US20110039261A1 - Mobile rapid test system for nucleic acid analysis - Google Patents

Mobile rapid test system for nucleic acid analysis Download PDF

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US20110039261A1
US20110039261A1 US12/820,569 US82056910A US2011039261A1 US 20110039261 A1 US20110039261 A1 US 20110039261A1 US 82056910 A US82056910 A US 82056910A US 2011039261 A1 US2011039261 A1 US 2011039261A1
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test system
amplification
marked
rapid test
mobile rapid
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US12/820,569
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Timo Hillebrand
Claus Knippschild
Benjamin Jaschinsky
Elmara Graser
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AJ Innuscreen GmbH
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AJ Innuscreen GmbH
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Publication of US20110039261A1 publication Critical patent/US20110039261A1/en
Priority to US13/723,315 priority Critical patent/US9260750B2/en
Abandoned legal-status Critical Current

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    • 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]
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
    • B01L3/502—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
    • B01L3/5023—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures with a sample being transported to, and subsequently stored in an absorbent for analysis
    • 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
    • B01L2200/00—Solutions for specific problems relating to chemical or physical laboratory apparatus
    • B01L2200/02—Adapting objects or devices to another
    • B01L2200/026—Fluid interfacing between devices or objects, e.g. connectors, inlet details
    • 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
    • B01L2200/04—Exchange or ejection of cartridges, containers or reservoirs
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2200/00—Solutions for specific problems relating to chemical or physical laboratory apparatus
    • B01L2200/10—Integrating sample preparation and analysis in single entity, e.g. lab-on-a-chip concept
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/06—Auxiliary integrated devices, integrated components
    • B01L2300/0627—Sensor or part of a sensor is integrated
    • B01L2300/0636—Integrated biosensor, microarrays
    • 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
    • B01L2300/0825—Test strips
    • 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
    • B01L2300/1822—Conductive heating, heat from thermostatted solids is conducted to receptacles, e.g. heating plates, blocks using Peltier elements

Definitions

  • a mobile equipment system for gene diagnostics is provided.
  • the invention is accomplished by means of a novel reaction cavity (consumable).
  • a novel reaction cavity in the sector of PCR consumables, various methods are known for their production. The most widespread is the production method using injection-molding. The consumables produced in this manner are commercially available in a large number of shapes and arrangements. However, these receptacles all have a very thick wall thickness (approximately 0.2 mm-0.35 mm), which opposes good heat transfer from the heated sample block into the sample, as a very great resistance.
  • thermocycler If these receptacles are used as intended, in a thermocycler, the sample block situated in the devices heats up at a speed of up to 5° C./s. The resulting speed in the sample, however, is significantly reduced by the receptacles, so that the sample (situated in the receptacle) is only heated up at approximately 1.5-2° C./s. Even those receptacles offered for sale as “thin-wall” receptacles (minimal wall thickness of approximately 0.19 mm; Eppendorf product catalog 07-08, p. 200) are not able to significantly improve this condition. The technical prerequisites (heating and cooling) for rapid processing of the temperatures in PCR are implemented technically, but the efficacy is greatly impaired, because of the consumable used.
  • Usual sample volumes used in PCR lie in the range of 5-50 ⁇ l.
  • thermocyclers having a very great heat capacity furthermore ensure that rapid temperature changes in the sample are impossible to implement, even when using strong heating elements.
  • PCR system The most well-known commercially available PCR system that will be mentioned here is the LightCycler from Roche Molecular Biochemicals (cat. No. 1909339 and cat. No. 2011468).
  • This system is based on the use of very thin glass capillaries as PCR consumables and carries out tempering by means of hot air that flows around the capillaries.
  • These capillaries can hold a volume of 10-20 ⁇ l and are characterized by their large surface area, which allows good heat transfer.
  • this large glass surface area absorbs components of standard PCR batches and thus causes the reaction to become more and more inactive.
  • different carrier molecules, etc. for example, have to be used (EP 1133359).
  • Another disadvantage in this connection is the handling of the very thin capillaries and their price. Miniaturization and simple handling of the receptacles continues to be impossible, however.
  • the object according to the invention of the published patent application U.S. 2005/0227275 A1 is furthermore carrying out a PCR reaction and detecting amplification products by means of a lateral-flow strip.
  • PCR with marked primers and nucleotides is described (claim 1 , FIG. 1, 2, 3, 4, 6).
  • a disadvantage of this method is that the PCR product is not hybridized with a marked probe.
