WO2022075981A1 - Membranes à effet de mèche de fluide - Google Patents

Membranes à effet de mèche de fluide Download PDF

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Publication number
WO2022075981A1
WO2022075981A1 PCT/US2020/054523 US2020054523W WO2022075981A1 WO 2022075981 A1 WO2022075981 A1 WO 2022075981A1 US 2020054523 W US2020054523 W US 2020054523W WO 2022075981 A1 WO2022075981 A1 WO 2022075981A1
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Prior art keywords
silica particles
membrane
coating layer
particle size
fluid
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PCT/US2020/054523
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English (en)
Inventor
Fredrick Muya MAKAU
Adam C. WEISMAN
Douglas Knight
Rajasekar Vaidyanathan
Alan Jacques
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Hewlett-Packard Development Company, L.P.
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Priority to PCT/US2020/054523 priority Critical patent/WO2022075981A1/fr
Publication of WO2022075981A1 publication Critical patent/WO2022075981A1/fr

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    • 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
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D69/00—Semi-permeable membranes for separation processes or apparatus characterised by their form, structure or properties; Manufacturing processes specially adapted therefor
    • B01D69/10—Supported membranes; Membrane supports
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D69/00—Semi-permeable membranes for separation processes or apparatus characterised by their form, structure or properties; Manufacturing processes specially adapted therefor
    • B01D69/12—Composite membranes; Ultra-thin membranes
    • B01D69/1216—Three or more layers
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D71/00—Semi-permeable membranes for separation processes or apparatus characterised by the material; Manufacturing processes specially adapted therefor
    • B01D71/02—Inorganic material
    • B01D71/0213—Silicon
    • 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
    • G01N33/54313—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals the carrier being characterised by its particulate form

Definitions

  • lateral flow assays and vertical flow assays are types of tests in which a sample fluid flows through a porous material such as a porous nitrocellulose membrane.
  • Lateral flow assays often include a test line and a control line.
  • the test line can include a suitable test reactant that is reactive with a target molecule in the sample fluid.
  • the test line can indicate the presence of the target molecule with a visible color change of the test line.
  • a control line is often located beyond the test line so that the sample fluid reaches the control line after the sample fluid has already flowed past the test line.
  • control line can indicate that the sample fluid has flowed sufficiently past the test line so that the test can be considered valid.
  • vertical flow assays can include a membrane with a test area having a test reactant that can indicate the presence of a target molecule with a visible color change in the test area.
  • a control reactant can also be placed in a control area on the membrane to indicate that the test can be considered valid.
  • FIG.1 is a cross-sectional view of an example fluid-wicking membrane in accordance with examples of the present disclosure
  • FIG.2 is a cross-sectional view of another example fluid-wicking membrane in accordance with the present disclosure
  • FIG.3 is a cross-sectional view of yet another example fluid-wicking membrane in accordance with the present disclosure
  • FIG.4 is a flowchart of an example method of making a fluid-wicking membrane in accordance with the present disclosure
  • FIG.5 is a cross-sectional view of an example lateral flow assay membrane in accordance with the present disclosure
  • FIG.6 is a cross-sectional view of an example vertical flow assay membrane in accordance with the present disclosure.
  • a fluid-wicking membrane includes a substrate and a porous coating layer over the substrate.
  • the porous coating layer includes silica particles bound together by a polymeric binder.
  • the silica particles have an average particle size from greater than 1 ⁇ m to 50 ⁇ m.
  • the porous coating layer also includes a surface-activating agent activating surfaces of the silica particles.
  • the surface-activating agent includes aluminum chloride hydrate, a trivalent metal oxide, a tetravalent metal oxide, or a combination thereof.
  • the porous coating layer can have a coating thickness from 1 ⁇ m to 300 ⁇ m.
  • the surface-activating agent can be included in an amount from 2 wt% to 20 wt% with respect to the total dry weight of the porous coating layer.
  • the polymeric binder can be included in an amount from 0.5 wt% to 20 wt% with respect to the total dry weight of the porous coating layer.
  • the silica particles can be functionalized by an organosilane, wherein a silicon atom of the organosilane bonds to oxygen atoms at a surface of the silica particles.
  • the organosilane can include an organic part including a hydrophobic group, a hydrophilic group, a zwitterionic group, a polar aprotic group, a primary amine group, a carboxylic acid group, or a combination thereof.
  • the organosilane can include N-(2-aminoethyl)-3-aminopropyltrimethoxysilane, 3-(triethoxysilylpropyl)-diethylenetriamine, poly(ethyleneimine)trimethoxysilane, aminoethylaminopropyl trimethoxysilane, aminoethylaminoethylaminopropyl trimethoxysilane, N-aminoethyl-3-aminopropylmethyldimethoxysilane, n-(2-aminoethyl)-11-aminoundecyltrimethoxysilane, aminophenyltrimethoxysilane, 3-aminopropyltrimethoxysilane, triethoxysilylundecanal, 3-mercaptopropyltrimethoxysilane, 3-(triethoxysilylpropyl)-p-nitrobenzamide, 3-cyanopropyltrime
  • the porous coating layer can include a bottom sublayer and a top sublayer over the bottom sublayer, wherein the bottom sublayer can include silica particles having a first average particle size and the polymeric binder in a first binder concentration, wherein the top sublayer can include silica particles having a second average particle size that is less than the first average particle size, and the polymeric binder in a second binder concentration that is greater than the first binder concentration.
