Classifications

• • G—PHYSICS
  • G01—MEASURING; TESTING
  • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
  • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
  • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
  • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
  • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
  • G01N33/543—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals
  • G01N33/54366—Apparatus specially adapted for solid-phase testing
  • G01N33/54386—Analytical elements
  • G01N33/54387—Immunochromatographic test strips
  • G01N33/54388—Immunochromatographic test strips based on lateral flow
• • G—PHYSICS
  • G01—MEASURING; TESTING
  • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
  • G01N35/00—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor
  • G01N35/00029—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor provided with flat sample substrates, e.g. slides
  • G01N2035/00099—Characterised by type of test elements
  • G01N2035/00108—Test strips, e.g. paper
• • G—PHYSICS
  • G01—MEASURING; TESTING
  • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
  • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
  • G01N21/75—Systems in which material is subjected to a chemical reaction, the progress or the result of the reaction being investigated
  • G01N21/77—Systems in which material is subjected to a chemical reaction, the progress or the result of the reaction being investigated by observing the effect on a chemical indicator
  • G01N21/78—Systems in which material is subjected to a chemical reaction, the progress or the result of the reaction being investigated by observing the effect on a chemical indicator producing a change of colour
• • G—PHYSICS
  • G01—MEASURING; TESTING
  • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
  • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
  • G01N21/84—Systems specially adapted for particular applications
  • G01N21/8483—Investigating reagent band

Definitions

• This disclosure relates to systems, methods and articles for use lateral flow analysis, such as bioanalysis, analysis of environmental or other chemicals, etc.
• a device may comprise: a sample collecting region configured to receive fluid samples; printed electronics configured to provide one or more visible indications of results of interactions of fluid samples with at least a portion of the printed electronics; and a membrane configured to wick fluid samples received by the sample collecting region and into contact with the at least a portion of the printed electronics.
• a device may comprise: a reaction region including molecules configured to selectively bind to molecules of fluid samples; and a results region configured to provide one or more visible indications of molecules of the reaction region binding to molecules of fluid samples, wherein the membrane is configured to wick fluid samples through the reaction region and through the results region.
• the printed electronics may comprise a printed electronics region configured to interact with fluid samples and a printed electronics region configured to provide the one or more visible indications of results of interactions with fluid samples.
• the membrane may comprise nitrocellulose.
• the device may comprise a plastic backing layer. At least part of the printed electronics may be printed on the membrane. At least part of the printed electronics may be printed on a plastic backing.
• a device may comprising a region configured to convert an analyte concentration into a quantitatively-related concentration of glucose, wherein the printed electronics are configured to provide an indication of the quantitatively-related
• the printed electronics may comprise at least one of an organic electrochemical transistor and an organic light-emitting diode.
• the device may comprise a compartment configured to store an organic solvent.
• a method may comprise: coupling a membrane to a backing, the membrane being configured to wick fluid samples; and printing electronics on at least one of the membrane and the backing, the printed electronics being configured to provide one or more visible indications of results of interactions between the electronics and fluid in the membrane.
• the printing electronics may comprise aerosol jet printing of at least part of the electronics.
• the membrane may be configured to wick fluid samples from a sample collecting region of the membrane through at least a portion of the printed electronics.
• the method may include incorporating molecules in a region of the membrane which are configured to selectively bind to molecules of fluid samples.
• the method may include configuring a region of the membrane to provide an indication of binding of the incorporated molecules to molecules of fluid samples.
• the membrane may comprise nitrocellulose.
• the backing may be a plastic backing.
• the method may include configuring a region of the membrane to convert an analyte concentration into a quantitatively-related concentration of glucose, wherein printing the electronics comprises printing circuitry configured to provide an indication of the quantitatively-related concentration of glucose.
• Printing the electronics may include printing at least one of an organic electrochemical transistor and an organic light-emitting diode.
• the method may include forming a compartment configured to store an organic solvent.
• a non-transitory computer-readable medium may contain contents which cause a manufacturing device to perform a method as disclosed herein.
• a device may comprise: a sample collecting region configured to receive fluid samples; one or more printed electronic components; and a membrane configured to wick fluid from a sample received by the sample collecting region into contact with at least one of the printed electronic components, the at least one of the printed electronic components being configured to react to the fluid.
• a device may include a reaction region including molecules configured to selectively bind to molecules of fluid samples; and a results region configured to provide one or more visible indications of molecules of the reaction region binding to molecules of fluid samples, wherein the membrane is configured to wick fluid from a sample received by the sample collecting region through the reaction region and through the results region.
