WO2004011672A1 - Capteur en film a nanostructure poreuse - Google Patents
Capteur en film a nanostructure poreuse Download PDFInfo
- Publication number
- WO2004011672A1 WO2004011672A1 PCT/IE2003/000106 IE0300106W WO2004011672A1 WO 2004011672 A1 WO2004011672 A1 WO 2004011672A1 IE 0300106 W IE0300106 W IE 0300106W WO 2004011672 A1 WO2004011672 A1 WO 2004011672A1
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- WO
- WIPO (PCT)
- Prior art keywords
- film
- sensing element
- porous nanostructured
- immobilised
- size
- Prior art date
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Classifications
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- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D67/00—Processes specially adapted for manufacturing semi-permeable membranes for separation processes or apparatus
- B01D67/0081—After-treatment of organic or inorganic membranes
- B01D67/0093—Chemical modification
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D67/00—Processes specially adapted for manufacturing semi-permeable membranes for separation processes or apparatus
- B01D67/0039—Inorganic membrane manufacture
- B01D67/0041—Inorganic membrane manufacture by agglomeration of particles in the dry state
- B01D67/00411—Inorganic membrane manufacture by agglomeration of particles in the dry state by sintering
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- 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
- B01D69/02—Semi-permeable membranes for separation processes or apparatus characterised by their form, structure or properties; Manufacturing processes specially adapted therefor characterised by their properties
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- 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
- B01D69/14—Dynamic membranes
- B01D69/141—Heterogeneous membranes, e.g. containing dispersed material; Mixed matrix membranes
- B01D69/1411—Heterogeneous membranes, e.g. containing dispersed material; Mixed matrix membranes containing dispersed material in a continuous matrix
- B01D69/14111—Heterogeneous membranes, e.g. containing dispersed material; Mixed matrix membranes containing dispersed material in a continuous matrix with nanoscale dispersed material, e.g. nanoparticles
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- 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
- B01D71/024—Oxides
- B01D71/0271—Perovskites
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
- C12Q1/001—Enzyme electrodes
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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
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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
- G01N33/54353—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals with ligand attached to the carrier via a chemical coupling agent
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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
- G01N33/54373—Apparatus specially adapted for solid-phase testing involving physiochemical end-point determination, e.g. wave-guides, FETS, gratings
- G01N33/5438—Electrodes
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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
- G01N33/551—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals the carrier being inorganic
- G01N33/553—Metal or metal coated
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
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- B01D2325/02—Details relating to pores or porosity of the membranes
- B01D2325/0283—Pore size
Definitions
- the invention relates to a porous nanostructured film having a sensing element and/or a signal detection element immobilised thereon having a signal transduction capability, sensors comprising such films and methods for preparing such films.
- a complementary receptor molecule Such a pair of molecules might comprise two complementary strands of nucleic acids, an enzyme substrate pair or an antigen and its specific antibody.
- a signal In order to detect the sensor's measurement, a signal must be generated and transduced by passing it to a circuit where it can be digitised. The digital information can then be stored in memory, displayed visually or made accessible via a digital communications port. Signal generation may be achieved electrochemically, (electrochemical sensors), optically by measuring changes in absorbance or luminescence (optical sensors) or by plasmon resonance.
- Luminescence methods such as fluorescence and chemiluminescence are currently popular. Luminescent detection relies on a marker in the form of fluorescent dye markers, chemiluminescent systems or fluorescent semiconductor nanoparticles.
- the marker is associated with the molecular recognition pair or targeted to the pair, which either directly gives off light, gives off light when an external stimulus is applied or catalyses a chemical reaction that produces light.
- the amount of light given out from a sensor is proportional to the amount of analyte present in a given sample.