  • the porous coating layer can include a bottom sublayer and a top sublayer over the bottom sublayer, wherein the bottom sublayer can include silica particles having a first average particle size and the polymeric binder in a first binder concentration, wherein the top sublayer can include silica particles having a second average particle size that is greater than the first average particle size, and the polymeric binder in a second binder concentration that is less than the first binder concentration.
  • a method of making a fluid wicking membrane includes coating a substrate with a coating composition.
  • the coating composition includes a dispersion of silica particles having an average particle size from greater than 1 ⁇ m to 50 ⁇ m.
  • the coating composition also includes a surface-activating agent activating surfaces of the silica particles, wherein the surface-activating agent includes aluminum chloride hydrate, a trivalent metal oxide, a tetravalent metal oxide, or a combination thereof.
  • the coating composition also includes a polymeric binder.
  • the method further includes drying the coating composition to form a porous coating layer over the substrate.
  • coating the substrate can include applying a first coating composition to form a bottom sublayer and applying a second coating composition to form a top sublayer over the bottom sublayer, wherein the first coating composition includes silica particles having a first average particle size and the second coating composition includes silica particles having a second average particle size that is less than the first average particle size.
  • a flow assay membrane includes a substrate, a porous coating layer over the substrate, and a test reactant in a test area of the porous coating layer.
  • the porous coating layer includes silica particles bound together by a polymeric binder and a surface-activating agent activating surfaces of the silica particles wherein the surface-activating agent includes aluminum chloride hydrate, a trivalent metal oxide, a tetravalent metal oxide, or a combination thereof.
  • the flow assay membrane can be a lateral flow assay membrane, wherein the substrate can be non-porous, wherein the test area can be a test line, and wherein the flow assay membrane can also include control reactant in a control line on the porous coating layer.
  • the flow assay membrane can be a vertical flow assay membrane, wherein the substrate can be porous, wherein the porous coating layer can include a bottom sublayer including silica particles having a first average particle size and a top sublayer over the bottom sublayer, wherein the top sublayer can include silica particles having a second average particle size that is less than the first average particle size.
  • Fluid Wicking Membranes [0012] As mentioned above, the present disclosure describes fluid wicking membranes. These membranes can be used in a variety of applications in which a liquid is transported along the membrane surface, or penetrates through the membrane, or a combination thereof.
  • the fluid wicking membranes described herein can include a porous coating layer that can transport liquid through the pores in the layer.
  • Some examples of devices that can include these fluid wicking membranes are: lateral flow assays, vertical flow assays, dot blot assays, western blots, and others.
  • the fluid wicking membranes can replace nitrocellulose membranes that are often used for fluid transport. Nitrocellulose membranes include pores that can wick liquids through capillary action. Therefore, such membranes are often used in flow assays and similar applications. However, nitrocellulose membranes can have low uniformity with respect to thickness of the membrane, pore size, pore distribution, and other properties.
  • Nitrocellulose membranes can be difficult to manufacture, and the manufacturing process can be imprecise. Nitrocellulose membranes can also be difficult to work with due to static electricity build up and flammability of the nitrocellulose material.
  • the fluid wicking membranes described herein can provide more precise control over membrane thickness, pore size, and pore distribution. The manufacturing process can also be more cost effective compared to nitrocellulose membranes.
  • the materials used in the fluid wicking membranes can also be non-flammable or have low flammability. These materials can include a substrate and a coating composition that is applied to the substrate to form a porous coating layer.
  • the porous coating layer can include silica particles bound together by a polymeric binder.
  • the silica particles can have an average particle size from greater than 1 ⁇ m to 50 ⁇ m.
  • the void spaces between the silica particles can act as pores for wicking fluids.
  • the silica particles can also be activated by a surface-activating agent.
  • the surface activating agent can include aluminum chloride hydrate, a trivalent metal oxide, a tetravalent metal oxide, or a combination thereof.
  • the silica particles can also be functionalized in some examples. Functional groups can be attached to the surfaces of the silica particles, such as functional groups for passivating the surfaces or reactive functional groups to provide a variety of chemical reactions. [0014] One example fluid-wicking membrane 100 is shown in FIG.1.
  • the membrane includes a substrate 110 and a porous coating layer 120 over the substrate.
  • the porous coating layer includes silica particles bound together by a polymeric binder. Silica particles with an average particle size from greater than 1 ⁇ m to 50 ⁇ m can provide sufficient void space between the particles for wicking fluids through the porous coating layer. Additionally, the polymeric binder can be included in an appropriate amount so that the silica particles are bound together and so that sufficient void space remains between the silica particles for wicking fluid. Thus, the polymeric binder is not included in such a great amount that all of the spaces between the silica particles are filled in by the polymeric binder.
  • the silica particles in the porous coating layer are also surface-activated by a surface-activating agent.
  • the surface-activating agent can include aluminum chloride hydrate, a trivalent metal oxide, a tetravalent metal oxide, or a combination thereof.