  • the sole detection of an amplification product in this manner is diagnostically very uncertain, however, since the required 100% specificity of the amplification product is not guaranteed.
  • a specific hybridization reaction is required.
  • the use of a design similar to a “chip” for accommodating a PCR chamber does not represent level of invention, because it is cited many times in the patent literature. Instead, the configuration of the heating/cooling mechanism, of the entire heat transfer, the feed of liquid/solid biochemical reaction components, and the implementation of the process parameter control represent innovation.
  • the reference WO 2007/092713 A2 discusses a consumable design in chip form that can comprise not only cell sorting and immunological protein detection but also a PCR chamber. Different cell types (precursors of cancer cells, and cancer cells) are separated by means of a lateral-flow test strip method, using appropriate antibodies, and discriminated. However, the lateral-flow method does not serve to detect amplification events.
  • RNA expression from RNA which previously took place in a so-called lab-on-a-chip system, is uncoupled from this lab-on-a-chip and takes place as described, on a “laboratory table, using known methods.” It is described that alternatively to this, an amplification reactor and a detector can be integral components of the lab-on-a-chip system.
  • This reference does not discuss the configuration of the PCR chamber in the sense of the aforementioned properties. There is also no mention of a PCR reaction in the claims. Nevertheless, a mobile variant of the equipment system (with consumable) can be discussed here.
  • power consumption must be optimized and be as low as possible. Because of the use of a large number of thermoelectric modules (“hydrogel ice valves”) and fluid pumps, a person skilled in the art recognizes that this device cannot be suitable for mobile battery operation.
  • thermoelectric modules are supposed to be accommodated here, on the equipment side. These modules, which are very power-intensive, as well as the consumable design, which is not optimized, thus preclude even the possibility of mobile battery operation.
  • the thermal resistance of this chamber still lies above that of commercially available reaction receptacles (wall thickness 200 ⁇ m to 300 ⁇ m; material polyethylene), in which rapid PCR is only possible by means of high-power equipment.
  • wall thickness 200 ⁇ m to 300 ⁇ m; material polyethylene in which rapid PCR is only possible by means of high-power equipment.
  • use of the concept for battery operation is excluded once again.
  • the inefficiency of the concept becomes evident to a person skilled in the art when the authors discuss the difficulties in achieving an acceptable cooling rate. Even with active heat transport by means of Peltier elements and the inclusion of a 14 watt fan (conventional fans for processors require 6 watts), only 2.6 K/second is achieved in the sample (see rapid PCR).
  • the concept must also be critically illuminated with regard to the formulated goal of cost minimization.
  • the invention was based on the task of developing a novel mobile gene-diagnostic rapid test system (combination of hardware and reagents), which is supposed to be easy to operate, allows extremely rapid diagnostic information, and is inexpensive both with regard to the device and with regard to the test to be performed. Therefore, the possibility of being able to carry out diagnostics of infectious diseases in developing countries, without qualitative restrictions, is also supposed to be created.
  • the amplification product and the hybridization probe contain at least one marker, in each instance
  • the test kit comprises at least one lateral-flow test strip, which contains a zone for coupling the markers, in each instance.
  • FIG. 1 shows the schematic representation of the cartridge.
  • FIG. 2 shows the schematic representation of the device (voltage source and reaction cartridge).
  • marker is understood to mean any atom or molecule that can be used to generate a detectable (preferably quantifiable) signal on a lateral-flow test strip, and that can be bound to a nucleic acid.
  • Markers can preferably generate signals by means of fluorescence, colorimetry, or enzymatic activity. Markers by means of biotin and FITC (fluorescein isothiocyanate) are preferred.
  • Marking of the amplification product takes place either by means of marking of a primer or from marking of the nucleic acid to be determined.
  • the devices and the test kit are integral components of the mobile rapid test system, and this system represents a miniaturized, mobile-operated, hand-held device that requires no external voltage source during operation, but rather is operated by means of a battery or a rechargeable battery.
  • Mobile rapid test system contains a reaction cavity for carrying out amplification of nucleic acids, preferably by means of rapid PCR technology, one or more inlet and/or outlet openings for the reaction cavity, one or more heatable sample blocks that are connected with miniaturized cooling bodies, and a possibility for reading off the result, whereby the reaction cavity contains a plastic film having a film thickness that is less than 300 ⁇ m, preferably less than 250 ⁇ m, 200 ⁇ m, 150 ⁇ m or 100 ⁇ m. These film thickness values include all intermediate values and subranges.
