates comprises, on its respective surface, a sample contact area for contacting a fluidic sample
  • the plates have a configuration for rapidly changing temperature of the
  • the sample contact areas face each other and are significant parallel
  • the average spacing between the contact areas is equal to or less than 200 microns
  • the two plates regulate (or confine) at least part of the sample into a layer of highly uniform thickness and substantially stagnant relative to the plates, d. the radiation absorbing layer is near the at least part of the sample of uniform thickness,
  • the area of the at least part of the sample and the radiation absorbing layer are substantially larger than the uniform thickness.
  • an "evaporation-prevention ring" outside of the liquid area (e.g. sample area) that prevents or reduces the vapor of the liquid escape the card, during a heating.
  • the sample in order to achieve fast and uniform thermal change in a sample, is compressed into a thin layer.
  • the thickness of the layer is 500 ⁇ or less, 200 ⁇ or less, 100 ⁇ or less, 50 ⁇ or less, 20 ⁇ or less, 10 ⁇ or less, 5 ⁇ or less , 2 ⁇ or less, 1 ⁇ or less, 500 nm or more, 1.5 ⁇ or more, 2.5 ⁇ or more, 7.5 ⁇ or more, 15 ⁇ or more, 30 ⁇ or more, 75 ⁇ or more, 150 ⁇ or more, or 250 ⁇ or more.
  • the small thickness of the sample layer results in a faster diffusion of reagents and/or faster transduction of heat.
  • the two plates are compressed by an imprecise pressing force, which is neither set to a precise level nor substantially uniform. In certain embodiments, the two plates are pressed directly by a human hand.
  • the QMAX card including the plates and spacer, is made of the material with low thermal conductivity to reduce the heat absorption by card self.
  • the clamp is also made of the material with low thermal conductivity to reduce the heat absorption by card self.
  • cover means that the areas on the plate that are in thermal conduction contact with a clamp.
  • the clamp covers some of the surface of QMAX card in a closed configuration means that the clamp has a thermal conduction contact with a part of the plate surface a QMAX card.
  • clamp by a clamp means that that the clamp prevents or reduce, in a closed configuration of the plates, at least a part of the sample flow from one location of the plate to the other location of the plate.
  • a clamp can be configured to seal a part of the sample or the entire sample.
  • clamp refers to a device comprising two elements that insert a compress force to holds a third element or more elements to together. For example, a clamp holds two plates together.
  • polymers e.g. plastics
  • the polymer materials include, not limited to, acrylate polymers, vinyl polymers, olefin polymers, cellulosic polymers, noncellulosic polymers, polyester polymers, Nylon, cyclic olefin copolymer (COC), poly(methyl methacrylate) (PMMA), polycarbonate (PC), cyclic olefin polymer (COP), liquid crystalline polymer (LCP), polyamide (PA), polyethylene (PE), polyimide (PI), polypropylene (PP), poly(phenylene ether) (PPE), polystyrene (PS), polyoxymethylene (POM), polyether ether ketone (PEEK), polyether sulfone (PES), poly(ethylene phthalate) (PET), polytetrafluoroethylene (PTFE), polyvinyl chloride (PVC), polyvinylidene fluoride (PV
  • these materials contain but not limit to inorganic materials including dielectric materials of silicon oxide, porcelain, orcelain (ceramic), mica, glass, oxides of various metals, etc.
  • these materials contain but not limit to inorganic compounds including aluminium oxide, aluminium chloride, cadmium sulfide, gallium nitride, gold chlorid, indium arsenide, lithium borohydride, silver bromide, sodium chloride, etc.
  • liquid including but not limit to water, ethane, methane, oil, benzene, Hexane, heptane, silicone oil, polychlorinated biphenyls, liquid air, liquid oxygen, liquid nitrogen etc.
  • these materials contain gas including but not limit to air, argon, helium, nitrogen, oxygen, carbon dioxide, etc.
  • the average thickness for at least one of the plates is in the range of 1 to 1000 ⁇ , 10 to 900 ⁇ , 20 to 800 ⁇ , 25 to 700 ⁇ , 25 to 800 ⁇ , 25 to 600 ⁇ , 25 to 500 ⁇ , 25 to 400 ⁇ , 25 to 300 ⁇ , 25 to 200 ⁇ , 30 to 200 ⁇ , 35 to 200 ⁇ , 40 to 200 ⁇ , 45 to 200 ⁇ , or 50 to 200 ⁇ .
  • the average thickness for at least one of the plates is in the range of 50 to 75 ⁇ , 75 to 100 ⁇ , 100 to 125 ⁇ , 125 to 150 ⁇ , 150 to 175 ⁇ , or 175 to 200 ⁇ .
  • the average thickness for at least one of the plates is about 50 ⁇ , about 75 ⁇ , about 100 ⁇ , about 125 ⁇ , about 150 ⁇ , about 175 ⁇ , or about 200 ⁇ .
  • the height of the spacers is selected by a desired regulated spacing between the plates and/or a regulated final sample thickness and the residue sample thickness.
  • the spacer height (the predetermined spacer height), the spacing between the plates, and/or sample thickness is 3 nm or less, 10 nm or less, 50 nm or less, 100 nm or less, 200 nm or less, 500 nm or less, 800 nm or less, 1000 nm or less, 1 ⁇ or less, 2 ⁇ or less, 3 ⁇ or less, 5 ⁇ or less, 10 ⁇ or less, 20 ⁇ or less, 30 ⁇ or less, 50 ⁇ or less, 100 ⁇ or less, 150 ⁇ or less, 200 ⁇ or less, 300 ⁇ or less, 500 ⁇ or less, 800 ⁇ or less, 1 mm or less, 2 mm or less, 4 mm or less, or in a range between any two of the values.
  • the spacer height, the spacing between the plates, and/or sample thickness is between 1 nm to 100 nm in one preferred embodiment, 100 nm to 500 nm in another preferred embodiment, 500 nm to 1000 nm in a separate preferred embodiment, 1 ⁇ (i.e. 1000 nm) to 2 ⁇ in another preferred embodiment, 2 ⁇ to 3 ⁇ in a separate preferred embodiment, 3 ⁇ to 5 ⁇ in another preferred embodiment, 5 ⁇ to 10 ⁇ in a separate preferred embodiment, and 10 ⁇ to 50 ⁇ in another preferred embodiment, 50 ⁇ to 100 ⁇ in a separate preferred embodiment.
  • the QMAX device is fully transparent or partially transparent to reduce the heat absorption by card self, wherein the transparence is above 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or a range between any two of the values.
  • the QMAX device is partially reflective to reduce the heat absorption by card self, wherein the reflectance of the surface is above 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or a range between any two of the values.
  • the QMAX and clamp is coated heat insulator layer to reduce the heat absorption by card self.
  • the heat insulator layer contains materials including the low thermal conductivity material above.
  • the clamp cover and seal all the QMAX card in close configuration are provided.
  • the clamp cover some of the surface of QMAX card in close configuration.
  • the clamp has a window which is transparent to allow the light go inside the QMAX card and out from the QMAX card.
  • the clamp is fully transparent to allow the light go inside the QMAX card and out from the QMAX card.
  • transparence of the clamp is above 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or a range between any two of the values.
  • liquid including but not limit to water, ethane, methane, oil, benzene, Hexane, heptane, silicone oil, polychlorinated biphenyls, liquid air, liquid oxygen, liquid nitrogen etc.
  • the pressure on QMAX card surface applied by the clamp is .01 kg/cm2, 0.1 kg/cm2, 0.5 kg/cm2, 1 kg/cm2, 2 kg/cm2, kg/cm2, 5 kg/cm2, 10 kg/cm2, 20 kg/cm2, 30 kg/cm2, 40 kg/cm2, 50 kg/cm2, 60 kg/cm2, 100 kg/cm2, 150 kg/cm2, 200 kg/cm2, or a range between any two of the values; and a preferred range of 0.1 kg/cm2 to 0.5 kg/cm2, 0.5 kg/cm2 to 1 kg/cm2, 1 kg/cm2 to 5 kg/cm2, 5 kg/cm2 to 10 kg/cm2 (Pressure).
  • the radiation absorbing layer 112 spans across the sample contact area. It should be noted, however, it is also possible that the lateral area of the radiation absorbing layer occupy only a portion of the sample contact area at a percentage about 1% or more, 5% or more, 10% or more, 20% or more, 50% or more, 80% or more, 90% or more, 95% or more, 99% or more, 85% or less, 75% or less, 55% or less, 40% or less, 25% or less, 8% or less, 2.5% or less.
  • the lateral area of the radiation absorbing layer is configured so that the sample 90 receive the thermal radiation from the radiation absorbing layer 112 substantially uniformly across the lateral dimension of the sample 90 over the sample contact area.
  • the radiation absorbing area is 10%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100% the total plate area, or a range between any two of the values.
  • the radiation absorbing layer 112 have a thickness of 10 nm or more, 20 nm or more, 50 nm or more, 100 nm or more, 200 nm or more, 500 nm or more, 1 ⁇ or more, 2 ⁇ or more, 5 ⁇ or more, 10 ⁇ or more, 20 ⁇ or more, 50 ⁇ or more, 100 ⁇ or more, 75 ⁇ or less, 40 ⁇ or less, 15 ⁇ or less, 7.5 ⁇ or less, 4 ⁇ or less, 1.5 ⁇ or less , 750 nm or less, 400 nm or less, 150 nm or less, 75 nm or less, 40 nm or less, or 15 nm or less, or in a range between any of the two values. In certain embodiments, the radiation absorbing layer 112 have thickness of 100 nm or less.
  • the area of the sample layer and the radiation absorbing layer 112 is substantially larger than the uniform thickness.
  • the term "substantially larger” means that the general diameter or diagonal distance of the sample layer and/or the radiation absorbing layer is at least 10 time, 15 times, 20 time, 25 times, 30 time, 35 times, 40 time, 45 times, 50 time, 55 times, 60 time, 65 times, 70 time, 75 times, 80 time, 85 times, 90 time, 95 times, 100 time, 150 times, 200 time, 250 times, 300 time, 350 times, 400 time, 450 times, 500 time, 550 times, 600 time, 650 times, 700 time, 750 times, 800 time, 850 times, 900 time, 950 times, 1000 time, 1500 times, 2000 time, 2500 times, 3000 time, 3500 times, 4000 time, 4500 times, or 5000 time, or in a range between any of the two values.
  • Fig. 2 shows perspective and sectional views of an embodiment of the system of the present invention.
  • the system comprise a sample unit 100 and a thermal control unit 200; the sample unit 100 comprise a first plate 10, a second plate 20, and a spacing mechanism (not shown); the thermal control unit 200 comprise a radiation source 202 and controller 204.
  • Panels (A) and (B) of Fig. 2 illustrate the perspective view and sectional view of the system when the sample unit 100 of the system is in a closed configuration.
  • the thermal control unit 200 comprise a radiation source 202 and controller 204.