  • the activated surfaces of the silica particles can be further functionalized with organosilane compounds.
  • fluid-wicking membranes can include a single, uniform porous coating layer on a substrate.
  • the porous coating layer can be made up of multiple sublayers.
  • the multiple sublayers can have different compositions.
  • FIG.2 shows one example fluid-wicking membrane 100 that includes two sublayers. A bottom sublayer 122 is applied to the substrate and a top sublayer 124 is applied over the bottom sublayer.
  • Both of the sublayers can include silica particles and a polymeric binder.
  • the compositions of the sublayers can differ one from another.
  • differences between the sublayers can include the type of silica particles, particle size of the silica particles, functional groups on surfaces of the silica particles, type of polymeric binder, amount of polymeric binder relative to the silica particles, and so on.
  • the particle size of the silica particles can be different in the individual sublayers. Varying the particle size can be used to adjust the pore size in the sublayers, and thereby the rate at which fluids can flow through the pores can be adjusted. Additionally, using more or less polymeric binder can also affect the rate at which fluids flow through the sublayers.
  • the silica particle size and the concentration of polymeric binder can be carried independently between the sublayers.
  • the bottom sublayer can have a larger silica particle size and a lower concentration of polymeric binder compared to the top sublayer. This can form a fluid-wicking membrane in which fluid flows more quickly through the bottom sublayer than through the top sublayer.
  • the bottom sublayer can have a smaller silica particle size and a higher concentration of polymeric binder compared to the top sublayer. This can form a fluid-wicking membrane in which fluid flows more quickly through the top layer than through the bottom sublayer.
  • the concentration of polymeric binder can be in terms of wt% with respect to the total weight of the sublayer.
  • FIG.3 shows another example fluid-wicking membrane 100 that includes a porous coating layer 120 on a substrate 110, where the porous coating layer is made up of three sublayers 122, 124, 126.
  • the individual sublayers can have different compositions as explained above.
  • the individual sublayers can have different silica particle sizes, different concentrations of polymeric binder, or both.
  • the silica particle size can increase from the top sublayer 124 to the middle sublayer 126 and from the middle sublayer to the bottom sublayer 122.
  • the concentration of polymeric binder can decrease from the top sublayer to the middle sublayer and from the middle sublayer to the bottom sublayer.
  • the silica particle size can decrease from the top sublayer to the middle sublayer and from the middle sublayer to the bottom sublayer.
  • the concentration of polymeric binder can also increase from the top sublayer to the middle sublayer and from the middle sublayer to the bottom sublayer.
  • the average pore size of pores in the porous coating layer can be sufficient to allow liquids to flow through the pores. In particular, liquid can wick through the pores by capillary action.
  • the porous coating layer can have an average pore size from 50 nm to 30 ⁇ m. In further examples, the average pore size can be from 200 nm to 15 ⁇ m or from 1 ⁇ m to 10 ⁇ m or from 5 ⁇ m to 8 ⁇ m.
  • the average pore size can be approximately one fourth of the average particle size of the silica particles.
  • the overall volume fraction of the pores, with respect to the total geometric volume of the porous coating layer can be from 20% to 60%, or from 25% to 48%, or from 30% to 45%, in various examples.
  • the average pore size can be measured using a standard measurement technique, such as mercury intrusion porosimetry, gas adsorption porosimetry, capillary flow porometry, and so on.
  • the silica particles in the porous coating layer can have an average particle size from greater than 1 ⁇ m to 50 ⁇ m.
  • the average particle size can be from 2 ⁇ m to 40 ⁇ m or from 3 ⁇ m to 30 ⁇ m or from 5 ⁇ m to 20 ⁇ m.
  • the average particle size can be based on volume of the particle size normalized to a spherical shape for diameter measurement, for example.
  • Particle size can be collected using a Malvern ZETASIZERTM system (Malvern Panalytical, United Kingdom), for example. Particle size information can also be determined and/or verified using a scanning electron microscope (SEM).
  • SEM scanning electron microscope
  • the polymeric binder can be included in the porous coating layer in an amount from 0.5 wt% to 20 wt% with respect to the total dry weight of the porous coating layer.
  • the concentration of polymeric binder can be from 1 wt% to 18 wt%, or from 2 wt% to 15 wt%, or from 3 wt% to 10 wt%.
  • the concentration of polymeric binder and the particle size of the silica particles in the porous coating layer can also influence the capillary flow time (CFT) of the membrane.
  • CFT capillary flow time
  • the CFT is defined as the time for a water front to traverse a distance of 4 cm across the membrane. Attaching various functional groups to the surfaces of the silica particles can also affect the CFT in some examples.
  • the fluid-wicking membrane can have a CFT from 75 seconds to 500 seconds. In further examples, the fluid-wicking membrane can have a CFT from 100 seconds to 400 seconds or from 200 seconds to 400 seconds.
  • a variety of polymeric binders can be included in the porous coating layer.
  • the polymeric binder can include polyvinyl alcohol or poly(vinylpolypyrrolidine).
  • the binder can be crosslinked.
  • crosslinking agents such as boric acid, citric acid, dianhydrides, glutaraldehyde, glyoxal, maleic acid, sodium hexametaphosphate, succinic acid, sulfosuccinic acid, or trisodium trimetaphosphate can be added to crosslink the binder.