  • the plastic film preferably consists of polypropylene, and is welded, with a stable shape, in a desired geometry, and pressed onto the sample block with light contact pressure, from above.
  • An amplification primer is preferably marked by means of biotin, and the hybridization probe is preferably marked with FITC, and is protected (“blocked”) against polymerization at the 3′ end.
  • This “blocking” can be achieved, for example, by using non-complementary bases or by adding a chemical group, such as a phosphate group, at the 3′-hydroxyl of the last nucleotide. Blocking can also be achieved by removing the 3′-OH or by using a nucleotide without the 3′-OH, such as a dideoxy nucleotide.
  • the lateral-flow test strip carries separate binding locations, preferably two, a streptavidin location for coupling the marked amplification products, and a binding location for function monitoring of the test strip, as well as a zone with conjugated detection particles (for example anti-FITC gold particles).
  • the object of the invention is also a method for detection of nucleic acids by means of the mobile rapid test system described above, having the following steps:
  • the invention solves the problems described in ideal manner, by means of the simple and synergistic combination of an equipment system for carrying out specific amplification reactions and simple detection chemistry for detection of a specific amplification event, whereby the equipment system is present in the form of a so-called hand-held system, and this is not only miniaturized but also can be operated in mobile manner, i.e. without the need for an external voltage source, particularly by means of battery operation.
  • the invention is based on the use of the so-called rapid PCR technology.
  • the invention solves the existing problems of a miniaturized, hand-held rapid PCR thermocycler in combination with a detection model as follows:
  • the invention is based on a novel arrangement and concept of heating elements and sample block, which are suitable for mobile use in terms of power and size, in combination with a completely novel consumable (reaction cavity for the amplification reaction) having a significantly improved heat transfer.
  • a completely novel consumable reaction cavity for the amplification reaction
  • the novel consumable is optimized in such a manner that the biggest problem, the physical resistance for effective PCR tempering, can be overcome.
  • An optimal heat transfer is present when a sample can be applied directly to the sample block or tempered medium, without interfering materials and additional heat transfers. Such implementation has been impossible up to now for reasons of contamination.
  • the non-heated surface areas are ⁇ 1.4, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0 or >2.0 times larger, particularly 1.7 times larger, than the heated surface areas.
  • a Peltier element operated by a battery is used as the sample block to be used; it is screwed onto a cooling body adapted to the system as a whole.
  • the geometry of the sample block that is used is also characterized by a maximal surface area, as a counterpart of the consumable.
  • the volume and thus also the capacity of the sample block are reduced to an absolute minimum, according to the invention. Therefore the sample block can theoretically be heated at a heating rate of 15° C./s.
  • the geometry of the consumable has been selected to be so large, according to the invention, that strong contact pressure onto the sample block is implemented by means of slight downward pressure from above and physical effects that are utilized and therefore uniform heating at these speeds is also promoted and implemented in this way.
  • the detection must be an integral component of the system as a whole.
  • This combination of amplification and detection is surprisingly implemented in very simple manner, according to the invention, by means of the use of so-called lateral-flow strips that are known to a person skilled in the art.
  • the two technologies rapid PCR and lateral-flow strips
  • lateral-flow strips exist as standard techniques, there is no link between the two technologies in the form of an integrative overall system that fulfills the requirements for a specific diagnostic system.
  • detection strategies that do not allow correct diagnostics or do not use an amplification reaction of nucleic acids (U.S. 2005/0227275 A1, WO 2007/092713 A2, Chen, Z., et al.; Ann. N.Y. Acad. Sci. (March 2007) 1098: 429-436, Wang, J. et al.; Lab on a Chip (2006) 6: 46-53).
  • the invention not only combines an amplification module with a lateral-flow strip, but also is based on a detection strategy that takes the diagnostic requirements into account. To underline the differences, it will be emphasized once again, in the following, how lateral-flow strips are used for DNA/RNA diagnostics.
  • a captor nucleic acid is a single-strand ribonucleic acid or deoxyribonucleic acid, or one that only becomes single-strand during the course of the process, which possibly contains chemically modified bases or base analogs, chemically modified sugars or sugar analogs, or is modified in some other way, and is characterized in that it binds to a specific, predetermined nucleic acid or class of nucleic acids at high specificity and selectivity.
  • this process requires the conversion of a double-strand DNA fragment (as the result of a specific amplification reaction) into a single-strand DNA fragment. For this purpose, the process must be carried out subsequent to a PCR reaction.