• a device may include at least one additional printed electronic component configured to provide one or more visible indications of results of interactions with fluid samples.
• the membrane may comprise nitrocellulose.
• a device may include a plastic backing layer. At least one printed electronic component may be printed on the membrane. At least part one printed electronic component may be printed on a plastic backing. A device may include a region configured to convert an analyte concentration into a quantitatively-related concentration of glucose, wherein the at least one printed electronic component is configured to provide an indication of the quantitatively-related concentration of glucose. At least one printed electronic component may include at least one of an organic electrochemical transistor and an organic light-emitting diode. A device may include a container configured to store an organic solvent.
• a method may comprise: coupling a membrane to a backing, the membrane being configured to wick fluid samples; and printing at least one electronic component on at least one of the membrane and the backing, the at least one printed electronic component being configured to interact with fluid in a fluid sample wick through the membrane.
• a method may comprise coupling a membrane to a backing, the membrane being configured to wick fluid samples; and printing at least one electronic component on at least one of the membrane and the backing, the at least one printed electronic component being configured to provide one or more visible indications of results of interactions between the electronics and fluid in the membrane.
• the printing at least one printed electronic component may include aerosol jet printing of an electronic component.
• a membrane may be configured to wick fluid samples from a sample collecting region of the membrane through a region containing a printed electronic component.
• a method may include incorporating molecules in a region of the membrane, the incorporated molecules being configured to selectively bind to molecules of fluid samples.
• a method may include
• the membrane may comprise nitrocellulose.
• the backing may be a plastic backing.
• a method may include configuring a region of the membrane to convert an analyte
• a method may include providing a container configured to store an organic solvent.
• Providing a container may include forming a compartment configured to store an organic solvent.
• Figure 1 illustrates a structure of a lateral flow device.
• Figure 2 illustrates an aerosol printing system and schematic drawing of an aerosol process.
• Figure 3 is a comparison of inkjet and aerosol jet technologies.
• Figure 4 illustrates binding of an analyte to a corresponding aptamer within a DNA complex anchored on a magnetic bead.
• Figure 5 illustrates a layout of an organic electrochemical transistor.
• Figure 6 is a functional block diagram of a lateral flow device.
• a rectilinear-shaped feature or element does not mean that a feature or element has a geometrically perfect rectilinear shape.
• the selection of a diagnostic test and its associated measurement instrument to accomplish a particular biological diagnostic task may involve the evaluation many different criteria. These criteria may include:
• Is a stable source of electrical power typically employed for an extended duration May the instrument typically be used only in a thoroughly clean and sanitary environment, or may it be used (e.g.) out of doors in a desert or a jungle? Is a stable refrigerated thermal environment typically required from the point of manufacture of the test (and its reagents) through to the test execution site, or can the test materials successfully withstand extremes of temperature variation without losing their effectiveness?
• sensitivity of, for example, a diagnostic test for a disease is the proportion of people who have the disease being tested for who in fact test positive for it; the specificity of the test is the proportion of people who do not have the disease who test negative for it. 2
• MRI magnetic resonance imaging
• Lateral flow devices take their name from a notable feature of their typical design: the test is typically driven by capillary flow of a liquid (usually containing the substance to be analyzed, the analyte) in a porous medium such as paper or nitrocellulose upon which reagents of various forms have been deposited and dried.
• a liquid usually containing the substance to be analyzed, the analyte
• a porous medium such as paper or nitrocellulose upon which reagents of various forms have been deposited and dried.
• Embodiments of lateral flow tests may have many desirable properties, such as:
• Lateral flow tests typically comprise little more than the porous membrane, dried reagents, a sponge, and mounting (typically plastic) to provide physical structural support.
• lateral flow tests may typically require no power. Packaged at the factory into sealed containers, lateral flow tests may be rugged and durable.
• the reagents typically used in lateral flow tests are usually quite thermally stable.
• the device comprises a porous membrane 102, usually nitrocellulose, through which the sample is drawn under capillary action.
• the porous membrane 102 is supported by a plastic backing layer 104, which may typically be a polyester film, such as biaxially-oriented polyethylene terephthalate, often sold under the trademark Mylar.
• the membrane 102 may typically be manufactured in large sheets directly on a plastic backing before being cut to size and assembled into the device.
• the sample passes through several distinct regions within the membrane, as described below.
• the strip 100 comprises a sample collection region 106 at the tip of the strip 100, onto which the user places a sample to initiate the test. Often, an absorbent sample pad 108 is present in the collection region 106 to aid in the acquisition of a significant volume of sample.