  • the silica particles used in the porous coating layer can initially be colloidal silica particles (i.e., silica particles suspended in a liquid).
  • the silica particles can be prepared as a suspension in an aqueous liquid.
  • the silica particles can be fumed silica particles, precipitated silica particles, silica gel particles, or combinations thereof.
  • the silica particles can be precipitated silica particles.
  • Specific examples of silica particles that can be used include CAB-O-SIL® M-5, CAB-O-SIL® H-5, CAB-O-SIL® LM-150, and CAB-O-SIL® EH-5 from Cabot Corporation (USA); ACEMATT® 82, ACEMATT® HK 125, ACEMATT® HK 400, ACEMATT® HK 440, ACEMATT® HK 450, ACEMATT® 790, ACEMATT® 810, ACEMATT® 3600, ACEMATT® OK 412, ACEMATT® OK 500, and ACEMATT® OK 520 from Evonik (Germany).
  • the silica particles can have a surface area from 0.045 m 2 /g to 120 m 2 /g. In further examples, the surface area can be from 100 m 2 /g to 500 m 2 /g or 160 m 2 /g to 300 m 2 /g or from 300 m 2 /g to 400 m 2 /g.
  • the silica particles can be surface-activated by a surface-activating agent such as aluminum chloride hydrate, a trivalent metal oxide, a tetravalent metal oxide, or a combination thereof. In some examples, the surface-activating agent can be added when formulating an aqueous dispersion of the silica particles.
  • Silica particles can be attached to surfaces of the silica particles, either while the silica particles are in the dispersion or after the porous coating layer has been formed.
  • Surface-activated refers to the surface of silica after being treated with an inorganic surface-activating agent, such as aluminum chloride hydrate and/or a multivalent metal oxide, in a sufficient amount to modify the net charge of the surface from negative ( ⁇ ) to positive (+). This is not to say that all negatively charged moieties are converted to positive, but that the net charge of the entire surface is positive.
  • Al n (OH) m Cl (3n-m) Al n (OH) m Cl (3n-m) , wherein n can be from 1 to 50, and m can be from 1 to 150.
  • Basicity can be defined by the term m/(3n) in that equation.
  • ACH can be supplied as a solution, but can also be supplied as a solid. [0026] There can be other ways of referring to ACH. Typically, ACH includes many different molecular sizes and configurations in a single mixture.
  • An example stable ionic species in ACH can have the formula [Al 12 (OH) 24 AlO 4 (H 2 O) 12 ] 7+ .
  • the composition can include aluminum chlorides and aluminum nitrates of the formula Al(OH) 2X to Al 3 (OH) 8X , where X is Cl or NO 3 .
  • the composition can be prepared by contacting silica particles with an aluminum chlorohydrate Al 2 (OH) 5 Cl or Al 2 (OH)Cl 5 .nH2O. It is believed that contacting a silica particle with an aluminum compound as described above causes the aluminum compound to become associated with or bind to the surface of the silica particles. This can be either by covalent association or through an electrostatic interaction to form a cationic charged silica, which can be measured by a Zeta potential instrument.
  • Trivalent or tetravalent metal oxide or “multivalent metal oxide” refers to compositions that can be used in conjunction with, or instead of, ACH to reverse the charge of a silica surface from negative ( ⁇ ) to positive (+). Specifically, the negative charge on silica can be reversed by adsorbing an excess of positively charged polyvalent metal oxide on the surface.
  • Coatings can include oxides of trivalent and tetravalent metals such as aluminum, chromium, gallium, titanium, and zirconium.
  • acidified silica can be mixed with a basic metal salt (such as Al 2 O 3 ) to substantially cover the surface of silica particulates.
  • the silica can carry a positive charge instead of a negative charge at below a pH of 7.
  • the surface-activating agent can be aluminum chloride hydrate.
  • the surface-activating agent can be a trivalent or tetravalent metal oxide, with metals such as aluminum, chromium, gallium, titanium, and zirconium. If, for example, aluminum chloride hydrate is used, it can be present in an amount from 2 wt % to 20 wt % compared to the silica content, and in another example, the aluminum chloride hydrate can be present at from 5 wt % to 10 wt %.
  • silica typically includes Si—OH groups at the surface of the individual particulates, which can act as a weak acid, liberating hydrogen and becoming ionized at a pH above about 2. As the pH is raised, the surface of the silica becomes more negative. The addition of aluminum chloride hydrate to silica causes the surface of the silica to become more positive. If enough aluminum chloride hydrate is added, then the net charge of the silica particulates becomes positive.
  • the process of surface-activating the silica particles can include increasing the density of Si-OH groups present at the surface of the silica particles prior to adding the surface-activating agent.
  • the silica particles can be treated with nitric acid, hydrogen peroxide, and ammonium hydroxide to increase the density of Si-OH groups at the surface. The silica particles can then be treated with the surface-activating agents described above.
  • organosilanes can also be attached to the surfaces of the silica particles through the Si-OH groups on the surfaces of the silica particles.
  • a variety of organic functional groups can be attached to the surfaces of the silica particles by reacting organosilanes with the silica particles.