  • the thermal control unit 200 provide the energy in the form of electromagnetic waves for temperature change of the sample.
  • the radiation source 202 is configured to project an electromagnetic wave 210 to the radiation absorbing layer 112 of the sample unit 100, which is configured to absorb the electromagnetic wave 210 and convert a substantial portion of the electromagnetic wave 210 into heat, resulting in thermal radiation that elevate the temperature of a portion of the sample 90 that is in proximity of the radiation absorbing layer 112.
  • the coupling of the radiation source 202 and the radiation absorbing layer 1 12 is configured to generate the thermal energy that is needed to facilitate the temperature change of the sample 90.
  • the radiation from the radiation source 202 comprises radio waves, microwaves, infrared waves, visible light, ultraviolet waves, X-rays, gamma rays, or thermal radiation, or any combination thereof.
  • the radiation absorbing layer 112 has a preferred range of light wavelength at which the radiation absorbing layer 112 has the highest absorption efficiency.
  • the radiation source 202 is configured to project the electromagnetic wave at a wavelength range within, overlapping with, or enclosing the preferred wavelength range of the radiation absorbing layer 112. In other embodiments, in order to facilitate the temperature change, the wavelength is rationally designed away from the preferred wavelength of the radiation absorbing layer.
  • the radiation source 202 comprises a laser source providing a laser light within a narrow wavelength range. In other embodiments, the radiation source 202 comprises a LED (light-emitting diode) of a plurality thereof.
  • the controller 204 is configured to control the electromagnetic wave 210 projected from the radiation source 202 for the temperature change of the sample.
  • the parameters of the electromagnetic wave 210 that the controller 204 controls include, but are not limited to, the presence, intensity, wavelength, incident angle, and any combination thereof.
  • the controller is operated manually, for instance, it is as simple as a manual switch that controls the on and off of the radiation source, and therefore the presence of the electromagnetic wave projected from the radiation source.
  • the controller includes hardware and software that are configured to control the electromagnetic wave automatically according to one or a plurality of pre-determined programs.
  • the pre-determined program refers to a schedule in which the parameter(s) (e.g. presence, intensity, and/or wavelength) of the electromagnetic wave 210 is/are set to pre-determined levels for respective pre-determined periods of time.
  • the pre-determined program refers to a schedule in which the temperature of the sample 90 is set to pre-determined levels for respective pre-determined periods of time and the time periods for the change of the sample temperature from one pre-determined level to another pre-determined level are also set respectively.
  • the controller 204 is configured to be programmable, which means the controller 204 comprises hardware and software that are configured to receive and carry out pre-determined programs for the system that are delivered by the operator of the system.
  • the thermal cycler system and associated methods of the present invention is used to facilitate a chemical, biological or medical assay or reaction.
  • the reaction requires temperature changes.
  • the reaction requires or prefers rapid temperature change in order to avoid non-specific reaction and/or reduce wait time.
  • the system and methods of the present invention is used to facilitate a reaction that requires cyclical temperature changes for amplification of a nucleotide in a fluidic sample; such reactions includes but not is limited to polymerase chain reaction (PCR).
  • PCR polymerase chain reaction
  • the sample 90 is a pre-mixed reaction medium for polymerase chain reaction (PCR).
  • PCR polymerase chain reaction
  • the reaction medium includes components such as but not limited to: DNA template, two primers, DNA polymerase (e.g. Taq polymerase), deoxynucleoside triphosphates (dNTPs), bivalent cations (e.g. Mg 2+ ), monovalent cation (e.g. K + ), and buffer solution.
  • DNA polymerase e.g. Taq polymerase
  • dNTPs deoxynucleoside triphosphates
  • bivalent cations e.g. Mg 2+
  • monovalent cation e.g. K +
  • buffer solution buffer solution.
  • concentrations of each component, and the overall volume varies according to rational design of the reaction.
  • the PCR assay requires a number of changes/alterations in sample temperature between the following steps: (i) the optional initialization step, which requires heating the sample to 92-98 °C; (2) the denaturation step, which requires heating the sample to 92-98 °C; (3) the annealing step, which requires lowering the sample temperature to 50-65 °C; (4) extension (or elongation) step, which requires heating the sample to 75-80 °C; (5) repeating steps (2)-(4) for about 20-40 times; and (6) completion of the assay and lowering the temperature of the sample to ambient temperature (e.g. room temperature) or cooling to about 4 °C.
  • the specific temperature and the specific time period for each step varies and depends on a number of factors, including but not limited to length of the target sequence, length of the primers, the cation concentrations, and/or the GC percentage.
  • the thermal cycler system of the present invention provides rapid temperature change for the PCR assay.
  • the sample 90 e.g. pre-mixed reaction medium
  • the plates is switched to the closed configuration to compress the sample 90 into a thin layer which has a thickness 102 that is regulated by a spacing mechanism (not shown);
  • the radiation source 202 projects a electromagnetic wave 210 to the first plate 10 (e.g.
  • the radiation absorbing layer 1 12 is configured to absorb the electromagnetic wave 210 and convert at least a substantial portion of said electromagnetic wave 210 into heat, which increases the temperature of the sample; the removal of the electromagnetic wave 210 results in a temperature decrease in the sample 90.
  • the thermal cycler systems by projecting a electromagnetic wave 210 to the radiation absorbing layer 112 or increasing the intensity of the electromagnetic wave, the thermal cycler systems provide rapid heating (increase temperature) for any or all of the initialization step, the denaturation step and/or the extension/elongation step; in some embodiments, with the removal of the electromagnetic wave projected from the radiation source 202 or the decrease of the intensity of the electromagnetic wave, the cooling to the annealing step and/or the final cooling step is achieved with rapid speed.
  • the electromagnetic wave 210 or an increase of the intensity of the electromagnetic wave 210 creates an ascending temperature ramp rate of at least 50 °C/s, 45 °C/s, 40 °C/s, 35 °C/s, 30 °C/s, 25 °C/s, 20 °C/s, 18 °C/s, 16 °C/s, 14 °C/s, 12 °C/s, 10 °C/s, 9 °C/s, 8 °C/s, 7 °C/s, 6 °C/s, 5 °C/s, 4 °C/s, 3 °C/s, or 2 °C/s, or in a range between any of the two values.
  • the average ascending temperature ramp rate in a PCR assay is 10 °C/s or more.
  • the removal of the electromagnetic wave 210 or a reduction of the intensity of the electromagnetic wave 210 results in a descending temperature ramp rate of at least 50 °C/s, 45 °C/s, 40 °C/s, 35 °C/s, 30 °C/s, 25 °C/s, 20 °C/s, 18 °C/s, 16 °C/s, 14 °C/s, 12 °C/s, 10 °C/s, 9 °C/s, 8 °C/s, 7 °C/s, 6 °C/s, 5 °C/s, 4 °C/s, 3 °C/s, or 2 °C/s, or in a range between any of the two values.
  • the average descending temperature ramp rate in a PCR assay is 5 °C/s or more.
  • the term “ramp rate” refers to the speed of temperature change between two pre-set temperatures.
  • the average ascending or descending temperature to each step is different.
  • the thermal cycler system of the present invention provides the temperature maintenance function by (1) adjusting the intensity of the electromagnetic wave 210, lowering it if the temperature has been raised to the target or increasing it if the temperature has been decreased to the target, and/or (2) keep the target temperature by balancing the heat provided to the sample and the heat removed from the sample.
  • Fig. 3 shows a sectional view of an embodiment of the present invention
  • the thermal cycler system comprises a sample unit 100 and a thermal control unit 200.
  • the sample unit 100 comprises a first plate 10, a second plate 20, a spacing mechanism 40, and a sealing element 30;
  • the thermal control unit 200 comprises a radiation source 202, a controller 204, a thermometer 206, and an expander 208.
  • Fig. 3 shows the sample unit 100 in a closed configuration, in which the inner surfaces 11 and 21 of the first and second plates 10 and 20 face each other and the spacing 102 between the two plates are regulated by a spacing mechanism 40. If a sample 90 has been deposited on one or both of the plates in the open configuration, when switching to the closed configuration, the first plate 10 and the second plate 20 are pressed by a human hand or other mechanisms, the sample 90 is thus compressed by the two plates into a thin layer. In some embodiments, the thickness of the layer is uniform and the same as the spacing 102 between the two plates. In certain embodiments, the spacing 102 (and thus the thickness of the sample layer) is regulated by the spacing mechanism 40.
  • the spacing mechanism comprises an enclosed spacer that is fixed to one of the plates.
  • the spacing mechanism 40 comprises a plurality of pillar shaped spacers that are fixed to one or both of the plates.
  • fixed means that the spacer(s) is attached to a plate and the attachment is maintained during at least a use of the plate.
  • the sample unit 10 is a compressed regulated open flow (CROF, also known as QMAX) device, such as but not limited to the CROF device described in U.S. Provisional Patent Application No. 62/202,989, which was filed on August 10, 2015, U.S. Provisional Patent Application No. 62/218,455, which was filed on September 14, 2015, U.S. Provisional Patent Application No. 62/293, 188, which was filed on February 9, 2016, U.S. Provisional Patent Application No. 62/305, 123, which was filed on March 8, 2016, U.S. Provisional Patent Application No. 62/369, 181 , which was filed on July 31 , 2016, U.S. Provisional Patent Application No.
  • CROF compressed regulated open flow
  • the sample unit 100 comprises a sealing element 30 that is configured to seal the spacing 102 between the first plate 10 and second plate 20 outside the medium contact area at the closed configuration.
  • the sealing element 30 encloses the sample 90 within a certain area (e.g. the sample receiving area) so that the overall lateral area of the sample 90 is well defined and measurable.
  • the sealing element 30 improves the uniformity of the sample 90, especially the thickness of the sample layer.
  • the sealing element 30 comprises an adhesive applied between the first plate 10 and second plate 20 at the closed configuration.
  • the adhesive is selective from materials such as but not limited to: starch, dextrin, gelatine, asphalt, bitumin, polyisoprenenatural rubber, resin, shellac, cellulose and its derivatives, vinyl derivatives, acrylic derivatives, reactive acrylic bases, polychloroprene, styrene - butadiene, sytyrene- diene-styrene, polyisobutylene, acrylonitrile-butadiene, polyurethane, polysulfide, silicone, aldehyde condensation resins, epoxide resins, amine base resins, polyester resins, polyolefin polymers, soluble silicates, phosphate cements, or any other adhesive material, or any combination thereof.
  • the adhesive is drying adhesive, pressure-sensitive adhesive, contact adhesive, hot adhesive, or one-part or multi-part reactive adhesive, or any combination thereof.
  • the glue is natural adhesive or synthetic adhesive, or from any other origin, or any combination thereof.
  • the adhesive is spontaneous-cured, heat-cured, UV-cured, or cured by any other treatment, or any combination thereof.
  • the sealing element 30 comprises an enclosed spacer (well).
  • the enclosed spacer has a circular shape (or any other enclosed shape) from a top view and encircle the sample 90, essentially restricting the sample 90 together with the first plate 10 and the second plate 20.