  • Another rapid detection method that also uses the detection of amplification products by means of a test strip and is available commercially is based on a completely different principle, in contrast to the above patent document.
  • implementation of the PCR reaction is carried out with a biotinylated primer and a non-biotinylated primer.
  • a PCR product is present, which is biotin-marked at one end.
  • the detection uses a test strip (for example from Millenia), which contains two separate binding locations. A streptavidin location for coupling the biotin-marked DNA strand and an FITC binding location for monitoring the function of the test strip.
  • the detection of the PCR product is implemented in that after PCR has been carried out, the PCR batch is denatured and hybridized with a probe that is complementary to the biotin-marked DNA strand.
  • the probe is FITC-marked.
  • the PCR batch is mixed with a running buffer and applied to the test strip.
  • the biotinylated DNA strand binds to the streptavidin binding location of the strip.
  • Detection takes place by way of the FITC marker of the probe hybridized with the DNA strand.
  • a typical signal is formed, in the shape of a strip. This signal is supposed to be the specific detection of the amplification product.
  • the method does not combine hybridization of the probe with the process of PCR, but rather carries this out as a separate method step. However, the method has a fundamental and dramatic error source.
  • the detection of the target nucleic acid to be detected is not specific.
  • the cause for this lies in the fact that artifacts that were formed during PCR, for example primer dimers, of course also bind specifically to the streptavidin binding location of the test strip, and therefore can cause a positive reaction, just like a specific PCR product (as already described multiple times in the above text).
  • a novel and very elegant possibility is based on a probe hybridization between amplificate and specific hybridization probe that is integrated into the amplification reaction. The detection of the specific hybridization event then takes place on a test strip.
  • Detection of an amplification/hybridization product takes place in that an amplification primer and the specific hybridization probe at the 3′-end are provided with a marking molecule, in each instance (for example biotin and FITC).
  • the amplification reaction takes place under standard conditions. In this connection, the actual amplification reaction is followed by a denaturing step for thermal strand separation of the amplification product generated during PCR.
  • the PCR reaction batch is cooled to the hybridization temperature of the probe.
  • the hybridization probe binds specifically to the complementary DNA strand of the amplification product.
  • this strand carries the biotin marker that was installed in the PCR product by means of the biotin-marked primer.
  • the reaction batch is transferred to the test strip.
  • detection of the specific hybridization event can take place as follows:
  • the test strip carries two separate binding locations, for example, in one embodiment variant; a streptavidin location for coupling the biotin-marked amplification products, and an FITC binding location for monitoring the function of the test strip.
  • the test strip contains a zone with conjugated detection particles (for example anti-FITC gold particles).
  • a detection signal can only become visible if the specific hybridization product between biotin-marked DNA strand and FITC-marked hybridization probe is present, since only this product is also coupled with the detection system (FITC/anti-FITC gold particles).
  • This embodiment variant is very elegant and does not entail the potential risk of false-positive signals. It is therefore the variant to be preferred for use of a lateral-flow test strip, for the mobile detection system according to the invention.
  • the invention should be understood as a combination of the novel method for detection of amplificates and a novel device for mobile use.
  • the detection strategy by means of lateral-flow strips, intelligent sample application, and energy-efficient tempering of sample volumes are combined, to produce a consumable that is cost-advantageous because it is simple to produce.
  • the consumable represents a design integration of the functional modules for application of the reaction mixture initially produced (nucleic acid to be investigated, dNTPs, primer, hybridization probe, as well as amplification buffer), for implementation of an energy-efficient amplification reaction, for storage and application of a running buffer, as well as for the detection reaction by means of test strips.
  • the battery-operated device is configured in such a manner that it represents an ideal means for processing the functional sections of the consumable.
  • the sequence of processing begins with application of the reaction mixture by way of the inlet opening, whereby the mixture is guided into the amplification chamber directly or by way of additional process segments. After the amplification/hybridization reaction has taken place, the reaction batch is transferred to the test strip by way of the outlet opening.
  • the running buffer is also passed to the test strip, from a separate reservoir, whereby in one embodiment variant, the running buffer can first pass through the reaction chamber.
  • the reservoir for the running buffer is also situated in the cartridge.
  • the diagnostic result is read off in a viewing zone.
  • the reaction cartridge which contains the amplification module and the test strip, as well as the reservoir for the running buffer, is preferably a disposable article, in other words, a new one is inserted into the base device for every reaction and disposed of after the test has been run.