  • organosilane reagents can be added to the surface-activated silica to add additional positively charged moieties to the surface, or to provide another desired function at or near the surface, such as hydrophobic groups, hydrophilic groups, passivating groups, reactive groups, test reactants, control reactants, and others.
  • the fluid-wicking membrane can be designed to be used for an assay such as a lateral flow assay, and the organosilanes can include an organic group that is non-reactive with a target compound that is to be detected by the lateral flow assay.
  • this type of assay is used to detect biological molecules such as proteins. In such cases, it can be useful to render the fluid-wicking membrane non-reactive with the target biological molecules so that the target molecules do not non-specifically bind to the membrane.
  • These assays can include a test line where a test reactant is present, and the test reactant can be selected to bind with the target molecule.
  • organosilanes that can be attached to the silica particles can include hydrophobic groups, hydrophilic groups, zwitterionic groups, polar aprotic groups, primary amine groups, carboxylic acid groups, or combinations thereof.
  • passivating organosilanes that can be attached to the silica particles can include mPEG-silane with a number average molecular weight Mn from 300 Mn to 5,000 Mn, or mPEG-propionic acid with a number average molecular weight Mn from 300 Mn to 5,000 Mn.
  • the organosilanes can include functional groups that can participate in a condensation reaction to link to additional molecules.
  • condensation reagent groups can include primary amines, thiols, and carboxylic acids.
  • the organosilane reagents can be amine-containing silanes.
  • the amine-containing silanes can include quaternary ammonium salts.
  • amine-containing silanes include 3-aminopropyltrimethoxysilane, N-(2-aminoethyl-3-aminopropyltrimethoxysilane, 3-(triethoxysilylpropyl)-diethylenetriamine, poly(ethyleneimine)trimethoxysilane, aminoethylaminopropyl trimethoxysilane, aminoethylaminoethylaminopropyl trimethoxysilane, N-aminoethyl-3-aminopropylmethyldimethoxysilane, N-(2-aminoethyl)-11-aminoundecyltrimethoxysilane, aminophenyltrimethoxysilane, and the quaternary ammonium salts of the amine coupling agents mentioned above.
  • organosilane reagent includes trimethoxysilylpropyl-N,N,N-trimethylammonium chloride.
  • organosilanes can include , triethoxysilylundecanal, 3-(triethoxysilylpropyl)-p-nitrobenzamide, 3-cyanopropyltrimethoxysilane, bis(2-hydroethyl)-3-aminopropyltriethoxysilane, 3-mercaptopropyltrimethoxysilane, 3-glycidoxypropyltrimethoxysilane, bis(triethoxysilylpropyl)disulfide, 3-aminopropyltriethoxysilane, 3-aminopropylsilsesquioxane, bis-(trimethoxysilylpropyl)amine, N-phenyl-3-aminopropyltrimethoxysilane,
  • the amount of organosilane included in the porous coating layer can vary depending on the type of organosilanes, the degree of functionalization of the silica particles with the organosilanes, and the size of the silica particles.
  • the organosilane can be present in an amount from 0.05 wt% to 3 wt%, or from 0.1 wt% to 1.5 wt%, or from 0.5 wt% to 1 wt%, with respect to the total weight of the porous coating layer.
  • Several processes may be used to treat the silica particles with the surface-activing agent and the organosilanes.
  • a surface-activating agent can be added to water prior to the silica, and then the silica can be added portion-wise over a period of time.
  • the silica can be dispersed in water first, and then the inorganic surface activating agent can be added to the silica dispersion.
  • the surface-activating agent can be added all at once, or portion-wise, depending on the desired result.
  • both the silica and the surface-activating agent can be added to water simultaneously.
  • the net surface charge of the silica can be converted from negative ( ⁇ ) to positive (+). This does not mean that every negatively charged moiety is converted from negative to positive, but that the surface charge as a whole becomes more positive than negative.
  • the organosilane reagent can then be added, though this order of addition is not limiting.
  • an organosilane reagent can be added to the surface-activating agent treated silica portion-wise.
  • Such an addition scheme can prevent flocculation of the silica.
  • the pH can be controlled to maintain the colloidal stability of the silica dispersion.
  • the ACH and the organosilane reagent can be added simultaneously to a silica dispersion. In these reaction schemes, little or no organic solvent may be used.
  • the aqueous environment can include a predominant amount of water, and may include small amounts of organic solvent, surfactant, crosslinking agent such as boric acid, etc.
  • the polymeric binders described above can also be added to the aqueous dispersion to form a coating composition that can be applied to a substrate to form the porous coating layers described herein.
  • the coating composition can be prepared without an organosilane reagent. This coating composition can be applied to a substrate to form a membrane, and then organosilane reagents can be applied to the membrane later. This can be useful if different organosilanes are desired in different areas of the membrane.
  • a lateral flow assay or vertical flow assay can include test reactants in certain areas of the membrane.
  • the test reagents can be organosilane reagents that can bond to the silica particles.
  • an organosilane linker can be used, which is capable of bonding to the silica particles in the membrane and also bonding with a test reactant.
  • the specific organosilanes desired can be applied in a certain area of the membrane, to form a test line or test spot, for example.