• a reaction region 1 10 near the sample collection region 106 contains reagents that interact with the urine as it wicks by under capillary action. In certain designs, the reaction region 1 10 may be adjacent to or housed within a conjugate pad 1 12 which connects the sample pad 108 to the porous membrane 102.
• the strip 100 comprises a test region 1 14, in which the result of the test will be indicated, such as on a test line 1 16, and a control region 1 18 used to indicate the test has been properly executed, such as on a control line 120.
• An absorbent wicking pad 122 is in contact with the membrane 102 at the end of the paper beyond the control region 1 18.
• test may be indicated by the presence of a change in color in both the test region and the control region.
• a negative result may be indicated by a color change only in the control region.
• the chemical underpinnings of a typical lateral flow pregnancy test are as follows. The test seeks to diagnose the presence or absence of a particular human hormone 8 which has been shown to be an indicator of pregnancy.
• the hormone will be referred to herein as H.
• H The hormone
• the reaction region 1 10 are dried anti-H antibodies. That is, the region contains some biologically derived molecules (typically rabbits are used to produce them) which when they encounter molecules of the hormone H will chemically bind to them with very high specificity (they typically do not bind to anything else).
• These antibodies are referred to herein as AR (the details are again omitted).
• the AR molecules are free to move about.
• the AR molecules are swept up in it and are carried along further down the paper strip, encountering and binding to H molecules as they go (if in fact any such H molecules are present; that is, if the subject being tested is pregnant).
• H molecules as they go (if in fact any such H molecules are present; that is, if the subject being tested is pregnant).
• the AR molecules are typically manufactured to have an additional enzyme (referred to herein as E) chemically conjugated (attached) to the AR molecules as, effectively, one of their sub-parts.
• E additional enzyme
• the test region 1 14 also contains some dried anti-H antibodies (referred to herein as AT molecules), but these are different than the AR molecules in a couple of ways.
• AT molecules bind to the H molecules in a different location (what's known as a different epitope) than do the AR molecules. Thus, it is possible for AR and AT molecules to bind simultaneously to a given H molecule.
• the AT molecules typically are not free floating but rather are chemically tethered to the paper membrane 102 and do not get caught up in the urine flow.
• the AT molecules lack the conjugated E enzyme.
• the AT molecules found there will bind to any passing H molecules (or at least a substantial portion of them). Because the AT molecules are fixed to the paper, this will stop the H molecules from flowing any further. If the H molecules in question have attached AR molecules from their encounter in the reaction region, the AR molecules will therefore be stopped as well, together with their attached enzyme E.
• a latent dye is also present in the test region 1 14 .
• this dye is invisible, however, the dye has been engineered so in the presence of the enzyme E the dye changes color and becomes visible.
• the test region changes color (e.g., the test line 1 16 appears).
• the AR molecules are not stopped, and the test region 1 14 remains invisible ⁇ e.g., the test line 1 16 does not appear).
• the control region 1 18 also contains antibodies (referred to herein as AC molecules) and latent dye. However, whereas the test region 1 14 is designed to stop and catch AR molecules if and only if the hormone H is present, the control region 1 18 is designed to stop the AR molecules. To that end, the AC molecules are actually anti-AR antibodies. Like the AT molecules, the AC molecules are anchored to the paper membrane 102. When the urine flow reaches the control region 1 18, the AR molecules flowing therein (there will always be some, as only a percentage of the AR molecules ever manage to react with H, even if H is present) are bound by the AC molecules and stopped, allowing the attached enzyme E to activate the latent dye in the control region 1 18.
• AC molecules antibodies
• the accurate diagnosis of many diseases may require the examination of more than a single molecular maker: the identification of infections such as malaria 9 , dengue fever 10 , or tuberculosis 11 by detection of the presence of tell-tale fingerprints of their DNA or RNA may also check for the presence or absence of possibly several different nucleic acid sequences in perhaps complex Boolean combinations. If it is further desired that the diagnostic test report not only the presence or absence of the core disease but also which of various treatment resistances it might possess, the number of sequences to be examined and the computational complexity grows. If the diagnostic were not for one disease, but rather for several different diseases, as would be very desirable, the complexity grows even further. A similar complexity is encountered if it is desired for greater effectiveness that the test execute two diagnoses for one disease: for example, a tuberculosis test might both perform nucleic acid fingerprinting and test for interferon- ⁇ 12 .
• these more complex diagnostics could be executed use a set of parallel lateral flow tests, as even the most complex of the diagnostics conceptually tests for the presence or absence of a certain set of analytes, each one of which could be the subject of its own lateral flow system.
• such an approach is not a practical one, for both operational and usability reasons.