- the detection means rely on light emission for assay quantification and are capable of extremely high sensitivity assays. In order to detect and quantify this light output a photodiode, photomultiplier tube, charge coupled device (CCD) camera or complementary metal oxide semiconductor (CMOS) image sensor may be used. Most commonly, quantification of the light emission is carried out using a photodiode, photomultiplier tube, charge coupled device (CCD) camera or complementary metal oxide semiconductor (CMOS) image sensor may be used. Most commonly, quantification of the light emission is carried out using a
- CCD camera or photomultiplier tube For applications such as biochip applications, where a number of light signals are detected simultaneously, a CCD device is typically used. While the CCD camera can be quite small, it can require cooling and this adds to the bulk of the sensor apparatus. There is currently an intense effort towards the miniaturisation and simplification of the reader element of sensors. Notably Motorola have developed an electrochemical method of detecting hybridisation between complementary DNA fragments which can be miniaturised to palm-top dimensions and requires no moving parts. This electrochemical method works through self assembled molecular wires on a gold electrode that are capable of detecting hybridisation events (1).
- a silicon photodiode is used to immobilise conducting polymer strands with associated molecular recognition moieties and redox active molecules. When molecular recognition occurs, the redox active molecules send a signal through the conducting polymer strand.
- the photoactive properties of the diode are not used to detect luminescence in this application, the diode being used to simplify the electronic configuration of the sensor.
- Dye sensitised solar cells are currently a research area of great interest (4,5). These cells work by sensitising a nanostructured, wide band-gap semiconductor with a molecular dye. When light hits the dye and a photon is absorbed, the dye is elevated to an excited state. When this excited state decays an electron is injected into the semiconductor creating an electrical current.
- the absorbtion characteristics of the dye determine which wavelengths of light the film will be most sensitive, i.e. if the absorbtion maximum of the dye is at 500 nm it will give a higher current efficiency here than at other wavelengths.
- nanostructured film employed in such solar cells is usually titanium dioxide (TiO 2 ). This material can be made into a nanostructured film by formulating
- TiO 2 nanoparticles in a suitable solvent with a polymer binder and depositing the TiO 2 nanoparticles using either a simple screen-printing or doctor-blading method. Sintering at elevated temperatures leads to the particles fusing and the binder being burned out to leave a porous network.
- this type of nanostructured film has also been used to immobilise proteins for biosensor applications (6,7). It has been demonstrated that the mesoporous nature of these films allows for immobilisation of proteins in quantities significantly greater than on a flat surface. Biochemical devices which utilise nanostructured titania films, comprising fused titania particles are described.
- biosensors based on these nanostructured films are stated to be: high biomolecule loading, optical transparency, stability and electrical conductivity as well as the possibility of immobilising proteins under mild conditions, so preserving the functionality of the protein.
- the high capacity for biomolecules is due to the high surface area to geometric area of the nanostructured film. However, due to small pore sizes (ca 15nm) this high surface area is not available to large proteins such as antibodies.
- Templating titania around latex spheres forming hollow titania shells followed by removal of the latex has been described (8).
- the titania is formed by hydrolysis of a titanium alkoxide precursor in situ forming a smooth and well defined layer of titania on the polymer surface.
- Polystyrene microspheres have also been used to engineer porosity into thin (thickness of nm), dense silica films (9). The microspheres are removed using an organic solvent. Similarly others have prepared photonic materials by forming titania around a densely packed crystalline structure comprised of latex spheres (10). The ordered packing of the resultant pores imparted useful optical properties on the film, such as inhibition of spontaneous emission or photon localisation.
- a porous nanostructured film having a sensing element covalently immobilised thereon.
- the pore size is between 1 and 3000nm in size.
- the film has a bimodal pore distribution.
- the film comprises a combination of mesopores and macropores.
- the mesopores are between 1 and 50nm in size.
- the macropores are greater than 50nm in size.
- the macropores are greater than lOOnm in size.
- the macropores are between 500nm and lOOOnm in size.
- the macropores are between lOOOnm and 3000nm in size.
- the film has a loading capacity greater than 5 ⁇ g/cm 2 , preferably greater than 10 ⁇ g/cm 2 , most preferably greater than 20 ⁇ g/cm 2 .
- the film is of a metal oxide material.
- the metal oxide may be selected from any one or more of titanium, zirconium, hafnium, chromium, molybdenum, tungsten, vanadium, niobium, tantalum, silver, zinc, strontium, iron (Fe 2+ and Fe 3+ ), nickel and perovskites thereof, preferably WO 3 , M0O 3 , ZnO or SNO 2 . Most preferably the metal oxide is TiO 2 .