  • a passivating organosilane reagent can be applied to the remainder of the membrane. Different organosilane reagents can be applied to different areas of the membrane using a variety of application processes.
  • the coating composition used to form the porous coating layer can also include an acid or a base in some examples, to adjust the pH of the composition.
  • the pH can be from 3 to 9.
  • the coating composition can include a weak acid or a weak base in an amount from 0.1 wt% to 5 wt%, based on the weight of dry ingredients in the coating composition.
  • a modified silica dispersion can be prepared first, and then the modified silica dispersion can be included in the coating composition for forming the porous coating layer.
  • the modified silica dispersion can include silica particles in an amount from 70 parts by weight to 100 parts by weight, aluminum chlorohydrate in an amount from 1 part by weight to 20 parts by weight, organosilane in an amount from 0.1 part by weight to 10 parts by weight, and a weak acid in an amount from 1 part by weight to 5 parts by weight.
  • the modified silica dispersion can also include a sufficient amount of water to bring the total solid content to 15 wt% to 35 wt%.
  • the modified silica dispersion can be combined with additional ingredients to form the coating composition.
  • the coating composition can include the modified silica dispersion in an amount from 70 parts by dry weight to 100 parts by dry weight, crosslinker in an amount from 1 part by dry weight to 5 parts by dry weight, a polymeric binder in an amount from 10 parts by dry weight to 20 parts by dry weight, humectant in an amount from 1 part by dry weight to 5 parts by dry weight, and surfactant and/or other additives in an amount from 0.1 part by dry weight to 5 parts by dry weight.
  • a sufficient amount of water can be added to bring the total solid content of the coating composition to 15 wt% to 35 wt%.
  • the coating composition can be applied to a substrate and dried to form a fluid-wicking membrane.
  • the substrates used in the fluid-wicking membranes described herein can include a variety of materials.
  • the substrate can be non-porous.
  • Non-porous membranes can be useful in applications where fluid is to flow along the surface of the membrane without penetrating through the membrane. These can be used in lateral flow assays, for example.
  • Non-limiting examples of non-porous substrates can include polymeric films such as polyethylene film, rigid substrates such as glass, poly(methy methacrylate), and others.
  • porous substrates can be used. Porous substrates can be particularly useful when fluid is to penetrate through the membrane. This type of membrane can be used in vertical flow assays, for example.
  • Non-limiting examples of porous substrates can include paper, nonwoven fabric, woven fabric, nitrocellulose, pads including glass and polymeric fibers, among others.
  • the coating compositions described above can be applied to the substrate using a variety of coating processes, such as curtain coating, air knife coating, blade coating, gate roll coating, doctor blade coating, Meyer rod coating, roller coating, reverse roller coating, gravure coating, brush coating, spray coating, and so on.
  • the coating can have a thickness, when dry, from 1 ⁇ m to 300 ⁇ m, or from 5 ⁇ m to 200 ⁇ m, or from 10 ⁇ m to 200 ⁇ m.
  • the coating process can provide a coating layer with good uniformity of coating thickness.
  • the coating thickness can be more uniform than is typical for nitrocellulose membranes.
  • the pore size and pore distribution can also be very uniform because the coating can include a homogeneous distribution of the silica particles and polymeric binder throughout the coating layer.
  • the coating thickness, pore size, and/or pore distribution can be uniform within a tolerance of 10% of the average value across the coating layer.
  • FIG.4 is a flowchart illustrating one example method 200 of making a fluid-wicking membrane.
  • This method includes: coating a substrate with a coating composition including a dispersion of silica particles having an average particle size from greater than 1 ⁇ m to 50 ⁇ m, a surface-activating agent activating surfaces of the silica particles, wherein the surface-activating agent includes aluminum chloride hydrate, a trivalent metal oxide, a tetravalent metal oxide, or a combination thereof, and a polymeric binder 210; and drying the coating composition to form a porous coating layer over the substrate 220.
  • any of the coating processes described above can be used. In certain examples, a curtain coating process can be used.
  • curtain coating can be particularly useful in some examples that include multiple layers of different coating compositions applied to a single substrate.
  • multiple different coating compositions can be applied to a substrate to form multiple porous coating layers with different properties, such as porosity, pore size, capillary flow time, surface energy, and so on.
  • a curtain coater can apply multiple coating compositions simultaneously with good control over the thickness of the individual coatings.
  • a method of making a fluid-wicking membrane with multiple sub-layers in the porous coating layer can include applying a first coating composition to form a bottom sublayer and a second coating composition to form a top sublayer. The properties of the sublayers can be adjusted in several ways.
  • the particle size of silica particles in the coating sublayers can be adjusted so that the individual sublayers have different silica particle sizes.
  • the concentration of polymeric binder in the sublayers can also be adjusted.
  • the bottom sublayer can have a larger silica particle size and a smaller polymeric binder concentration compared to the top sublayer.
  • the bottom sublayer can have a smaller silica particle size and a larger polymeric binder concentration compared to the top sublayer.
  • three sublayers can be applied using three different coating compositions.
  • the silica particle size can decrease from the top sublayer to the bottom sublayer and the polymeric binder concentration can increase from the top sublayer to the bottom sublayer.