  • the enclosed spacer (well) also function as the spacing mechanism 40. In such embodiments, the enclosed spacer seals the lateral boundary of the sample 90 as well as regulate the thickness of the sample layer.
  • the controller 204 is configured to adjust the temperature of the sample to facilitate an assay and/or reaction involving the sample 90 according to a pre- determined program.
  • the assay and/or reaction is a PCR.
  • the controller 204 is configured to control the presence, intensity, and/or frequency of the electromagnetic wave from the radiation source 206.
  • the thermal control unit 200 comprises a thermometer 206.
  • the thermometer 206 provides a monitoring and/or feedback mechanism to control/monitor/adjust the temperature of the sample 90.
  • the thermometer 206 is configured to measure the temperature at or in proximity of the sample contact area.
  • the thermometer 206 is configured to directly measure the temperature of the sample 90.
  • the thermometer 206 is selected from the group consisting of: fiber optical thermometer, infrared thermometer, fluidic crystal thermometer, pyrometer, quartz thermometer, silicon bandgap temperature sensor, temperature strip, thermistor, and thermocouple.
  • the thermometer 206 is an infrared thermometer.
  • the thermometer 206 is configured to send signals to the controller 204.
  • signals comprise information related to the temperature of the sample 90 so that the controller 204 makes corresponding changes.
  • the controller 204 sends a signal to the controller 204, indicating that the measured temperature of the sample 90 is actually 94.8 °C; the controller 204 thus alters the output the radiation source 202, which projects a electromagnetic wave or adjust particular parameters (e.g. intensity or frequency) of an existing electromagnetic wave so that the temperature of the sample 90 is increased to 95 °C.
  • Such measurement-signaling-adjustment loop is applied to any step in any reaction/assay.
  • the thermal control unit 200 comprises a beam expander 208, which is configured to expand the electromagnetic wave from the radiation source 202 from a smaller diameter to a larger diameter.
  • the electromagnetic wave projected from the radiation source 202 is sufficient to cover the entire sample contact area; in some embodiments however, it is necessary to expand the covered area of the
  • the beam expander 208 employs any known technology, including but not limited to the bean expanders described in U.S. Pat. Nos. 4,545,677, 4,214,813, 4, 127,828, and 4,016,504, and U.S. Pat. Pub. No. 2008/0297912 and 2010/0214659, which are
  • the thermal cycler system of the present invention comprises a sample unit 100 and a thermal control unit 200;
  • the sample unit 100 comprises a first plate 10, a plurality of second plates 20, and a plurality of spacing mechanisms (not shown);
  • the thermal control unit 200 comprises a radiation source 202 and a controller 204.
  • one or both of the plates comprises a plurality of sample contact areas (not marked).
  • one or both of the plates comprises a plurality of radiation absorbing layers 1 12.
  • Panel (A) of Fig. 4 shows the sample unit 100 in an open configuration, in which the first plate 10 and the second plates 20 are partially or entirely separated apart, allowing the deposition of one or more samples on one or both of the plates. In the open configuration, the spacing between the first plate 10 and the second plates 20 are not regulated by the spacing mechanisms.
  • Panel (B) of Fig. 4 shows the sample unit 100 in a closed configuration, in which the inner surfaces of the two plates face each other and the spacing 102 between the two plates are regulated by the spacing mechanism (not shown). If one or more samples have been deposited on the plates, the plates are configured to compress each sample into a layer, the thickness of the layer is regulated by the spacing mechanism.
  • each second plate 20 covers a single sample contact area, onto which a sample is deposited.
  • a spacing mechanism is present for each sample contact area and the spacing mechanisms have different heights, resulting in different spacing 102 for each sample contact area and for different thickness for each sample layer.
  • the spacing mechanism is pillar shaped spacers; each sample contact area has a set of spacers having a uniform height; different sets of spacers have the same or different heights, resulting in same or different sample layer thickness for the different samples.
  • the controller 204 directs the radiation source 202 to project a electromagnetic wave 210 to the first plate 10 (and thus the radiation absorbing layer 1 12), where the electromagnetic wave 210 is absorbed by the radiation absorbing layer 112 and converted to heat, resulting in change of temperature in the samples.
  • the controller 204 directs the radiation source 202 to project a electromagnetic wave 210 to the first plate 10 (and thus the radiation absorbing layer 1 12), where the electromagnetic wave 210 is absorbed by the radiation absorbing layer 112 and converted to heat, resulting in change of temperature in the samples.
  • multiple samples are processed and analyzed.
  • each of the samples is a pre-mixed PCR reaction medium having different components.
  • One sample unit 100 is used to test different conditions for amplifying the same nucleotide and/or amplifying different nucleotides with the same or different conditions.
  • Fig. 5 illustrates a cross-sectional view of an exemplary procedure for nucleic acid amplification using a QMAX card device.
  • steps include (A) introducing sample containing nucleic acids onto the inner side of a first plate (substrate); (B) pressing a second plate (QMAX card) onto the inner surface of the first plate to form a closed configuration of the device, where necessary reagents for nucleic acid amplification are dried on the inner surface of the second plate; (c) accumulating nucleic acid amplification products in the chamber enclosed by the first and the second plates.
  • Fig. 5 illustrates a cross-sectional view of an exemplary procedure for nucleic acid amplification using a QMAX card device.
  • the "sample” can be any nucleic acid containing or not containing samples, including but not limited to human bodily fluids, such as whole blood, plasma, serum, urine, saliva, and sweat, and cell cultures (mammalian, plant, bacteria, fungi).
  • the sample can be freshly obtained, or stored or treated in any desired or convenient way, for example by dilution or adding buffers, or other solutions or solvents.
  • Cellular structures can exist in the sample, such as human cells, animal cells, plant cells, bacteria cells, fungus cells, and virus particles.
  • nucleic acid refers to any DNA or RNA molecule, or a DNA/RNA hybrid, or mixtures of DNA and/or RNA.
  • the term “nucleic acid” therefore is intended to include but not limited to genomic or chromosomal DNA, plasmid DNA, amplified DNA, cDNA, total RNA, mRNA and small RNA.
  • the term “nucleic acid” is also intended to include natural DNA and/or RNA molecule, or synthetic DNA and/or RNA molecule.
  • cell-free nucleic acids are presence in the sample, as used herein "cell-free” indicates nucleic acids are not contained in any cellular structures.
  • nucleic acids are contained within cellular structures, which include but not limited to human cells, animal cells, plant cells, bacterial cells, fungi cells, and/or viral particles. Nucleic acids either in the form of cell-free nucleic acids or within cellular structures or a combination thereof, can be presence in the sample. In some further embodiments, nucleic acids are purified before introduced onto the inner surface of the first plate. In yet further embodiments, nucleic acids can be within a complex associated with other molecules, such as proteins and lipids.
  • the method of the invention is suitable for samples of a range of volumes. Sample having different volumes can be introduced onto the plates having different dimensions.
  • the sample can be introduced onto either the first plate or the second plate, or even both when necessary.
  • Fig. 5. herein provides an example of introducing sample onto the first plate inner surface. More particularly, in step (b), a second plate is pressed onto the inner surface of the first plate, in contact with the sample, to form a closed configuration of the device.
  • a second plate refers to a QMAX card with periodic spacers on the inner surface contacting samples.
  • nucleic acid amplification includes any techniques used to detect nucleic acids by amplifying (generating numerous copies of) the target molecules in samples, herein “target” refers to a sequence, or partial sequence, of nucleic acid of interest.
  • Suitable nucleic acid amplification techniques include but not limited to, different polymerase chain reaction (PCR) methods, such as hot-start PCR, nested PCR, touchdown PCR, reverse transcription PCR, RACE PCR, digital PCR, etc., and isothermal amplification methods, such as Loop-mediated isothermal amplification (LAMP), strand displacement amplification, helicase-dependent amplification, nicking enzyme amplification, rolling circle amplification, recombinase polymerase amplification, etc.
  • PCR polymerase chain reaction
  • LAMP Loop-mediated isothermal amplification
  • strand displacement amplification strand displacement amplification
  • helicase-dependent amplification nicking enzyme amplification
  • rolling circle amplification recombinase polymerase amplification
  • Necessary reagents include but not limited to, primers, deoxynucleotides (dNTPs), bivalent cations (e.g. Mg2+), monovalent cation (e.g. K+), buffer solutions, enzymes, and reporters.
  • Necessary reagents for nucleic acid amplification can be either in the dry form on the inner surface of the first or the second plate or both, or in a liquid form encased in, embedded in, or surrounded by, a material that melts with increasing temperatures, such as, for example, paraffin.
  • primers in some embodiments, can refer to a pair of forward and reverse primers. In some embodiments, primers can refer to a plurality of primers or primer sets.
  • enzymes suitable for nucleic acid amplification include, but not limited to, DNA-dependent polymerase, or RNA-dependent DNA polymerase, or DNA-dependent RNA polymerase.
  • reporter refers to any tag, label, or dye that can bind to, or intercalate within, the nucleic acid molecule or be activated by byproducts of the amplification process to enable visualization of the nucleic acid molecule or the amplification process.
  • Suitable reporters include but are not limited to fluorescent labels or tags or dyes, intercalating agents, molecular beacon labels, or bioluminescent molecules, or a combination thereof.
  • “necessary reagents” can also include cell lysing reagent, which facilitates to break down cellular structures.
  • Cell lysing reagents include but not limited to salts, detergents, enzymes, and other additives.
  • the term “salts” herein include but not limited to lithium salt (e.g. lithium chloride), sodium salt (e.g. sodium chloride), potassium (e.g. potassium chloride).
  • detergents” herein can be ionic, including anionic and cationic, non-ionic or zwitterionic.
  • ionic detergent as used herein includes any detergent, which is partly or wholly in ionic form when dissolved in water.
  • Suitable anionic detergents include but not limited to sodium dodecyl sulphate (SDS) or other alkali metal alkylsulphate salts or similar detergents, sarkosyl, or combinations thereof.
  • SDS sodium dodecyl sulphate
  • the term "enzymes” herein include but not limited to lysozyme, cellulase, and proteinase.
  • chelating agents including but not limited to EDTA, EGTA and other polyamino carboxylic acids, and some reducing agents, such as dithiotreitol (dTT), can also be included in cell lysing reagents.
  • dTT dithiotreitol
  • the compositions of necessary reagents herein vary according to rational designs of different amplification reactions.
  • a radiation source projects an electromagnetic wave to the radiation absorbing layer on the inner or outer surface of the first plate, or the second plate or both.
  • the radiation absorbing layer is configured to absorb the electromagnetic wave and convert at least a substantial portion of the energy from the said electromagnetic wave into the form of heat, which transmitted to the sample in the closed chamber.
  • the radiation source is programmed to adjust the temperature of the said sample in a range from ambient temperature to 98°C.
  • the sample is first heated to 98°C, and then undergoes a repeated cycle of 94°C, 50-65°C, and 72°C for 15-40 times.