• number of different physical tests units quickly becomes unwieldy to manufacture, distributed, stock, and administer, etc., and executing a large number of tests may require a prohibitively large volume of the sample to be tested be used in the execution of the many tests.
• the usability side even if the multitude of lateral flow tests of a complex diagnostic were somehow successfully executed, leaving the interpretation of the particular combination of yes / no results to be carried out by the human diagnostician may be an error-prone and unreasonable design.
• electronics For example, it is possible using electronics to construct a circuit which can form any Boolean combination of inputs desired, providing a useful function for the analysis found in the complex lateral flow tests hypothesized earlier. Other circuits can perform other useful tasks, including signal amplification, signal filtering, timing and sequencing, and so on. Electronics are also a natural technique for the creation of a wide range of sophisticated yet easy-to-use user interfaces for bioanalysis devices. Electronics may be very useful indeed.
• the inventor has realized that new forms of printing technology allow printing electronics directly onto the paper substrate of a lateral flow device using conductive inks. This can be done with a cost structure sufficiently inexpensive to be incorporated into a disposable lateral flow test.
• the whole gamut of electronic components and circuits may be printed in this manner: wires, resistors, capacitors, transistors, inductors, and so on.
• Printed electronics technologies exist in several forms, including offset lithography, rotogravure, and inkjet, to name a few. 18,19 Whilst each of these electronics printing technologies may be useful and effective in certain aspects of the production of lateral flow bioanalysis systems with integrated electronics, the inventor has recognized that a relative newcomer to the field, aerosol jet technology 20"23 , warrants particular attention.
• a manufacturer and developer of aerosol jet printing technology describes it in this way:
• Aerosol Jet process begins with the atomization of a print material to produce droplets on the order of one to two microns in diameter. Materials with viscosities ranging for 1 cP to 1 ,000 cP have been successfully atomized and deposited using Aerosol
• a second gas is introduced around the aerosol stream to focus the droplets into a tightly collimated beam and also to eliminate
• the combined gas streams exit the print head through a converging nozzle that compresses the aerosol stream to a diameter as small as 10 microns.
• the jet stream of droplets exits the print head at high velocity and impinges upon the substrate. 22
• Aerosol Jet printing system and schematic drawing of the aerosol generation process, (a) The Aerosol Jet printer stand with PC
• Arrow I indicates the laser, II the substrate table, which is movable in the j-direction, and III the aerosol generation unit, (b) Magnification of the Aerosol Jet printing module.
• Arrow IV indicates the printing nozzle and arrow V the shutter of the
• the droplet stream typically flows continuously in aerosol jet printing
• a shutter between the nozzle and the substrate blocks the flow whenever desried, allowing very fine-grained control of the femtoliter-sized droplets, thus achieving precision control of the amount of material deposited, significantly better than other technologies such as inkjet.
• the sub-10-micron typically achievable feature size With the sub-10-micron typically achievable feature size, increasingly fine and precise features can be printed.
• the wide range of viscosities printable with the device facilitates doing such things as adding ethylene glycol to the aerosol to reduce overspray effects or adding sugar or glycerol preservatives in order to increase ligand stability and shelf-life.
• Such useful techniques may be difficult or impossible to achieve with other printing technologies which can handle only a more restricted range of ink viscosities.
• Aerosol jet printing is an effective method for printing electronic components. 26"31
• the technology has been used for printing electronics as diverse as large solar arrays, thin-film transistors, antennae, resistors, capacitors, and so on.
• these techniques may be applied to print electronics onto the plastic substrate (usually Mylar) upon which the porous wicking material (usually nitrocellulose) of the device is positioned.
• the plastic substrate usually Mylar
• the porous wicking material usually nitrocellulose
• certain areas of the plastic can be manufactured devoid of the usual coating of porous material, thus facilitating said components to be positioned in closer proximity to the parts of the porous material with which they interact.
• An embodiment provides a methodology by which a concentration of virtually any analyte of interest that it is desired to determine may be converted within a lateral flow device into a quantitatively-related measure of one of the above (or similar) properties. Once that is accomplished, application of the corresponding electronic measuring circuit facilitates converting the level of that quantitatively-related property into electrical signals, which can then be manipulated, analyzed, combined, presented as output, etc. using well- understood techniques of electrical engineering.
• gold nanoparticles 36 which have unique optical properties 37 , are today not infrequently used as visual output indicators in lateral flow devices. 3,38 In this usage, the optical color intensity created in the test range of the device serves as a quantitatively-related measure of the concentration of the analyte of interest.
• gold nanoparticles being conductive, also have interesting electrical properties.