  • the silica particle size can increase from the top sublayer to the bottom sublayer and the polymeric binder concentration can decrease from the top sublayer to the bottom sublayer.
  • Flow Assay Membranes [0044] The present disclosure also describes flow assay membranes that can be made using the fluid-wicking membranes described above.
  • the flow assay membranes can include a test reactant in an area of the membrane.
  • the test reactant can be a reactant that is reactive with a particular target molecule that the assay is designed to detect.
  • a reaction between the target molecule and the test reactant can be detected in a variety of ways, such as by a visible color change, a change in fluorescence, or others.
  • the test reactant can bond selectively with the target molecule.
  • the test reactant can also be bonded to the membrane surface, for example by bonding to a linking group on an organosilane attached to the surface of a silica particle in the porous coating layer.
  • the test reactant can include an antibody, an aptamer, a peptide, a DNA segment, an RNA segment, and others.
  • the flow assay membrane can be used in a lateral flow assay. Lateral flow assays often include a test reactant forming a test line on the membrane. A sample fluid can be wicked through the membrane until the sample fluid contacts the test line.
  • the target molecule can bind to the test line and produce a visible color change at the test line.
  • the visible color change is achieved by mixing the sample fluid with a conjugate reactant that bonds with the target molecule and which has a visible color, so that the visible color can intensify as target molecules and bonded conjugate reactants accumulate at the test line.
  • Lateral flow assays can also include a control line on the membrane, positioned beyond the test line. The control line can produce a visible color change when the sample fluid reaches the control line, to verify that the sample fluid flowed a sufficient distance through the membrane for a valid test.
  • the substrate in the lateral flow assay membrane can be a non-porous substrate.
  • FIG.5 shows an example lateral flow assay membrane 300.
  • the membrane includes a substrate 110, a porous coating layer 120, a test line 330, and a control line 340.
  • the substrate is a non-porous substrate.
  • the lateral flow assay membrane can be combined with additional components to make a full lateral flow assay test. Additional components can include a housing, a sample pad, a conjugate pad, an absorber pad, and others.
  • the flow assay membrane can be a vertical flow assay membrane.
  • Vertical flow assays often include a wicking pad beneath the membrane.
  • a sample fluid can be applied on the top of the membrane, and the sample fluid can wick through the membrane to the wicking pad.
  • the membrane can be porous throughout the thickness of the membrane to allow the sample fluid to penetrate through the membrane. Therefore, in these examples the substrate of the fluid-wicking membrane can be a porous substrate.
  • target molecules can bond to a test reactant located in a test region on the membrane.
  • a label fluid can be applied after the sample fluid.
  • the label fluid can include a label reactant that can bond to the target molecules that have been immobilized in the test region of the membrane, producing a visible color change at the test region.
  • vertical flow assay membranes can include a porous coating layer made up of multiple sublayers.
  • the sublayers can have different properties as described above.
  • the porous coating layer can include a top sublayer that has a smaller average silica particle size and a bottom sublayer that has a larger average silica particle size.
  • the bottom sublayer can have a larger average pore size and a shorter capillary flow time so that sample fluid can be drawn down into the bottom sublayer.
  • the capillary flow time of the top sublayer can be longer to allow more time for target molecules in the sample fluid to bond to the test reactants, which can be present on the top surface of the membrane.
  • FIG.6 shows an example vertical flow assay membrane 400.
  • the membrane includes a porous substrate 110 with a porous coating layer 120 applied thereon.
  • the porous coating layer includes a bottom sublayer 122 and a top sublayer 124.
  • a test reactant is applied to the top sublayer in a test area 430.
  • the individual silica particles 128 are shown in this figure, represented as circles.
  • the bottom sublayer includes silica particles having a larger average particle size compared to the silica particles in the top sublayer.
  • the larger silica particles leave larger spaces between the particles, which can allow for faster flow of fluid through the bottom sublayer.
  • a sample fluid can flow more slowly through the top sublayer so that target molecules in the sample fluid can have more time to react with test reactants in the test area.
  • additional components can be added to make a complete vertical flow assay.
  • additional components can include a housing, wicking pad, and other components.
  • the wicking pad can be omitted because the vertical flow assay membrane described herein can operate without a wicking pad.
  • the porous substrate and bottom sublayer having a larger pore size can be sufficient to cause sample fluid to wick through the top sublayer of the membrane.
  • a vertical flow assay membrane as shown in FIG.6 can be incorporated in a vertical flow assay.
  • the test reactant can be a capture antibody that is immobilized on the top sublayer of the porous coating layer of the membrane.
  • capture antibodies can be immobilized by linking the antibodies to organosilanes that are bonded to the surface of the silica particles in the porous coating layer.
  • the membrane can be placed in a housing and stored at appropriate conditions to avoid contamination or rehydration of the antibodies.
  • the vertical flow assay can be used to perform a test by introducing a sample fluid onto the membrane.
  • the sample fluid can include an antigen (the target molecule) that will bind to the capture antibodies.
  • the top layer of the porous coating layer having a small pore size, can act as a filter for the sample fluid.
  • the antigen in the sample fluid can come into contact with the capture antibodies in the top sublayer.
  • the antigens can then bind with the capture antibodies.
  • washing and blocking of the membrane can be performed after the sample fluid has been applied to the membrane.