  • the temperature of the sample is maintained at a constant temperature.
  • the sample is heated to 60-65 oC for about 1-70 min.
  • nucleic acid amplification product refers to various nucleic acids generated by nucleic acid amplification techniques. Types of nucleic acid amplification products herein include but not limited to single strand DNA, single strand RNA, double strand DNA, linear DNA, or circular DNA, etc. In some embodiments, nucleic acid amplification product can be identical nucleic acids having the same length and configuration. In some other embodiments, nucleic acid amplification products can be a plurality of nucleic acids having different lengths and configurations.
  • nucleic acids accumulated after nucleic acid amplification is quantified using reporters.
  • reporter having quantifiable features that is correlated with the presence or the absence, or the amount of the nucleic acid amplicons accumulated in the closed chamber.
  • Fig. 6 illustrates a cross-sectional view of an exemplary assay procedure combining nucleic acid extraction and amplification using a QMAX card device.
  • steps include (a) immobilizing capture probes on the inner surface of a first plate (substrate); (b) introducing samples onto the inner surface of the first plate; (c) pressing a second plate (QMAX card 1) onto the inner surface of the first plate to form a closed configuration of the device, where necessary reagents 1 to facilitate releasing and capturing nucleic acids are dried on the inner surface of the second plate; (d) capturing nucleic acids from the above said sample onto the inner surface of the first plate; (e) detaching the second plate and cleaning the inner surface of the first plate using sponge; (f) pressing a third plate (QMAX card 2) onto the inner surface of the first plate, where necessary reagents 2 for nucleic acid amplification are dried on the inner surface of the third plate; (g) accumulating nucleic acid amplification products in the chamber
  • capture probes are immobilized on the inner surface of the first plate.
  • capture probes refer to oligonucleotides having the length between 1-200bp, preferably between 5-50bp, more preferably between 10-20bp. Capture probes have complementary sequence to nucleic acid sequences of interest in the sample. In some embodiments, identical capture probes are immobilized on the surface of the first plate. In some other embodiments, different capture probes having different base pair compositions are immobilized on the surface of the first plate. Capture probes can be DNA, or RNA, or both, but preferably to be single strand DNA. As used herein, “immobilize” refers to a process to anchor the capture probe on the plate surface.
  • capture probes are anchored through covalent bond, wherein, for example, either 5' or 3' end of the capture probe is modified to facilitate coating on the plate surface.
  • 3' end modifications include but not limited to thiol, dithiol, amine, biotin, etc.
  • capture probes can be passively absorbed on the substrate surface.
  • Suitable blockers include but not limited to 6-Mercapto-hexanol, bovine serum albumin, etc.
  • the "sample” can be any nucleic acid containing or not containing samples, including but not limited to human bodily fluids, such as whole blood, plasma, serum, urine, saliva, and sweat, and cell cultures (mammalian, plant, bacteria, fungi).
  • the sample can be freshly obtained, or stored or treated in any desired or convenient way, for example by dilution or adding buffers, or other solutions or solvents.
  • Cellular structures can exist in the sample, such as human cells, animal cells, plant cells, bacteria cells, fungus cells, and virus particles.
  • nucleic acid refers to any DNA or RNA molecule, or a DNA/RNA hybrid, or mixtures of DNA and/or RNA.
  • the term “nucleic acid” therefore is intended to include but not limited to genomic or chromosomal DNA, plasmid DNA, amplified DNA, cDNA, total RNA, mRNA and small RNA.
  • the term “nucleic acid” is also intended to include natural DNA and/or RNA molecule, or synthetic DNA and/or RNA molecule.
  • cell-free nucleic acids are presence in the sample, as used herein "cell-free” indicates nucleic acids are not contained in any cellular structures.
  • nucleic acids are contained within cellular structures, which include but not limited to human cells, animal cells, plant cells, bacterial cells, fungi cells, and/or viral particles. Nucleic acids either in the form of cell-free nucleic acids or within cellular structures or a combination thereof, can be presence in the sample. In some further embodiments, nucleic acids are purified before introduced onto the inner surface of the first plate. In yet further embodiments, nucleic acids can be within a complex associated with other molecules, such as proteins and lipids.
  • the method of the invention is suitable for samples of a range of volumes. Sample having different volumes can be introduced onto the plates having different dimensions.
  • the sample can be introduced onto either the first plate or the second plate, or even both when necessary.
  • Fig. 6 herein provides an example of introducing sample onto the first plate inner surface.
  • a second plate (QMAX card 1) is pressed onto the inner surface of the first plate (substrate), in contact with the sample, to form a closed configuration of the device.
  • Necessary reagents 1 for nucleic acid amplification can be either in the dry form on the inner surface of the first or the second plate or both, or in a liquid form encased in, embedded in, or surrounded by, a material that melts with increasing temperatures, such as, for example, paraffin.
  • necsary reagent 1 refers to cell lysing reagent, or hybridization reagents, or a combination thereof.
  • cell lysing reagents intend to include but not limited to salts, detergents, enzymes, and other additives, which facilitates to disrupt cellular structures.
  • salts herein include but not limited to lithium salt (e.g. lithium chloride), sodium salt (e.g. sodium chloride), potassium (e.g. potassium chloride).
  • detergents herein can be ionic, including anionic and cationic, non-ionic or zwitterionic.
  • ionic detergent as used herein includes any detergent which is partly or wholly in ionic form when dissolved in water.
  • Suitable anionic detergents include but not limited to sodium dodecyl sulphate (SDS) or other alkali metal alkylsulphate salts or similar detergents, sarkosyl, or combinations thereof.
  • SDS sodium dodecyl sulphate
  • the term "enzymes” herein include but not limited to lysozyme, cellulase, and proteinase.
  • chelating agents including but not limited to EDTA, EGTA and other polyamino carboxylic acids, and some reducing agents, such as dithiotreitol (dTT), can also be included in cell lysing reagents.
  • dTT dithiotreitol
  • the compositions of necessary reagents herein vary according to rational designs of different amplification reactions.
  • hybridization reagents refer to reagents that facilitate the hybridization between immobilized capture probes and nucleic acid of interest in the sample, herein including but not limited to sodium chloride, sodium acetate, ficoll, dextran, polyvinylpyrrolidone, bovine serum albumin, etc.
  • step (d) after in contact with the above said sample, dried necessary reagent 1 dissolves in the sample.
  • Nucleic acids of interest either released from disrupted cellular structures or presence as cell-free nucleic acids, or a combination thereof, hybridize to the complementary capture probes on the plate surface.
  • Time used for hybridization varies, largely depending on the specifications of the spacers on the inner surface of the QMAX card 1.
  • experimental data indicated after 2min, hybridization between nucleic acids of interest and immobilized capture probes reached equilibrium.
  • "unhybridized nucleic acids” refer to nucleic acids that are not captured by the immobilized capture probes.
  • the second plate (QMAX card 1) is detached from the first plate (substrate) and the surface of the first plate (substrate) is cleaned using sponge.
  • sponge refers to a class of flexible porous materials that change pore sizes under different pressures. Sponges containing washing buffer are in contact with the first plate surface to remove contaminates. In some embodiments, sponges are in contact with the first plate surface for one time. In some other embodiments, sponges are in contact with the first plate surface for twice, or more than twice.
  • contaminates refer to compounds including but not limited to cell debris, proteins, non-specific nucleic acid, etc. that are detrimental to the nucleic acid amplification reaction.
  • a third plate (QMAX card 2) is pressed onto the inner surface of the first plate, in contact with the sample, to form a closed configuration of the device.
  • Necessary reagent 2 for nucleic acid amplification can be either in the dry form on the inner surface of the first or the third plate or both, or in a liquid form encased in, embedded in, or surrounded by, a material that melts with increasing temperatures, such as, for example, paraffin.
  • nucleic acid amplification includes any techniques used to detect nucleic acids by amplifying (generating numerous copies of) the target molecules in samples, herein “target” refers to a sequence, or partial sequence, of nucleic acid of interest.
  • Suitable nucleic acid amplification techniques include but not limited to, different polymerase chain reaction (PCR) methods, such as hot-start PCR, nested PCR, touchdown PCR, reverse transcription PCR, RACE PCR, digital PCR, etc., and isothermal amplification methods, such as Loop-mediated isothermal amplification, strand displacement amplification, helicase- dependent amplification, nicking enzyme amplification, rolling circle amplification, recombinase polymerase amplification, etc.
  • PCR polymerase chain reaction
  • Necessary reagent 2 include but not limited to, primers, deoxynucleotides (dNTPs), bivalent cations (e.g. Mg2+), monovalent cation (e.g. K+), buffer solutions, enzymes, and reporters.
  • Necessary reagent 2 for nucleic acid amplification can be either in the dry form on the inner surface of the first or the second plate or both, or in a liquid form encased in, embedded in, or surrounded by, a material that melts with increasing temperatures, such as, for example, paraffin.
  • primers in some embodiments, can refer to a pair of forward and reverse primers.
  • primers can refer to a plurality of primers or primer sets.
  • enzymes suitable for nucleic acid amplification include, but not limited to, DNA-dependent polymerase, or RNA-dependent DNA polymerase, or DNA-dependent RNA polymerase.
  • reporter refers to any tag, label, or dye that can bind to, or intercalate within, the nucleic acid molecule or be activated by byproducts of the amplification process to enable visualization of the nucleic acid molecule or the amplification process.
  • Suitable reporters include but are not limited to fluorescent labels or tags or dyes, intercalating agents, molecular beacon labels, or bioluminescent molecules, or a combination thereof.
  • a radiation source projects an electromagnetic wave to the radiation absorbing layer on the inner or outer surface of the first plate, or the third plate or both.
  • the radiation absorbing layer is configured to absorb the electromagnetic wave and convert at least a substantial portion of the energy from the said electromagnetic wave into the form of heat, which transmitted to the sample in the closed chamber.
  • the radiation source is programmed to adjust the temperature of the said sample in a range from ambient temperature to 98°C.
  • the sample is first heated to 98°C, and then undergoes a repeated cycle of 94°C, 50-65°C, and 72°C for 15-40 times.
  • the temperature of the sample is maintained at a constant temperature.
  • the sample is heated to 60-65 oC for about 1-70 min.
  • nucleic acid amplification product refers to various nucleic acids generated by nucleic acid amplification techniques. Types of nucleic acid amplification products herein include but not limited to single strand DNA, single strand RNA, double strand DNA, linear DNA, or circular DNA, etc. In some embodiments, nucleic acid amplification product can be identical nucleic acids having the same length and configuration. In some other embodiments, nucleic acid amplification products can be a plurality of nucleic acids having different lengths and configurations.
  • nucleic acids accumulated after nucleic acid amplification is quantified using reporters.
  • reporter having quantifiable features that is correlated with the presence or the absence, or the amount of the nucleic acid amplicons accumulated in the closed chamber.
  • the sample contact area of one or both of the plates comprises a compressed open flow monitoring surface structures (MSS) that are configured to monitoring how much flow has occurred after COF.