  • the device according to the invention is an object of the invention described, even without the detection system according to the invention, and can also be combined with the detection system for captor nucleic acids that was mentioned above.
  • a system is made available that consists of the device according to the invention, according to the embodiments described herein, and a test strip on which special captor nucleic acids are immobilized, and with which detection of the nucleic acids to be determined takes place by means of hybridization with the captor nucleic acids on the test strip.
  • such a system will comprise a device that is a miniaturized hand-held device that can be operated in mobile manner, which does not require any external voltage source during operation, but rather is operated by means of a battery or a rechargeable battery, and which integrates said device and said test kit.
  • the hand-held device can comprise a reaction cavity for carrying out an amplification of nucleic acids by means of the rapid PCR technology, one or more inlet and/or outlet openings for the reaction cavity, one or more heatable sample blocks that are connected with miniaturized cooling bodies, and a means for reading the result, wherein the reaction cavity contains a plastic film having a film thickness that is less than 300 ⁇ m, preferably a film thickness of less than 100 ⁇ m.
  • the plastic film may consist of polypropylene and is welded in a desired geometry, in shape-stable manner, and is pressed against the sample block by means of slight contact pressure from above.
  • the reaction cavity and the test strip can be disposed in a reaction cartridge, and the plastic film produces connection channels with the reaction cartridge.
  • the system may further comprise a reservoir and an outlet opening for running buffer or contain connection channels between a reaction cavity, test strip, and running buffer reservoir, which can be closed off.
  • the reaction cavity may have two surfaces that can be connected with one another at channel or chamber edges, with force fit and/or shape fit, whereby at least one of these surfaces consists of a plastically or elastically deformable material.
  • the reaction cavity can also comprise a depression and the sample block can be configured in convex manner with the chamber opening being circular.
  • This system may contain reaction cavity that contains movable pistons and related hollow cylinders for storage of reactants. It may also comprise a heatable sample block, which is connected with a miniaturized cooling body, that contains a battery-operated Peltier element having a heating rate of ⁇ 5° C./s, 5° C./s, 10° C./s, 12.5° C./s and up to 15° C./s.
  • reaction mixture is fed into the inlet opening.
  • the inlet opening is welded shut by means of a heated wire that is integrated into the device.
  • the heated wire is moved to the inlet opening by means of a simple pressure mechanism.
  • reaction cavity both the consumable used for the amplification/hybridization reaction, according to the invention (reaction cavity), and the test strip are placed in a reaction cartridge, one behind the other.
  • the embodiment variant of the consumable is structured in such a manner that one or all the fluids on the consumable are transported from one functional module to the next by way of novel fluid structures.
  • These structures are produced by means of production technology, in that two surfaces are applied to one another, whereby at least one of these surfaces consists of a plastic or elastically deformable material.
  • the two surfaces are connected with one another, by means of force fit and/or shape fit.
  • fluid pressure is applied to the small gap that this structure can represent, then at least one of the surfaces domes up and releases a larger gap for passage between the two surfaces.
  • the reaction chamber represents a perforation or depression in the carrier material of the consumable. Closure of the chamber is achieved in that the film that lies on top of it is pressed against the edges of the perforation or depression.
  • the pressure is produced by the sample block, so that the latter brings about not only the heat transfer but also the chamber closure. The increased demands on the pressure seal during PCR are achieved in that the sample block is configured in convex manner and the chamber opening is circular.
  • Storage and application of the running buffer can be configured as follows, in one embodiment variant: A cavity is created between the film and the carrier material, by means of production methods that create a space. This cavity is filled with running buffer during production/outfitting of the consumable.
  • the outlet opening of the reservoir is closed off with a pressure-dependent valve, which can be implemented, for example, by means of a welding seam that can be re-opened.
  • the buffer chamber In order to feed the buffer into the reaction chamber, the buffer chamber has pressure applied to it, by the device or by the user, in such a manner that the valve opens and the buffer is moved to the test strip.
  • movable pistons and related hollow cylinders are part of the consumable.
  • these cylinders can be filled with fluid on the production side (for example running buffer, reactants).
  • the inlet opening of the consumable is shaped in such a manner that a sample application tool can be connected in shape-fit manner.
  • This tool is also composed of a hollow cylinder that has a piston.
  • the piston is pulled up into the cylinder and then connected with the consumable.
  • the pistons of the consumable and of the sampling tool can be moved by the user or by the device.
  • the sample is pressed into the reaction chamber by means of the piston movement at the sample application tool.
  • one or more sample blocks are pressed down from one or more sides of the reaction chamber.