  • a gold conjugated antibody label reactant
  • the gold conjugated antibody can bind to the antigens that were captured by the capture antibody, producing a visible color change in the test area.
  • multiple different test reactants such as multiple different antibodies, can be immobilized in different areas of the membrane to allow for multiplexing.
  • different organosilanes can be attached to silica particles in different sublayers of the porous coating layer to provide different chemical reactivity in the individual sublayers.
  • particle size with respect to the silica particles, or any other particles can be based on volume of the particle size normalized to a spherical shape for diameter measurement, for example.
  • Particle size can be collected using a Malvern ZETASIZERTM system (Malvern Panalytical, United Kingdom), for example. Particle size information can also be determined and/or verified using a scanning electron microscope (SEM).
  • the term “about” is used to provide flexibility to a numerical range endpoint by providing that a given value may be “a little above” or “a little below” the endpoint. The degree of flexibility of this term can be dictated by the particular variable based on experience and the associated description herein.
  • a plurality of items, structural elements, compositional elements, and/or materials may be presented in a common list for convenience. However, these lists should be construed as though individual members of the list are individually identified as a separate and unique member. Thus, no individual member of such list should be construed as a de facto equivalent of any other member of the same list solely based on their presentation in a common group without indications to the contrary.
  • a weight ratio range of about 1 wt% to about 20 wt% should be interpreted to include the explicitly recited limits of about 1 wt% and about 20 wt%, but also to include individual weights such as 2 wt%, 11 wt%, 14 wt%, and sub-ranges such as 10 wt% to 20 wt%, 5 wt% to 15 wt%, etc.
  • Example 1 – Modified Silica Dispersion An example modified silica dispersion was prepared from the following ingredients: 3 parts by dry weight of aluminum chlorohydrate (surface-activating agent), 9 parts by dry weight of an organosilane, 1.25 parts by dry weight of a weak acid, 100 parts by dry weight of ACEMATT® OK 412 silica particles from Evonik (Germany), and a sufficient amount of deionized water to provide a solid content of 25 wt% in the dispersion.
  • surface-activating agent 9 parts by dry weight of an organosilane
  • 1.25 parts by dry weight of a weak acid 100 parts by dry weight of ACEMATT® OK 412 silica particles from Evonik (Germany)
  • ACEMATT® OK 412 silica particles from Evonik (Germany)
  • a sufficient amount of deionized water to provide a solid content of 25 wt% in the dispersion.
  • the modified silica dispersion had a pH of 4.54, a zeta potential of 5.75 mV, and a viscosity 406.8 cP.
  • Example 2 – Coating Composition An example coating composition was prepared using the modified silica dispersion from Example 1. The coating composition included the following ingredients: 100 parts by dry weight of the modified silica dispersion of Example 1, 2.5 parts by dry weight of a crosslinker, 14.2 parts by dry weight of a polymeric binder, 1 part by dry weight of polyethylene glycol (humectant), and 0.5 part by dry weight of a surfactant. The coating composition had a solid content of 22 wt%, a pH of 4.54, and viscosity of 774 cP.
  • This coating composition may be coated onto a substrate to make a fluid-wicking membrane as described above.

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Abstract

La présente invention concerne des membranes à effet de mèche de fluide, des procédés de fabrication de membranes à effet de mèche de fluide, et des membranes de dosage d'écoulement. Dans un exemple, une membrane à effet de mèche de fluide peut comprendre un substrat et une couche de revêtement poreuse sur le substrat. La couche de revêtement poreuse peut comprendre des particules de silice liées ensemble par un liant polymère. Les particules de silice peuvent avoir une taille moyenne de particule de plus de 1 pm à 50 pm. La couche de revêtement poreuse peut également comprendre un agent d'activation de surface activant des surfaces des particules de silice. L'agent d'activation de surface peut comprendre un hydrate de chlorure d'aluminium, un oxyde métallique trivalent, un oxyde métallique tétravalent, ou une combinaison de ceux-ci.
PCT/US2020/054523 2020-10-07 2020-10-07 Membranes à effet de mèche de fluide WO2022075981A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002099139A1 (fr) * 2001-06-04 2002-12-12 Cuno, Incorporated Membrane microporeuse modifiee pour capture d'acide nucleique non specifique, et specifique d'une sequence, et procedes d'utilisation
US20110117540A1 (en) * 2008-05-05 2011-05-19 Los Alamos National Laboratory Highly Simplified Lateral Flow-Based Nucleic Acid Sample Preparation and Passive Fluid Flow Control
EP2604331A1 (fr) * 2011-12-15 2013-06-19 Gambro Lundia AB Membranes dopées

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002099139A1 (fr) * 2001-06-04 2002-12-12 Cuno, Incorporated Membrane microporeuse modifiee pour capture d'acide nucleique non specifique, et specifique d'une sequence, et procedes d'utilisation
US20110117540A1 (en) * 2008-05-05 2011-05-19 Los Alamos National Laboratory Highly Simplified Lateral Flow-Based Nucleic Acid Sample Preparation and Passive Fluid Flow Control
EP2604331A1 (fr) * 2011-12-15 2013-06-19 Gambro Lundia AB Membranes dopées

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