• a second example approach to electrical quantitative measurement of analyte concentration involves first the conversion of the analyte concentration to a quantitatively-related concentration of glucose, then the measurement of that glucose concentration using the circuitry of an electronic glucose meter. This approach may be particularly appealing because significant research and development has gone into the design and
• DNA aptamers 41 ,42 are first raised to the analyte using in vitro selection 73 in a well- known procedure.
• Aptamers are by nature comprised of a strand of DNA of particular sequence that binds to the ligand to which they are raised with high specificity and possess the property that once bound undergoes a significant conformational change.
• Xiang and Lu use this conformational change to initiate what in other literature is known as a DNA strand displacement reaction 43"46 within a preassembled DNA complex anchored to a magnetic bead (see Figure 4).
• invertase 47 ⁇ -fructofuranosidase
• Figure 4 illustrates binding of an analyte (here, cocaine) to a corresponding aptamer within a DNA complex anchored on a magnetic bead. This causes a conformational change in the aptamer, initiating a strand displacement reaction which ultimately releases a DNA strand to which invertase has been conjugated.
• analyte here, cocaine
• Figure 4 illustrates binding of an analyte (here, cocaine) to a corresponding aptamer within a DNA complex anchored on a magnetic bead.
• the DNA complexes containing the aptamers can be immobilized on the porous medium of the device in a first part of the reaction region thereof.
• DNA-immobilization technologies exist by which this anchoring may be performed, including the
• biotin/streptavidin 48 system used by Xiang and Lu and many others, and the use of a poly(T) tail on an anchoring DNA strand 49 of the DNA complex (such tails possess a natural affinity for nitrocellulose).
• a poly(T) tail on an anchoring DNA strand 49 of the DNA complex (such tails possess a natural affinity for nitrocellulose).
• the particular form of DNA strand displacement reaction used by Xiang and Lu is but one of a whole class of such reactions that might be used: the field of DNA nanotechnology has matured to the point where designing and synthesizing sets of interacting DNA complexes to perform virtually most any given computational task is routine and commonplace. 46
• the design may be such that the execution of the reaction is initiated by the particular conformational change of the aptamer which is caused by its binding to its ligand.
• sucrose to be catalyzed by the freed invertase may preexist in dried form in a second (downstream) part of the reaction region of the device; it need not be applied in a time-sequenced step as in Xiang and Lu's design.
• an embodiment Having converted the concentration of the analyte into a corresponding concentration of glucose, the next step of an embodiment is to measure that glucose concentration. While Xiang and Lu used a commercial glucose meter to accomplish this task, and use of such a commercial meter might be practical and even interesting in a certain application of lateral flow tests, this approach may not be ideal in all cases (for cost reasons, if nothing else). Thus, an embodiment employs a suitable printable electronic glucose meter circuit. An example circuit is based on the work of Shim et a/.
• An organic electrochemical transistor is utilized in an embodiment, specifically one manufactured using the conducting polymer Poly(3,4-ethylenedioxythiophene) doped with poly(styrene sulfonate), otherwise known as PEDOTPSS (see Figure 5).
• the transistor comprises two conducting regions: a narrow channel connecting source and drain, and a wider gate electrode.
• the solution whose glucose concentration is to be measured is allowed to flow between the two conducting regions.
• Also mixed into the solution are particular concentrations of ferrocene 51 , glucose oxidase 52 , and phosphate buffered saline (PBS) 53 .
• PBS phosphate buffered saline
• the chemical reactions that occur within the resulting system are such that for a given gate voltage the magnitude of current that flows in the channel is modulated by the concentration of glucose present in a quantitatively-related manner.
• ferrocene is not water-soluble .
• the inventor has recognized the ferrocene, glucose oxidase, and PBS containing solution used in the transistor may also contain some form of organic solvent, such as ethanol.
• organic solvent such as ethanol.
• the solvent may be provided as part of the manufactured device.
• organic solvents typically are volatile and evaporate quickly.
• an embodiment provides of an airtight compartment within the lateral flow device that remains sealed until the execution of the test.
• a separate supply of an organic solvent ⁇ e.g., a bottle), may be provided with the test.
• a user may, for example, squirt solution from the bottle into a hole or holes in a plastic housing of the lateral flow device ⁇ e.g., in a manner similar to the one through which a sample is placed in the lateral flow device).
• the creation of the walls of such a compartment may make use of a technique of creating isolated regions within the porous membrane analogous to the manner in which wax printing has been used for this purpose. 54"56 If printed with sufficient width, volume and subjected to sufficient heat, the application of wax can fill the porous cavities of the membrane, creating the walls of the compartment.