  • MSS comprises, in some embodiments, shallow square array, which will cause friction to the components (e.g. blood cells in a blood) in a sample.
  • the depth of the MSS can be 1/1000, 1/100, 1/100, 1/5, 1/2 of the spacer height or in a range of any two values, and in either protrusion or well form.
  • a device for assaying a thin fluidic sample layer comprising: a first plate, a second plate, spacers, and a clamp, wherein:
  • the first plate and the second plate are movable relative to each other into different configurations, including an open configuration and a closed configuration;
  • each of the plates comprises, on its respective surface, a sample contact area for contacting a fluidic sample
  • one or both of the plates comprise the spacers that are fixed to the respective plate;
  • the spacers have a predetermined substantially uniform height that is equal to or less than 200 microns, wherein at least one of the spacers is inside the sample contact area;
  • the two plates are partially or completely separated apart, the spacing between the plates is not regulated by the spacers, and the sample is deposited on one or both of the plates; and wherein in a closed configuration, which is configured after the sample is deposited in the open configuration, at least a part of the sample is compressed by the two plates into a layer of substantially uniform thickness and is substantially stagnant relative to the plates, wherein the uniform thickness of the layer is confined by the sample contact areas of the two plates and is regulated by the plates and the spacers.
  • a device for rapidly changing temperature of a thin fluidic sample layer comprising:
  • each of the plates comprises, on its respective surface, a sample contact area for contacting a fluidic sample
  • one or both of the plates comprise the spacers that are fixed to the respective plate;
  • the spacers have a predetermined substantially uniform height that is equal to or less than 200 microns, wherein at least one of the spacers is inside the sample contact area;
  • the two plates are partially or completely separated apart, the spacing between the plates is not regulated by the spacers, and the sample is deposited on one or both of the plates; and wherein in a closed configuration, which is configured after the sample is deposited in the open configuration, at least a part of the sample is compressed by the two plates into a layer of substantially uniform thickness and is substantially stagnant relative to the plates, wherein the uniform thickness of the layer is confined by the sample contact areas of the two plates and is regulated by the plates and the spacers; and wherein the plates and the clamp are configured to allow a temperature of the sample changed at a rate of 10 °C/s or higher.
  • a device for rapidly changing temperature of a thin fluidic sample layer comprising: a first plate, a second plate, and spacers, wherein:
  • the first plate has a thickness of 100 urn (micron) or less;
  • the fist plate and the second plate are movable relative to each other into different configurations, including an open configuration and a closed configuration;
  • each of the plates comprises, on its respective surface, a sample contact area for contacting a fluidic sample
  • one or both of the plates comprise the spacers that are fixed to the respective plate;
  • the spacers have a predetermined substantially uniform height that is equal to or less than 200 microns;
  • At least one of the spacers is inside the sample contact area
  • the two plates are partially or completely separated apart, the spacing between the plates is not regulated by the spacers, and the sample is deposited on one or both of the plates; and wherein in a closed configuration, which is configured after the sample is deposited in the open configuration, at least a part of the sample is compressed by the two plates into a layer of substantially uniform thickness and is substantially stagnant relative to the plates, wherein the uniform thickness of the layer is confined by the sample contact areas of the two plates and is regulated by the plates and the spacers; and wherein the plates and the clamp are configured to allow a temperature of at least a part of the sample to be changed at a rate of 10 °C/s or higher.
  • a device for rapidly changing temperature of a thin fluidic sample layer comprising:
  • the first plate and the second plate are movable relative to each other into different configurations, including an open configuration and a closed configuration;
  • each of the plates comprises, on its respective surface, a sample contact area for contacting a fluidic sample to be assayed;
  • the two plates are partially or completely separated apart, the average spacing between the plates is 250 urn or larger, and the sample is deposited on one or both of the plates; and wherein in a closed configuration, which is configured after the sample is deposited in the open configuration, at least a part of the sample is compressed by the two plates into a layer of substantially uniform thickness and is substantially stagnant relative to the plates, wherein the uniform thickness of the layer is confined by the sample contact areas of the two plates and is 200 urn thick or less.
  • the device of any prior embodiments further comprising a radiation absorbing lay near the at least part of the sample of uniform thickness, whereas the area of the at least part of the sample and the radiation absorbing layer are substantially larger than the uniform thickness. In some embodiments, the device of any prior embodiments, wherein the area of the at least part of the sample and the radiation absorbing layer are substantially larger than the uniform thickness of the sample.
  • the device has one of the plates of a thickness of 100 urn or less.
  • the device further comprising a radiation absorbing lay near the at least part of the sample of uniform thickness, wherein the device has one of the plates of a thickness of 100 urn or less.
  • a clamp that compresses the first plate and the second plate together in the closed configuration, and further comprising a radiation absorbing lay near the at least part of the sample of uniform thickness, wherein the pressure of the clamp inserted on the plates is 0.01 kg/cm A 2 or higher.
  • a system for rapidly changing temperature of a thin fluidic sample layer comprising:
  • a controller is configured to control the radiation source and change the
  • a method for rapidly changing temperature of a thin fluidic sample layer comprising:
  • the clamp is configured to comprise a heat insulator layer to reduce the heat conduction between the clamp and the plates, wherein the heat insulator layer comprises a material of a thermal conductivity of 2 W/m-K.
  • the device, system, or method of any prior embodiments wherein the clamp is configured to comprise a heat insulator layer to reduce thermal mass that needs to heating or cooling the sample, wherein the heat insulator layer comprises a material of a thermal conductivity of 2 W/m-K.
  • the device, system, or method of any prior embodiments wherein, in a close configuration, the clamp is configured to seal all the QMAX card.
  • the device, system, or method of any prior embodiments wherein, in a close configuration, the clamp is configured to have thermal conduction contact with a part of the surface of the plates.
  • the device, system, or method of any prior embodiments wherein, in a close configuration, the clamp has a thermal conduction contact with only the peripheral surface area of the plates.
  • the device, system, or method of any prior embodiments wherein, in a close configuration, the clamp has a thermal conduction contact with only a surface area of the plates, wherein the surface area is outside the portion of the sample that nucleic acids to be amplified.
  • the device, system, or method of any prior embodiments wherein the clamp comprises a window that is transparent allowing light outside going to the plates or the light inside plates going out.
  • the device, system, or method of any prior embodiments wherein the clamp comprises a window that is transparent allowing light outside going to the plates or the light inside plates going out, wherein the transparence is above 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or a range between any two of the values.
  • the device, system, or method of any prior embodiments wherein the clamp insert a pressure to compress the first plates and the second plates, wherein the pressure is 0.01 kg/cm2, 0.1 kg/cm2, 0.5 kg/cm2, 1 kg/cm2, 2 kg/cm2, kg/cm2, 5 kg/cm2, 10 kg/cm2, 20 kg/cm2, 30 kg/cm2, 40 kg/cm2, 50 kg/cm2, 60 kg/cm2, 100 kg/cm2, 150 kg/cm2, 200 kg/cm2, 400 kg/cm2, or a range between any two of the values.
  • the device, system, or method of any prior embodiments wherein the clamp insert a pressure to compress the first plates and the second plates, wherein the pressure is from 0.1 kg/cm2 to 20kg/cm2. In some embodiment, the device, system, or method of any prior embodiments, wherein the clamp insert a pressure to compress the first plates and the second plates, wherein the pressure is from 0.1 kg/cm2 to 20kg/cm2.
  • the device, system, or method of any prior embodiments wherein the clamp insert a pressure to compress the first plates and the second plates, wherein the pressure is from 0.5 kg/cm2 to 40 kg/cm2.
  • the device, system, or method of any prior embodiments further comprising a clamp that compresses the first plate and the second plate together in the closed configuration, and further comprising a sealing material between at least part of the first plate and the second plate, wherein the pressure of the clamp inserted on the plates is 0.01 kg/cm A 2 or higher.
  • the device, system, or method of any prior embodiments wherein the spacer has subtainilaly flat top.
  • the device, system, or method of any prior embodiments wherein one of the plate is 50 urn or less. In some embodiments, the device, system, or method of any prior embodiments, wherein the changing temperature of the sample is a thermal cycling that changes the temperature up and down in cyclic fashion.
  • the device, system, or method of any prior embodiments wherein the changing temperature of the sample is a thermal cycling, wherein the thermal cycling is for amplification of nucleic acid using polymerase chain action (PCR).
  • PCR polymerase chain action
  • the device, system, or method of any prior embodiments wherein the changing of the temperature of the sample is for isothermal amplification of nucleic acid.
  • the device, system, or method of any prior embodiments the area of the at least part of the sample and the radiation absorbing layer are substantially larger than the uniform thickness.
  • the radiation absorbing layer comprises a disk-coupled dots-on-pillar antenna (D2PA) array, silicon sandwich, graphene, superlattice or other plasmonic materials, other a combination thereof.
  • D2PA disk-coupled dots-on-pillar antenna
  • the device, system, or method of any prior embodiments wherein the radiation absorbing layer comprises carbon or black nanostructures or a combination thereof. In some embodiments, he device, system, or method of any prior embodiments, wherein the radiation absorbing layer is configured to absorb radiation energy.
  • the device, system, or method of any prior embodiments wherein the radiation absorbing layer is configured to radiate energy in the form of heat after absorbing radiation energy.
  • the device, system, or method of any prior embodiments wherein the radiation absorbing layer is positioned underneath the sample layer and in direct contact with the sample layer.
  • the device, system, or method of any prior embodiments wherein the radiation absorbing layer is configured to absorbing electromagnetic waves selected from the group consisting of: radio waves, microwaves, infrared waves, visible light, ultraviolet waves, X-rays, gamma rays, and thermal radiation.
  • the device, system, or method of any prior embodiments wherein at least one of the plates does not block the radiation that the radiation absorbing layer absorbs.
  • the device, system, or method of any prior embodiments wherein one or both of the plates have low thermal conductivity. In some embodiments, the device, system, or method of any prior embodiments, wherein the uniform thickness of the sample layer is regulated by one or more spacers that are fixed to one or both of the plates.
  • the device, system, or method of any prior embodiments wherein the sample is a pre-mixed polymerase chain reaction (PCR) medium.
  • PCR polymerase chain reaction
  • the device, system, or method of any prior embodiments, 1 wherein the device is configured to facilitate PCR assays for changing temperature of the sample according to a predetermined program. In some embodiments, the device, system, or method of any prior embodiments, wherein the device is configured to conduct diagnostic testing, health monitoring, environmental testing, and/or forensic testing.
  • the device, system, or method of any prior embodiments wherein the device is configured to conduct DNA amplification, DNA quantification, selective DNA isolation, genetic analysis, tissue typing, oncogene identification, infectious disease testing, genetic fingerprinting, and/or paternity testing.
  • the device of any prior embodiments wherein the sample layer is laterally sealed to reduce sample evaporation.