  • the reaction chamber is sealed in airtight manner, as in Example 4, so that energetically advantageous tempering of the sample can take place.
  • the sample blocks are removed, the sample can now be pressed further in the direction of the detection chamber.
  • the piston of the sample application tool and/or the piston of the cylinder with the running buffer can be moved. Air and/or fluids from the cylinders described displaces the sample from the reaction chamber and moves it toward the test strip.
  • the detection region just like the application tool, can be reversibly removed from and connected with the consumable as a whole, and can be replaced by an alternative detection system.
  • the prerequisites for very simple and inexpensive gene-diagnostic on-site analysis have been created for the first time.
  • the hand-held device is much less expensive than the previously proposed high-technology equipment systems, particularly for military applications. This is also supposed to universally allow use of gene-diagnostic rapid tests in developing countries.
  • the method according to the invention it is made possible to carry out an extremely rapid amplification reaction.
  • the subsequent detection on a test strip is also very fast and robust.
  • the invention represents a real rapid test system.

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US12/820,569 2007-12-20 2010-06-22 Mobile rapid test system for nucleic acid analysis Abandoned US20110039261A1 (en)

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US10458978B2 (en) 2006-08-22 2019-10-29 Triad National Security, Llc Miniaturized lateral flow device for rapid and sensitive detection of proteins or nucleic acids
US9944922B2 (en) 2008-05-05 2018-04-17 Los Alamos National Security, Llc Highly simplified lateral flow-based nucleic acid sample preparation and passive fluid flow control
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US9399793B2 (en) 2010-04-08 2016-07-26 Aj Innuscreen Gmbh Device for detecting nucleic acids
US10881342B2 (en) 2010-10-15 2021-01-05 Atomo Diagnostics Pty Limited Sampling assembly
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US9428781B2 (en) 2011-04-20 2016-08-30 Mesa Biotech, Inc. Oscillating amplification reaction for nucleic acids
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US10428375B2 (en) 2012-02-03 2019-10-01 Axxin Pty Ltd Nucleic acid amplification and detection apparatus and method
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US10006867B2 (en) 2012-12-03 2018-06-26 The Secretary of State of Environment, Food and Rural Affairs, acting through the Animal and Plant Health Agency. Device and apparatus
JP2016533746A (ja) * 2013-08-19 2016-11-04 ゼネラル・エレクトリック・カンパニイ 多孔質基材における核酸増幅の検出
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US10352899B2 (en) 2014-10-06 2019-07-16 ALVEO Technologies Inc. System and method for detection of silver
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US10463290B2 (en) 2014-11-14 2019-11-05 Axxin Pty Ltd. Biological sample collection and storage assembly
US12023672B2 (en) 2015-04-24 2024-07-02 Mesa Biotech, Inc. Fluidic test cassette
US11198122B2 (en) 2015-07-17 2021-12-14 Axxin Pty Ltd Diagnostic test assembly, apparatus, method
US20220315981A1 (en) * 2015-07-24 2022-10-06 Sense Biodetection Limited Nucleic acid detection method
WO2017045992A1 (de) 2015-09-17 2017-03-23 Robert Bosch Gmbh Trockenchemisch gesteuerte vorrichtung zur analyse einer probe biologischen materials
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CN107513494A (zh) * 2017-08-17 2017-12-26 湖北伽诺美生物科技有限公司 一种核酸检测卡及其使用方法
US11709175B2 (en) 2017-09-27 2023-07-25 Axxin Pty Ltd Diagnostic test system and method utilizing a closure/sample dispensing mechanism to dispense a sample subvolume for testing
WO2020173446A1 (zh) * 2019-02-25 2020-09-03 上海快灵生物科技有限公司 一种生化反应试纸条管及其使用方法和试剂盒
CN112891986A (zh) * 2021-01-30 2021-06-04 哈尔滨工业大学 一种集成封闭式核酸自动提取装置
CN114015552A (zh) * 2021-11-04 2022-02-08 贵州医科大学附属医院 一种用于鉴定人骨髓间充质干细胞的试剂盒
US12128414B2 (en) 2022-09-02 2024-10-29 Mesa Biotech LLC Automated method for performing an assay

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US9260750B2 (en) 2016-02-16
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EP2227330A2 (de) 2010-09-15
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WO2009080817A2 (de) 2009-07-02
EP2227330B1 (de) 2014-07-30
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US20130130257A1 (en) 2013-05-23
ES2519042T3 (es) 2014-11-06

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