• wax specifically, paraffin wax
• this technique cannot typically be used directly.
• an embodiment utilizes an analogous phase- changing material such as a UV-curable resin: in its initial, liquid form, a UV- curable resin can be printed onto the porous membrane. Once printed, the resin will wick through the membrane much like liquid wax but more slowly due to its higher viscosity.
• UV light can be applied to cure the resin.
• a secondary heat curing may also be applied.
• One specific UV-curable resin notably applicable in an embodiment is UV CURE 60-7156 57 from Expoxies.com. This resin has a sufficiently low viscosity ⁇ e.g., 600 cP) to both be handled with aerosol jet printing and to penetrate the porous membrane (albeit slowly). Moreover, its abilities to continue to cure once initially exposed to UV light helps and its ability to be heat cured as a secondary cure operation help facilitate complete curing.
• the resin UV10 58,59 from MasterBond may similarly be used and has lower viscosity (300- 400 cP), but it lacks a secondary curing ability.
• the floor of the sealed compartment may be neatly formed by the existing plastic backing material which underlies the membrane (see backing 104 of Figure 1 ).
• the ceiling of the compartment can be created in an analogous manner by laying a second detachable plastic sheet atop the porous membrane and applying moderate but sufficient pressure so as to form a seal against the res in -constructed compartment walls.
• the compartment in which the ferrocene-containing solution is stored can be constructed to physically interact with the remainder of the lateral flow device in the following manner.
• the gate and channel electrodes of the organic electrochemical transistor are printed in the main porous membrane of the device, either underneath the membrane (between it and the plastic backing) or on top of it.
• the ferrocene-containing solution is then contained in a
• electrochemical transistors are employed in one lateral flow device, a single auxiliary membrane with its single detachable membrane may serve for them all.
• the overall lateral flow device can be constructed such that the detachable sheet extends beyond the housing of the device and augmented with a pull-tab; the application of a moderate amount of force on the tab will then remove the sheet from the device.
• the two membranes come in fact-to- face contact, and the ferrocene-containing solution quickly diffuses into the space surrounding the electrodes on the porous membrane, as desired.
• Other mechanisms for breaching the compartment may be employed, such as punctures, etc.
• Shim et al. constructed the electrodes of their transistor using a classic photolithography approach.
• the PEDOTPSS material with which the electrodes are manufactured has been shown to be directly printable with aerosol jet printing, simplifying the overall manufacturing process.
• the influx of the to-be-measured glucose in a water-based solvent such as urine
• the glucose oxidase and other chemicals are rehydrated and mix with the glucose present.
• the concentration of the glucose is then electrically measured using additional electronic equipment affixed to the electrodes and the application of
• chronoamperometry 60 This approach to electronic glucose measurement may be applied to use in lateral flow devices with integrated printed electronics as discussed above.
• Electronics integrated into a lateral flow device may typically employ some source of energy with which the electronics can be powered. There are several possible sources for this power.
• One approach is to provide a connection to a source of power external to the entire device. This can be accomplished using a USB
• connection (a truly-global DC power connection standard) or some other electrical connection standard. While functional, connecting to external power in this way is difficult to achieve without significantly increasing the cost of manufacture of the device. Moreover, a requirement for an external source of power makes it difficult to use the device in low infrastructure settings.
• a related approach makes use of a battery external to the mechanism of the lateral flow structure per se but integrated into the overall device housing and packaging. This, too, may significantly increase the cost of the device, both for the manufacture of the battery (with it its own housing, chemicals, etc.) and for the assembly of the interconnect between the battery and the printed electronics on the device membrane.
• a more integrated approach is to print the battery or other power source ⁇ e.g., a circuit for extracting power from signals) directly onto the lateral flow device membrane or plastic backing along with the rest of the printed electronics. This eliminates the cost associated with the manufacture and integration of an external battery or power source.
• Printed batteries are an emerging subfield of the printed electronics industry, and several commercial batteries are presently available using a variety of core technologies.
• a refinement of the printable battery approach is that of printing a battery where a portion of the sample being analyzed is used as an integral part of the functioning of the battery (typically the electrolyte).
• the battery typically the electrolyte.
• 64"67 and some forms of urine-powered batteries are commercially available 68"70 .
• One advantage of this approach is that the battery is inert until it comes in contact with the sample. Thus, it is less likely to suffer from a self- discharge effect, which may otherwise limit the usable shelf-life of the battery and thus the overall device. While this is an interesting and useful feature, few biobattery designs so far developed have been created with an eye to printable manufacturing.