  • the system of any of embodiments further comprising a controller, which is configured to control the presence, intensity, wavelength, frequency, and/or angle of the electromagnetic waves.
  • thermometer which is configured to measure the temperature at or in proximity of the sample contact area and send a signal to the controller based on the measured
  • thermometer is selected from the group consisting of: fiber optical thermometer, infrared thermometer, liquid crystal thermometer, pyrometer, quartz thermometer, silicon bandgap temperature sensor, temperature strip, thermistor, and thermocouple.
  • the controller is configured to control the present, intensity, wavelength, frequency, and/or angle of the electromagnetic waves from the radiation source.
  • the system or method of any prior embodiments wherein the radiation source and the radiation absorbing layer are configured that the electromagnetic waves cause an average ascending temperature rate ramp of at least 10 °C/s; and the removal of the electromagnetic waves results in an average descending temperature rate ramp of at least 5 °C/s.
  • the device, system, or method of any prior embodiments wherein the radiation source and the radiation absorbing layer are configured to create an average ascending temperature rate ramp of at least 10 °C/s and an average descending temperature rate ramp of at least 5 °C/s.
  • the device, system, or method of any prior embodiments wherein the radiation source and the radiation absorbing layer are configured to create an average ascending temperature rate ramp of at least 10 °C/s to reach the initialization step, the denaturation step and/or the extension/elongation step during a PCR, and an average descending temperature rate ramp of at least 5 °C/s to reach the annealing step and/or the final cooling step during a PCR.
  • the device, system, or method of any prior embodiments wherein the PCR sample comprises: template DNA, primer DNA, cations, polymerase, and buffer.
  • the method of any prior embodiments, wherein the step of pressing the plates into a closed figuration comprises pressing the plates with an imprecise pressing force.
  • the method of any prior embodiments, wherein the step of pressing the plates into a closed figuration comprises pressing the plates directly with human hands.
  • the method of any prior embodiments, wherein the layer of highly uniform thickness has a thickness variation of less than 10 %.
  • the device, system, or method of any prior embodiments further comprising reagents selected from DNA template, primers, DNA polymerase, deoxynucleoside triphosphates (dNTPs), bivalent cations (e.g. Mg 2+ ), monovalent cation
  • buffer solution (e.g. K + ), and buffer solution.
  • the device, system, or method of any prior claims wherein the changing temperature of the sample is a thermal cycling, wherein the thermal cycling is for amplification of nucleic acid using polymerase chain action (PCR), that is selected from a group of hot-start PCR, nested PCR, touchdown PCR, reverse transcription PCR, RACE
  • PCR polymerase chain action
  • the device, system, or method of any prior claims wherein the changing of the temperature of the sample is for isothermal amplification of nucleic acid, that is selected from a group of Loop-mediated isothermal amplification, strand displacement amplification, helicase-dependent amplification, nicking enzyme amplification, rolling circle amplification, and recombinase polymerase amplification.
  • the spacers are pillars that have a flat top and a foot fixed on one plate, wherein the flat top has a smoothness with a small surface variation, and the variation is less than 5, 10 nm, 20 nm, 30 nm, 50 nm, 100 nm, 200 nm, 300 nm, 400 nm, 500 nm, 600 nm, 700 nm, 800 nm, 1000 nm, or in a range between any two of the values.
  • a preferred flat pillar top smoothness is that surface variation of 50 nm or less.
  • the surface variation is relative to the spacer height and the ratio of the pillar flat top surface variation to the spacer height is less than 0.5%, 1 %, 3%,5%,7%, 10%, 15%, 20%, 30%, 40%, or in a range between any two of the values.
  • a preferred flat pillar top smoothness has a ratio of the pillar flat top surface variation to the spacer height is less than 2 %, 5%, or 10%.
  • the spacers are pillars that have a sidewall angle.
  • the sidewall angle is less than 5 degree (measured from the normal of a surface), 10 degree, 20 degree, 30 degree, 40 degree, 50 degree, 70 degree, or in a range between any two of the values. In a preferred embodiment, the sidewall angle is less 5 degree, 10 degree, or 20 degree.
  • a uniform thin fluidic sample layer is formed by using a pressing with an imprecise force.
  • the term “imprecise” in the context of a force refers to a force that
  • (a) has a magnitude that is not precisely known or precisely predictable at the time the force is applied; (b) has a pressure in the range of 0.01 kg/cm 2 (centimeter square) to 100 kg/cm 2 , (c) varies in magnitude from one application of the force to the next; and (d) the imprecision (i.e. the variation) of the force in (a) and (c) is at least 20% of the total force that actually is applied.
  • An imprecise force can be applied by human hand, for example, e.g., by pinching an object together between a thumb and index finger, or by pinching and rubbing an object together between a thumb and index finger.
  • the imprecise force by the hand pressing has a pressure of 0.01 kg/cm2, 0.1 kg/cm2, 0.5 kg/cm2, 1 kg/cm2, 2 kg/cm2, kg/cm2, 5 kg/cm2, 10 kg/cm2, 20 kg/cm2, 30 kg/cm2, 40 kg/cm2, 50 kg/cm2, 60 kg/cm2, 100 kg/cm2, 150 kg/cm2, 200 kg/cm2, or a range between any two of the values; and a preferred range of 0.1 kg/cm2 to 0.5 kg/cm2, 0.5 kg/cm2 to 1 kg/cm2, 1 kg/cm2 to 5 kg/cm2, 5 kg/cm2 to 10 kg/cm2
  • spacer filling factor refers to the ratio of the spacer contact area to the total plate area
  • the spacer contact area refers, at a closed configuration, the contact area that the spacer's top surface contacts to the inner surface of a plate
  • the total plate area refers the total area of the inner surface of the plate that the flat top of the spacers contact. Since there are two plates and each spacer has two contact surfaces each contacting one plate, the filling fact is the filling factor of the smallest.
  • the spacers are pillars with a flat top of a square shape (10 um x 10 um), a nearly uniform cross-section and 2 um tall, and the spacers are periodic with a period of 100 um, then the filing factor of the spacer is 1 %. If in the above example, the foot of the pillar spacer is a square shape of 15 um x 15 um, then the filling factor is still 1 % by the definition.
  • inter spacer distance is equal or less than about 120 um (micrometer).
  • inter spacer distance SD
  • fourth power of the inter- spacer-distance (ISD) divided by the thickness (h) and the Young's modulus (E) of the flexible plate (ISD 4 /(hE)) is 5x10 6 um 3 /GPa or less.
  • the fourth power of the inter- spacer-distance (ISD) divided by the thickness (h) and the Young's modulus (E) of the flexible plate (ISD 4 /(hE)) is 5x10 5 um 3 /GPa or less.
  • the spacers have pillar shape, a substantially flat top surface, a predetermined substantially uniform height, and a predetermined constant inter-spacer distance that is at least about 2 times larger than the size of the analyte, wherein the Young's modulus of the spacers times the filling factor of the spacers is equal or larger than 2 MPa, wherein the filling factor is the ratio of the spacer contact area to the total plate area, and wherein, for each spacer, the ratio of the lateral dimension of the spacer to its height is at least 1 (one).
  • the spacers have pillar shape, a substantially flat top surface, a predetermined substantially uniform height, and a
  • the predetermined constant inter-spacer distance that is at least about 2 times larger than the size of the analyte, wherein the Young's modulus of the spacers times the filling factor of the spacers is equal or larger than 2 MPa, wherein the filling factor is the ratio of the spacer contact area to the total plate area, and wherein, for each spacer, the ratio of the lateral dimension of the spacer to its height is at least 1 (one), wherein the fourth power of the inter- spacer-distance (ISD) divided by the thickness (h) and the Young's modulus (E) of the flexible plate (ISD 4 /(hE)) is 5x10 6 um 3 /GPa or less.
  • ISD inter- spacer-distance
  • E Young's modulus
  • the device of any prior device claim wherein the ratio of the inter-spacing distance of the spacers to the average width of the spacer is 2 or larger, and the filling factor of the spacers multiplied by the Young's modulus of the spacers is 2 MPa or larger.
  • the analyte is protein, peptide, nucleic acids, virus, bacterial, cell, nanoparticle, molecule, synthetic compounds, or inorganic compounds.
  • the sample is a biological sample selected from amniotic fluid, aqueous humour, vitreous humour, blood (e.g., whole blood, fractionated blood, plasma or serum), breast milk, cerebrospinal fluid (CSF), cerumen (earwax), chyle, chime, endolymph, perilymph, feces, breath, gastric acid, gastric juice, lymph, mucus (including nasal drainage and phlegm), pericardial fluid, peritoneal fluid, pleural fluid, pus, rheum, saliva, exhaled breath condensates, sebum, semen, sputum, sweat, synovial fluid, tears, vomit, and urine.
  • blood e.g., whole blood, fractionated blood, plasma or serum
  • CSF cerebrospinal fluid
  • cerumen earwax
  • chyle chime
  • endolymph perilymph
  • perilymph perilymph
  • feces breath
  • the spacers have a shape of pillars and a ratio of the width to the height of the pillar is equal or larger than one.
  • the spacers have a shape of pillar, and the pillar has substantially uniform cross-section.
  • samples is for the detection, purification and quantification of chemical compounds or biomolecules that correlates with the stage of certain diseases.
  • samples is related to infectious and parasitic disease, injuries, cardiovascular disease, cancer, mental disorders, neuropsychiatric disorders, pulmonary diseases, renal diseases, and other and organic diseases.
  • samples is related to virus, fungus and bacteria from environment, e.g., water, soil, or biological samples.
  • samples is related to the detection, quantification of chemical compounds or biological samples that pose hazard to food safety or national security, e.g. toxic waste, anthrax.
  • samples is related to glucose, blood, oxygen level, total blood count.
  • samples is related to the detection and quantification of specific DNA or RNA from biosamples.
  • samples is related to the sequencing and comparing of genetic sequences in DNA in the chromosomes and mitochondria for genome analysis.
  • samples is related to detect reaction products, e.g., during synthesis or purification of pharmaceuticals.
  • samples is cells, tissues, bodily fluids, and stool.
  • sample is the sample in the fields of human, veterinary, agriculture, foods, environments, and drug testing.
  • sample is a biological sample is selected from hair, finger nail, ear wax, breath, connective tissue, muscle tissue, nervous tissue, epithelial tissue, cartilage, cancerous sample, or bone.
  • inter-spacer distance is in the range of 5 ⁇ to 120 ⁇ .
  • inter-spacer distance is in the range of 120 ⁇ to 200 ⁇ .
  • the flexible plates have a thickness in the range of 20 um to 250 um and Young's modulus in the range 0.1 to 5 GPa.
  • the thickness of the flexible plate times the Young's modulus of the flexible plate is in the range 60 to 750 GPa- um.
  • the layer of uniform thickness sample is uniform over a lateral area that is at least 1 mm 2 .
  • the layer of uniform thickness sample is uniform over a lateral area that is at least 3 mm 2 .
  • the layer of uniform thickness sample is uniform over a lateral area that is at least 5 mm 2 .