- the sensing element is selected from any one or more of an antibody; IgG. IgM, IgA, IgD, IgE antibody fragment; Fab, F(ab)'2, Fv, Fc receptors, drug receptors, ligands, enzymes, substrates, aptamers, affibodiesTM , affinity binding agents, proteins, cell or tissue samples, cells, antigen or DNA.
- an oligonucleotide probe bacteria, fibrin binding protein, EGF receptor, collagenase, plasminogen, vitamin K, somatostatin receptors,
- the porous nanostructured film has a sensing element and a signal detection element immobilised thereon.
- the sensing element and signal detection element are distributed throughout the film.
- At least one portion of the film has a sensing element and at least one portion of the film has a signal detection element immobilised thereon.
- the signal detection element is immobilised by covalent binding, chemisorption or physisorption, most pre erably by covalent binding.
- the signal detection element comprises a dye material.
- the dye material has the generic structure
- C is the chromophore, chemical entity capable of absorbing electromagnetic radiation in the desired region of the spectrum
- n 1 or more ;
- n >1 R may be the same or different.
- the dye material has an absorbance range of 300 to 700nm, most preferably an absorbance range of 350 to 550nm.
- the dye material may be selected from any one or more of coumarins, porphyrins, ruthenium complexes, Ru tris (bpy) derivatives, or any molecule with a chromophore attached.
- the dye is a porphyrin dye.
- the dye may be a porphyrin dye such as hematin. Most preferably the dye is Protoporphyrin IX.
- the invention also provides a method of preparing a film of the invention having a sensing element attached comprising the steps of:-
- the sensing element reacts directly with the functional silane.
- the invention also provides a method of preparing a film comprising attaching a sensing element to the film and subsequently attaching a signal detection element to the film in the spaces between the sensing element on the film.
- the invention provides a method of preparing a film comprising attaching a signal detection element to the film and subsequently attaching a sensing element to the signal detection element.
- the signal detection element may be a dye and the sensing element may be an antibody.
- the invention also provides a method of preparing a film of the invention having a sensing element and a signal detecting element attached comprising the steps of:-
- the functional silane has the general formula
- R is CH 3 , CH 2 CH 3 ;
- bifunctional or a polyfunctional cross linking reagent has the general formula
- X is -(CH 2 )n or an aromatic, and wherein n is 1 or more.
- the invention provides use of a porous nanostructured film of the invention in a bioassay, immunoassay, biocatalysis or any sensor that comprises a chemiluminescent reaction.
- the invention further provides a sensor for detecting an analyte comprising a substrate and a porous nanostructured film of the invention immobilised thereon.
- the substrate is selected from any one or more glass or metal or plastic having a conducting layer of indium tin oxide (ITO) or fluorine doped tin oxide (FTO) coated thereon.
- ITO indium tin oxide
- FTO fluorine doped tin oxide
- the senor has dual spectrophotometric and electrochemical measurement means.
- the invention also provides use of a sensor of the invention in a bioassay or immunoassay.
- the invention further provides a method of manufacturing a sensor of the invention comprising the steps of:-
- nanoparticles comprising a metal oxide with solvent and polymeric binder to form a printable paste
- the nanoparticles comprise single nanocrystallites and/or agglomerates of nanocrystallites.
- the nanoparticles are templated around spheres during deposition of the printable paste onto a conducting substrate, most preferably the nanoparticles are templated around polymer fibres, surfactants, starches, or other small molecules used in templating.
- the polymer spheres are removed during sintering.
- the printable paste is deposited onto a conducting substrate by screen printing, doctor-blading or ink-jetting.
- a porous nanostructured film having a signal detection element covalently immobilised thereon.
- the invention further provides a porous nanostructured film having a sensing element and a signal detection element immobilised thereon.
- the sensing element and signal detection element are distributed throughout the film. Most preferably at least one portion of the film has a sensing element and at least one portion of the film has a signal detection element immobilised thereon.
- the sensing element is immobilised by covalent binding, chemisorption or physisorption, preferably by covalent binding.
- the signal detection element is immobilised by covalent binding, chemisorption or physisorption, preferably by covalent binding.
- the signal detection element comprises a dye material.
- the dye material has the generic structure
- C is the chromophore, chemical entity capable of absorbing electromagnetic radiation in the desired region of the spectrum
- n 1 or more ;
- the dye has an absorbance range of 300 to 700nm. Most preferably the dye has an absorbance range of 350 to 550nm.