• a notable exception is the work of Phillips et al ⁇ who have developed an architecturally simple biobattery capable of being powered by urine and which is amenable to manufacture with printed electronics technology such as aerosol jet printing.
• the core of lateral flow devices typically contains a porous membrane with an underlying plastic backing. It is possible to construct the device such that the membrane is absent in certain areas, exposing the plastic backing. One technique by which this may be achieved is to selectively cut out sections of the porous membrane before affixing it to the backing. Constructing devices with exposed backing in this manner is
• membrane and the backing may have different properties, including the following.
• capillary action may be active in the porous membrane, but not in the raw plastic backing.
• electronics printed on the membrane might come in contact with the wicking sample, while electronics printed on the plastic backing may not.
• some of the electronics typically will contact the sample.
• the ability to control which parts of the electronics need deal with becoming wet (mixing electronics and water must be done with care) is a design advantage in some
• printing electronics on plastic may be more reliable and is a more established industry practice than printing on porous membranes such as paper.
• printing electronics on the membrane may be confined to parts of the design as needed or desirable, more reliable and consistent devices can be manufactured.
• a sophisticated and complex lateral flow device it may from time to time be desirable to perform perhaps several simultaneous independent tests, measurements, or chemical reactions involving the sample.
• the mechanism (chemistry, electronics, etc.) of these parallel tests is such that though independent the tests can in fact be performed within one sample flow.
• the mechanisms of the tests may be mutually incompatible.
• one approach for dealing with such situations is to spit the flow of the sample into two or more parallel channels using a "Y" construction in the porous membrane. Once diverged from the stem of the "Y" into its arms, the flow of the sample becomes split and independent, ultimately leading (in one form of the design) to separate and independent absorbent pads, effectively creating internal, mini sub-devices within the larger lateral flow device.
• the mutually incompatible mechanisms can be carried out without interference from surrounding mechanisms.
• the separation of the flow into "Y" or other shapes can be carried out by either physical separation of the porous membrane, or by the use of wax or other appropriate impermeable barrier as was discussed above in the context of creating walls of isolated compartments within the porous membrane.
• OLEDs organic light-emitting diodes
• aerosol jets can be printed with aerosol jet and other printing technologies.
• OLEDs have been assembled into arrays to form flat panel displays; a similar approach might be applicable to lateral flow devices.
• a less ambitious approach arranges the printed OLEDs into one or more seven segment displays 72 ; this provides a mechanism by which quantitative or numerical output results can be displayed to the user directly on a lateral flow device.
• the color produced by OLEDs on a device can indicate certain conditions or results of significance to the user.
• electronics on lateral flow devices can be used to induce chemical reactions within reagents printed on paper the output of which are by nature visually discernible by the user.
• This last approach is described by Kauffman et a/. 15
• the ability to reasonably embed sophisticated electronics within lateral flow devices opens up a whole range of possibilities for vastly better device user interfaces than the simple one-bit outputs of classical devices.
• Other output interfaces may be employed in some embodiments, such as using printed RFID devices read by a reader, etc., and various combinations of output interface may be employed.
• FIG. 6 is a functional block diagram of an embodiment of a lateral flow device 600.
• the device comprises a porous membrane 602, such as nitrocellulose, through which the sample is drawn under capillary action.
• the porous membrane 602 is supported by a plastic backing layer 604, which may typically be a polyester film, such as biaxially-oriented polyethylene terephthalate, often sold under the trademark Mylar.
• the membrane 602 may typically be manufactured in large sheets directly on a plastic backing before being cut to size and
• the sample As the sample is drawn through the device, the sample passes through several distinct regions within the membrane 602, as described below.
• the device 600 comprises a sample collection region 606 at the tip of the device 600, onto which the user places a sample to initiate the test. Often, an absorbent sample pad 608 is present in the collection region 106 to aid in the acquisition of a significant volume of sample.
• An optional first reaction region 610 near the sample collection region 606 contains reagents that are configured to interact with the sample ⁇ e.g., blood, urine, etc.) as it wicks by under capillary action.
• the sample e.g., blood, urine, etc.
• the first reaction region 610 may be adjacent to or housed within a conjugate pad which connects the sample pad 608 to the porous membrane 602 (see conjugate pad 1 12 of Figure 1 ).
• the device 600 comprises an optional first test results region 614, in which the result of the test of the first reaction region 610 may be indicated, such as on a test line (see test line 1 16 of Figure 1 ), and an optional first control region 618 used to indicate the test of the first reaction region has been properly executed, such as on a control line (see control line 120 of Figure 1 ).
• An absorbent wicking pad 622 is in contact with the membrane 602 at the end of the paper beyond the control region 618.