  • the layer of uniform thickness sample is uniform over a lateral area that is at least 10 mm 2 .
  • the device of any prior device claim wherein the layer of uniform thickness sample is uniform over a lateral area that is at least 20 mm 2 .
  • the device of any prior device claim wherein the layer of uniform thickness sample is uniform over a lateral area that is in a range of 20 mm 2 to 100 mm 2 .
  • the device of any prior device claim, wherein the layer of uniform thickness sample has a thickness uniformity of up to +1-5% or better.
  • the layer of uniform thickness sample has a thickness uniformity of up to +/-10% or better.
  • the layer of uniform thickness sample has a thickness uniformity of up to +1-20% or better.
  • the layer of uniform thickness sample has a thickness uniformity of up to +/-30% or better.
  • the present invention finds use in a variety of different applications in various fields, where determination of the presence or absence, and/or quantification of one or more analytes in a sample are desired.
  • the present inventions finds use in the detection of atoms, molecules, proteins, peptides, nucleic acids, synthetic compounds, inorganic compounds, organic compounds, bacteria, virus, cells, tissues, nanoparticles, and the like.
  • the sample can be a sample in various fields, that include, but not limited to, human, veterinary, agriculture, foods, environments, health, wellness, beauty, and others.
  • the present invention includes a variety of embodiments, which can be combined in multiple ways as long as the various components do not contradict one another.
  • the embodiments should be regarded as a single invention file: each filing has other filing as the references and is also referenced in its entirety and for all purpose, rather than as a discrete independent. These embodiments include not only the disclosures in the current file, but also the documents that are herein referenced, incorporated, or to which priority is claimed.
  • CROF Card or card
  • COF Card or card
  • COF Card QMAX-Card
  • Q-Card CROF device
  • COF device COF device
  • QMAX-device CROF plates
  • COF plates COF plates
  • QMAX-plates are interchangeable, except that in some embodiments, the COF card does not comprise spacers; and the terms refer to a device that comprises a first plate and a second plate that are movable relative to each other into different configurations (including an open configuration and a closed configuration), and that comprises spacers (except some embodiments of the COF card) that regulate the spacing between the plates.
  • X-plate refers to one of the two plates in a CROF card, wherein the spacers are fixed to this plate. More descriptions of the COF Card, CROF Card, and X-plate are given in the provisional application serial nos. 62/456065, filed on February 7, 2017, which is incorporated herein in its entirety for all purposes.
  • the devices, systems, and methods herein disclosed can include or use Q-cards, spacers, and uniform sample thickness embodiments for sample detection, analysis, and quantification.
  • the Q-card comprises spacers, which help to render at least part of the sample into a layer of high uniformity.
  • the structure, material, function, variation and dimension of the spacers, as well as the uniformity of the spacers and the sample layer, are herein disclosed, or listed, described, and summarized in PCT Application (designating U.S.) Nos. PCT/US2016/045437 and PCT/US0216/051775, which were respectively filed on August 10, 2016 and September 14, 2016, US Provisional Application No. 62/456065, which was filed on February 7, 2017, US Provisional Application No. 62/456287, which was filed on February 8, 2017, and US Provisional Application No. 62/456504, which was filed on February 8, 2017, all of which applications are incorporated herein in their entireties for all purposes.
  • the devices, systems, and methods herein disclosed can include or use Q-cards for sample detection, analysis, and quantification.
  • the Q-card comprises hinges, notches, recesses, and sliders, which help to facilitate the manipulation of the Q card and the measurement of the samples.
  • the structure, material, function, variation and dimension of the hinges, notches, recesses, and sliders are herein disclosed, or listed, described, and summarized in PCT Application (designating U.S.) Nos. PCT/US2016/045437 and PCT/US0216/051775, which were respectively filed on August 10, 2016 and September 14, 2016, US Provisional Application No. 62/456065, which was filed on February 7, 2017, US Provisional Application No.
  • the devices, systems, and methods herein disclosed can include or use Q-cards for sample detection, analysis, and quantification.
  • the Q-cards are used together with sliders that allow the card to be read by a smartphone detection system.
  • the structure, material, function, variation, dimension and connection of the Q-card, the sliders, and the smartphone detection system are herein disclosed, or listed, described, and summarized in PCT Application (designating U.S.) Nos. PCT/US2016/045437 and PCT/US0216/051775, which were respectively filed on August 10, 2016 and September 14, 2016, US Provisional Application No. 62/456065, which was filed on February 7, 2017, US Provisional Application No. 62/456287, which was filed on February 8, 2017, and US Provisional Application No. 62/456504, which was filed on February 8, 2017, all of which applications are incorporated herein in their entireties for all purposes.
  • the devices, systems, and methods herein disclosed can include or be used in various types of detection methods.
  • the detection methods are herein disclosed, or listed, described, and summarized in PCT Application (designating U.S.) Nos. PCT/US2016/045437 and PCT/US0216/051775, which were respectively filed on August 10, 2016 and September 14, 2016, US Provisional Application No. 62/456065, which was filed on February 7, 2017, US Provisional Application No. 62/456287, which was filed on February 8, 2017, and US Provisional Application No. 62/456504, which was filed on February 8, 2017, all of which applications are incorporated herein in their entireties for all purposes.
  • the devices, systems, and methods herein disclosed can employ various types of labels that are used for analytes detection.
  • the labels are herein disclosed, or listed, described, and summarized in PCT Application (designating U.S.) Nos. PCT/US2016/045437 and PCT/US0216/051775, which were respectively filed on August 10, 2016 and September 14, 2016, US Provisional Application No. 62/456065, which was filed on February 7, 2017, US Provisional Application No. 62/456287, which was filed on February 8, 2017, and US Provisional Application No. 62/456504, which was filed on February 8, 2017, all of which applications are incorporated herein in their entireties for all purposes.
  • the devices, systems, and methods herein disclosed can be applied to manipulation and detection of various types of analytes (including biomarkers).
  • the analytes and are herein disclosed, or listed, described, and summarized in PCT Application (designating U.S.) Nos. PCT/US2016/045437 and PCT/US0216/051775, which were respectively filed on August 10, 2016 and September 14, 2016, US Provisional Application No. 62/456065, which was filed on February 7, 2017, US Provisional Application No. 62/456287, which was filed on February 8, 2017, and US Provisional Application No. 62/456504, which was filed on February 8, 2017, all of which applications are incorporated herein in their entireties for all purposes.
  • the devices, systems, and methods herein disclosed can be used for various applications (fields and samples).
  • the applications are herein disclosed, or listed, described, and summarized in PCT Application (designating U.S.) Nos. PCT/US2016/045437 and PCT/US0216/051775, which were respectively filed on August 10, 2016 and September 14, 2016, US Provisional Application No. 62/456065, which was filed on February 7, 2017, US Provisional Application No. 62/456287, which was filed on February 8, 2017, and US Provisional Application No. 62/456504, which was filed on February 8, 2017, all of which applications are incorporated herein in their entireties for all purposes. (9) Cloud
  • the devices, systems, and methods herein disclosed can employ cloud technology for data transfer, storage, and/or analysis.
  • the related cloud technologies are herein disclosed, or listed, described, and summarized in PCT Application (designating U.S.) Nos. PCT/US2016/045437 and PCT/US0216/051775, which were respectively filed on August 10, 2016 and September 14, 2016, US Provisional Application No. 62/456065, which was filed on February 7, 2017, US Provisional Application No. 62/456287, which was filed on February 8, 2017, and US Provisional Application No. 62/456504, which was filed on February 8, 2017, all of which applications are incorporated herein in their entireties for all purposes.
  • adapted and “configured” mean that the element, component, or other subject matter is designed and/or intended to perform a given function.
  • the use of the terms “adapted” and “configured” should not be construed to mean that a given element, component, or other subject matter is simply “capable of” performing a given function.
  • subject matter that is recited as being configured to perform a particular function may additionally or alternatively be described as being operative to perform that function.
  • the phrase, "for example,” the phrase, “as an example,” and/or simply the terms “example” and “exemplary” when used with reference to one or more components, features, details, structures, embodiments, and/or methods according to the present disclosure, are intended to convey that the described component, feature, detail, structure, embodiment, and/or method is an illustrative, non-exclusive example of components, features, details, structures, embodiments, and/or methods according to the present disclosure.
  • the phrases "at least one of” and “one or more of,” in reference to a list of more than one entity, means any one or more of the entity in the list of entity, and is not limited to at least one of each and every entity specifically listed within the list of entity.
  • “at least one of A and B” (or, equivalently, “at least one of A or B,” or, equivalently, “at least one of A and/or B”) may refer to A alone, B alone, or the combination of A and B.
  • the term "and/or" placed between a first entity and a second entity means one of (1) the first entity, (2) the second entity, and (3) the first entity and the second entity.
  • Multiple entity listed with “and/or” should be construed in the same manner, i.e., "one or more" of the entity so conjoined.
  • Other entity may optionally be present other than the entity specifically identified by the "and/or” clause, whether related or unrelated to those entities specifically identified.
  • adapted and “configured” mean that the element, component, or other subject matter is designed and/or intended to perform a given function.
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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Clinical Laboratory Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Analytical Chemistry (AREA)
  • Hematology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Biochemistry (AREA)
  • Molecular Biology (AREA)
  • Apparatus Associated With Microorganisms And Enzymes (AREA)

Abstract

La présente invention concerne des dispositifs, des systèmes et des procédés pour une utilisation rapide et facile dans un cyclage thermique d'échantillon ou des changements de température pour faciliter des réactions telles que, mais sans limitation, la PCR.
PCT/US2018/018405 2017-02-15 2018-02-15 Dosage à changement rapide de température WO2018152351A1 (fr)

Priority Applications (32)

Application Number Priority Date Filing Date Title
CN201880024948.7A CN111194409B (zh) 2017-02-15 2018-02-15 采用快速温度变化的测定
US16/484,998 US20200078792A1 (en) 2017-02-15 2018-02-15 Assay with rapid temperature change
JP2019544049A JP2020508043A (ja) 2017-02-15 2018-02-15 急速な温度変化を伴うアッセイ
EP18753608.1A EP3583423A4 (fr) 2017-02-15 2018-02-15 Dosage à changement rapide de température
CA3053295A CA3053295A1 (fr) 2017-02-15 2018-02-15 Dosage a changement rapide de temperature
PCT/US2018/018521 WO2018152422A1 (fr) 2017-02-16 2018-02-16 Dosage à surface texturée
CA3053301A CA3053301A1 (fr) 2017-02-16 2018-02-16 Dosage a surface texturee
US16/485,347 US10966634B2 (en) 2017-02-16 2018-02-16 Assay with textured surface
US16/485,126 US11523752B2 (en) 2017-02-16 2018-02-16 Assay for vapor condensates
PCT/US2018/018520 WO2018152421A1 (fr) 2017-02-16 2018-02-16 Dosage pour condensats de vapeur
JP2019544634A JP7107953B2 (ja) 2017-02-16 2018-02-16 テクスチャ表面を用いたアッセイ
CN201880025156.1A CN111448449B (zh) 2017-02-16 2018-02-16 采用纹理化表面的测定方法及装置
CN201880041351.3A CN111771125B (zh) 2017-04-21 2018-04-23 通过控制温度的分子操作和测定
EP18788089.3A EP3612841A4 (fr) 2017-04-21 2018-04-23 Manipulation et dosage moléculaires à température contrôlée (ii)
JP2019556963A JP2020517266A (ja) 2017-04-21 2018-04-23 制御された温度を用いた分子操作およびアッセイ（ｉｉ）
CA3060971A CA3060971C (fr) 2017-04-21 2018-04-23 Manipulation et dosage moleculaires a temperature controlee (ii)
CN202311781492.8A CN118218039A (zh) 2017-04-21 2018-04-23 通过控制温度的分子操作和测定
US16/605,853 US10926265B2 (en) 2017-04-21 2018-04-23 Molecular manipulation and assay with controlled temperature (II)
PCT/US2018/028784 WO2018195528A1 (fr) 2017-04-21 2018-04-23 Manipulation et dosage moléculaires à température contrôlée (ii)
EP18805264.1A EP3631000A4 (fr) 2017-05-23 2018-05-23 Changement rapide de température d'échantillon pour dosage
US16/616,680 US12064771B2 (en) 2017-05-23 2018-05-23 Rapid sample temperature changing for assaying
PCT/US2018/034230 WO2018217953A1 (fr) 2017-05-23 2018-05-23 Changement rapide de température d'échantillon pour dosage
JP2019565255A JP7335816B2 (ja) 2017-05-23 2018-05-23 アッセイのための急速な試料温度変化
CN201880048466.5A CN112218939A (zh) 2017-05-23 2018-05-23 用于测定的样品温度的快速变化
CA3064744A CA3064744A1 (fr) 2017-05-23 2018-05-23 Changement rapide de temperature d'echantillon pour dosage
US16/772,396 US11648551B2 (en) 2017-12-12 2018-12-12 Sample manipulation and assay with rapid temperature change
PCT/US2018/065297 WO2019118652A1 (fr) 2017-12-12 2018-12-12 Manipulation d'échantillon et dosage avec changement de température rapide
US17/150,730 US11369968B2 (en) 2017-04-21 2021-01-15 Molecular manipulation and assay with controlled temperature (II)
JP2022109424A JP2022125266A (ja) 2017-04-21 2022-07-07 制御された温度を用いた分子操作およびアッセイ（ｉｉ）
US17/980,400 US20230077906A1 (en) 2017-02-16 2022-11-03 Assay for vapor condensates
US18/121,534 US12226769B2 (en) 2017-12-12 2023-03-14 Sample manipulation and assay with rapid temperature change
US18/809,075 US20250099965A1 (en) 2017-05-23 2024-08-19 Rapid sample temperature changing for assaying

Applications Claiming Priority (62)

Application Number Priority Date Filing Date Title
US201762459554P 2017-02-15 2017-02-15
US201762459577P 2017-02-15 2017-02-15
US201762459496P 2017-02-15 2017-02-15
US201762459303P 2017-02-15 2017-02-15
US201762459267P 2017-02-15 2017-02-15
US201762459598P 2017-02-15 2017-02-15
US201762459602P 2017-02-15 2017-02-15
US201762459337P 2017-02-15 2017-02-15
US201762459232P 2017-02-15 2017-02-15
US62/459,267 2017-02-15
US62/459,577 2017-02-15
US62/459,303 2017-02-15
US62/459,337 2017-02-15
US62/459,496 2017-02-15
US62/459,554 2017-02-15
US62/459,598 2017-02-15
US62/459,602 2017-02-15
US62/459,232 2017-02-15
US201762460083P 2017-02-16 2017-02-16
US201762460091P 2017-02-16 2017-02-16
US201762460076P 2017-02-16 2017-02-16
US201762460069P 2017-02-16 2017-02-16
US201762460047P 2017-02-16 2017-02-16
US201762460062P 2017-02-16 2017-02-16
US201762459920P 2017-02-16 2017-02-16
US201762460075P 2017-02-16 2017-02-16
US201762460088P 2017-02-16 2017-02-16
US201762459972P 2017-02-16 2017-02-16
US62/460,076 2017-02-16
US62/460,047 2017-02-16
US62/460,062 2017-02-16
US62/460,075 2017-02-16
US62/459,972 2017-02-16
US62/460,083 2017-02-16
US62/459,920 2017-02-16
US62/460,088 2017-02-16
US62/460,069 2017-02-16
US62/460,091 2017-02-16
PCT/US2018/017307 WO2018148342A1 (fr) 2017-02-07 2018-02-07 Dosage et utilisation d'écoulement ouvert comprimé
USPCT/US2018/017307 2018-02-07
USPCT/US2018/017502 2018-02-08
PCT/US2018/017492 WO2018148461A1 (fr) 2017-02-09 2018-02-08 Dosage avec amplification
USPCT/US2018/017489 2018-02-08
PCT/US2018/017504 WO2018148471A2 (fr) 2017-02-08 2018-02-08 Optique, dispositif et système d'essai
USPCT/US2018/017492 2018-02-08
USPCT/US2018/017504 2018-02-08
PCT/US2018/017502 WO2018148470A1 (fr) 2017-02-08 2018-02-08 Collecte et manipulation d'échantillons pour analyse retardée
PCT/US2018/017489 WO2018148458A1 (fr) 2017-02-08 2018-02-08 Dosage numérique
PCT/US2018/017494 WO2018148463A1 (fr) 2017-02-08 2018-02-08 Dosage d'hybridation d'acide nucléique
USPCT/US2018/017494 2018-02-08
USPCT/US2018/017499 2018-02-08
PCT/US2018/017713 WO2018148607A1 (fr) 2017-02-09 2018-02-09 Dosage utilisant différentes hauteurs d'espacement
USPCT/US2018/017716 2018-02-09
USPCT/US2018/017713 2018-02-09
PCT/US2018/017716 WO2018148609A2 (fr) 2017-02-09 2018-02-09 Dosages colorimétriques
PCT/US2018/017712 WO2018148606A1 (fr) 2017-02-09 2018-02-09 Dosage et applications qmax (ii)
USPCT/US2018/017712 2018-02-09
USPCT/US2018/018007 2018-02-13
PCT/US2018/018007 WO2018148729A1 (fr) 2017-02-08 2018-02-13 Dispositifs et procédés de dosage à base de carte qmax
PCT/US2018/018108 WO2018148764A1 (fr) 2017-02-08 2018-02-14 Manipulation moléculaire et dosage à température contrôlée
PCT/US2018/017499 WO2018152005A1 (fr) 2017-02-08 2018-02-14 Dosages qmax et applications
USPCT/US2018/018108 2018-02-14

Related Parent Applications (3)

Application Number Title Priority Date Filing Date
PCT/US2018/017501 Continuation WO2018148469A1 (fr) 2017-02-08 2018-02-08 Extraction et dosage de matières bio/chimiques
PCT/US2018/018108 Continuation WO2018148764A1 (fr) 2017-02-08 2018-02-14 Manipulation moléculaire et dosage à température contrôlée
PCT/US2018/028784 Continuation WO2018195528A1 (fr) 2017-04-21 2018-04-23 Manipulation et dosage moléculaires à température contrôlée (ii)

Related Child Applications (9)

Application Number Title Priority Date Filing Date
PCT/US2018/017307 Continuation WO2018148342A1 (fr) 2017-02-07 2018-02-07 Dosage et utilisation d'écoulement ouvert comprimé
PCT/US2018/018108 Continuation WO2018148764A1 (fr) 2017-02-08 2018-02-14 Manipulation moléculaire et dosage à température contrôlée
US16/485,126 Continuation US11523752B2 (en) 2017-02-16 2018-02-16 Assay for vapor condensates
US16/605,853 Continuation US10926265B2 (en) 2017-04-21 2018-04-23 Molecular manipulation and assay with controlled temperature (II)
PCT/US2018/028784 Continuation WO2018195528A1 (fr) 2017-04-21 2018-04-23 Manipulation et dosage moléculaires à température contrôlée (ii)
PCT/US2018/034230 Continuation WO2018217953A1 (fr) 2017-05-23 2018-05-23 Changement rapide de température d'échantillon pour dosage
US16/616,680 Continuation US12064771B2 (en) 2017-05-23 2018-05-23 Rapid sample temperature changing for assaying
US16/772,396 Continuation US11648551B2 (en) 2017-12-12 2018-12-12 Sample manipulation and assay with rapid temperature change
PCT/US2018/065297 Continuation WO2019118652A1 (fr) 2017-12-12 2018-12-12 Manipulation d'échantillon et dosage avec changement de température rapide

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USD893470S1 (en) 2018-11-28 2020-08-18 Essenlix Corporation Phone holder
USD893469S1 (en) 2018-11-21 2020-08-18 Essenlix Corporation Phone holder
USD897555S1 (en) 2018-11-15 2020-09-29 Essenlix Corporation Assay card
USD898221S1 (en) 2018-11-15 2020-10-06 Essenlix Corporation Assay plate
USD898224S1 (en) 2018-11-15 2020-10-06 Essenlix Corporation Assay plate with sample landing mark
USD898222S1 (en) 2019-01-18 2020-10-06 Essenlix Corporation Assay card
USD898939S1 (en) 2018-11-20 2020-10-13 Essenlix Corporation Assay plate with sample landing mark
USD910202S1 (en) 2018-11-21 2021-02-09 Essenlix Corporation Assay plate with sample landing mark
USD910203S1 (en) 2018-11-27 2021-02-09 Essenlix Corporation Assay plate with sample landing mark
USD912842S1 (en) 2018-11-29 2021-03-09 Essenlix Corporation Assay plate

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USD897555S1 (en) 2018-11-15 2020-09-29 Essenlix Corporation Assay card
USD898221S1 (en) 2018-11-15 2020-10-06 Essenlix Corporation Assay plate
USD898224S1 (en) 2018-11-15 2020-10-06 Essenlix Corporation Assay plate with sample landing mark
USD898939S1 (en) 2018-11-20 2020-10-13 Essenlix Corporation Assay plate with sample landing mark
USD893469S1 (en) 2018-11-21 2020-08-18 Essenlix Corporation Phone holder
USD910202S1 (en) 2018-11-21 2021-02-09 Essenlix Corporation Assay plate with sample landing mark
USD910203S1 (en) 2018-11-27 2021-02-09 Essenlix Corporation Assay plate with sample landing mark
USD893470S1 (en) 2018-11-28 2020-08-18 Essenlix Corporation Phone holder
USD912842S1 (en) 2018-11-29 2021-03-09 Essenlix Corporation Assay plate
USD898222S1 (en) 2019-01-18 2020-10-06 Essenlix Corporation Assay card

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