• the components 602-618 of an embodiment of Figure 6 may operate, for example, in a manner similar to the operation of the test strip 100 of Figure 1 .
• the device 600 includes printed electronics. As illustrated, the printed electronics are split into two regions.
• a second reaction region 630 comprises printed electronics configured to interact with a sample as it passes through the device 600.
• the second reaction region 630 comprises printed electronics including a processor P, a memory M and discrete circuitry such as a diode.
• Embodiments may comprise other, fewer or additional printed electronics, such as organic transistors, a power supply (such as a power supply configured to use sample fluid as an electrolyte), etc.
• the second reaction region 630 as illustrated is printed on the membrane 602. In some embodiments, all or a portion of the second reaction region may be printed on the plastic backing 604 in addition to or instead of on the membrane, as discussed in more detail above.
• the second reaction region 630 receives a sample after the sample has interacted with the optional first reaction region 610.
• a sample may interact with the second reaction region 630 before or in parallel with the sample interacting with the first reaction region 610.
• the second reaction region 630 may comprise printed electronics configured, for example, to react with a sample as discussed above.
• the device 600 also comprises a second test results region 640 electrically coupled to the second reaction region, as illustrated by a bus 642, and including another portion of the printed electronics configured to provide results of the interaction of the printed electronics of second reaction region with the sample.
• the bus 640 may, for example, be printed on the membrane 602, on the plastic backing 604, and various combinations thereof.
• the second test results region 640 comprises printed electronics including a processor P, a memory M and discrete circuitry such as an OLED. Embodiments may comprise other, fewer or additional printed electronics, such as diodes, power supplies, etc.
• the second test results region 640 as illustrated is printed on the plastic backing 604.
• all or a portion of the second test results region 640 may be printed on the membrane 602 in addition to or instead of on the plastic backing, as discussed in more detail above.
• the second test results region 640 is separated from the membrane 602 by a barrier 644, which may be a barrier such as was discussed above in the context of creating walls of isolation compartments.
• the second test results 640 may comprise printed electronics configured, for example, to provide results as discussed above.
• the second test results region 640 may be configured to visually display results on an OLED.
• the device 600 comprises sealed compartments
• an embodiment 646, 648 configured to store an organic solvent, which may be released by pulling a second plastic backing 650, for example as discussed above in the context of providing an organic solvent to an organic electrochemical transistor.
• the device as illustrated also comprises a plastic top 652. It should be understood that the details of the device just described are but one approach to implementing a lateral flow based device.
• Embodiments may comprise additional or fewer regions, compartments, plastic layers, walls, membranes, bus systems, etc., in various configurations.
• an embodiment may comprise a single printed electronics region configured to interact with a sample and to display results of the interaction.
• Some embodiments may take the form of or comprise computer program products.
• a computer readable medium comprising a computer program adapted to perform one or more of the methods or functions described above, such as to control a system of manufacturing lateral flow devices, to control electronics on a lateral flow device, etc.
• the medium may be a non-transitory medium such as a physical storage medium, for example, a Read Only Memory (ROM) chip, or a disk such as a Digital Versatile Disk (DVD-ROM), Compact Disk (CD-ROM), a hard disk, a memory, a network, or a portable media article to be read by an appropriate drive or via an appropriate connection, a look-up table, including as encoded in one or more barcodes or other related codes stored on one or more such computer-readable mediums and being readable by an appropriate reader device.
• ROM Read Only Memory
• DVD-ROM Digital Versatile Disk
• CD-ROM Compact Disk
• some or all of the systems and/or modules may be implemented or provided in other manners, such as at least partially in firmware and/or hardware, including, but not limited to, one or more application-specific integrated circuits (ASICs), digital signal processors, discrete circuitry, logic gates, state machines, standard integrated circuits, controllers ⁇ e.g., programmed by executing appropriate instructions, and including microcontrollers and/or embedded controllers), field-programmable gate arrays (FPGAs), complex programmable logic devices (CPLDs), etc., as well as devices that employ RFID technology, and various combinations thereof.
• ASICs application-specific integrated circuits
• DSPs digital signal processors
• discrete circuitry discrete circuitry
• logic gates logic gates
• state machines standard integrated circuits
• controllers ⁇ e.g., programmed by executing appropriate instructions, and including microcontrollers and/or embedded controllers
• FPGAs field-programmable gate arrays
• CPLDs complex programmable logic devices
• Aerosol Jet is not Inkjet
• HCV hepatitis C virus

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• 2013
  • 2013-03-01 WO PCT/US2013/028656 patent/WO2013130995A1/fr not_active Ceased

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