- the dye may be selected from any one or more of coumarins, porphyrins, ruthenium complexes, Ru tris (bpy) derivatives, or any molecule with a chromophore attached.
- the dye is a porphyrin dye, most preferably Protoporphyrin IX
- the invention further provides a porous nanostructured film having a sensing element covalently immobilised thereon.
- the pore size is between 1 and 3000nm in size.
- the film has a bimodal pore distribution.
- the film comprises a combination of mesopores and macropores.
- the mesopores are between 1 and 50nm in size and the macropores are greater than 50nm in size. Most preferably the macropores are greater than lOOnm in size.
- the macropores are between 500nm and lOOOnm in size.
- the macropores are between lOOOnm and 3000nm in size.
- the film is of a metal oxide material.
- the metal oxide may be selected from any one or more of titanium, zirconium, hafnium, chromium, molybdenum, tungsten, vanadium, niobium, tantalum, silver, zinc, strontium, iron (Fe 2+ and Fe 3+ ), nickel and perovskites thereof, preferably WO 3 , MoO 3 , ZnO or SNO 2 .
- the metal oxide is TiO 2 ,
- the sensing element may be selected from any one or more of an antibody; IgG, IgM, IgA, IgD, IgE, antibody fragment; Fab, F(ab)'2, Fv, Fc, receptors, drug receptors, ligands, enzymes, substrates, aptamers, affibodiesTM, affinity binding agents, proteins, cell or tissue samples, cells, antigen or DNA, including, oligonucleotide probe, bacteria, fibrin binding protein, EGF receptor, collagenase, plasminogen, vitamin K, somatostatin receptors, Monoamine oxidase, dopamine receptors, prostaglandin synthase or Hydroxy-methyl glutaryl (HMG)Co-A.
- the invention provides use of a porous nanostructured film of the invention in a bioassay, immunoassay, biocatalysis or any sensor that comprises a chemiluminescent reaction.
- the invention further provides a method of preparing a film of the invention having
- the invention also provides a method of preparing a film having a sensing element and a signal detecting element attached comprising the steps of:-
- the invention also provides a method of preparing a film having a sensing element attached comprising the steps of:-
- the sensing element reacts directly with the functional silane.
- the functional silane has the general formula
- R is CH 3 , CH 2 CH 3 ;
- R 1 is selected from any one or more of NH 2 , NH-NH 2 , CHO, SH, COOH,
- X is -(CH 2 )n or an aromatic, and wherein n is 1 or more.
- the bifunctional cross linking reagent has the general formula
- R-X-R 1 wherein R and R 1 are selected from any one or more of NH 2 , CHO, SH,
- R may be the same or different to R 1 ;
- X is -(CH 2 )n, aromatic, and wherein n is 1 or more.
- the invention provides a sensor for detecting an analyte comprising a substrate and a porous nanostructured film having a sensing element and signal detection element immobilised thereon.
- the substrate is selected from any one or more glass or metal or plastic having a conducting layer of indium tin oxide (ITO) or fluorine doped tin oxide (FTO) coated thereon.
- ITO indium tin oxide
- FTO fluorine doped tin oxide
- the porous nanostructured film comprises a pore size between 1 and 3000nm in size.
- the porous nanostructured film has a bimodal pore distribution.
- the porous nanostructured film comprises a combination of mesopores and macropores.
- the invention provides an integrated sensor comprising a conducting film as a solid phase support.
- the invention also provides an integrated sensor comprising a semi-conducting film as a solid phase support.
- the integrated sensor comprises a sensing element and signal detecting element immobilised on the solid phase support.
- the senor has dual spectrophotometric and electrochemical methods.
- the invention provides a method of manufacturing a sensor comprising the steps of :-
- nanoparticles comprising a metal oxide with solvent and polymeric binder to form a printable paste
- the nanoparticles comprise single nanocrystallites and/or agglomerates of nanocrystallites.
- the nanoparticles are templated around spheres during deposition of the printable paste onto a conducting substrate.
- the nanoparticles may be templated around polymer fibres, surfactants, starches, or other small molecules used in templating.
- the polymer spheres are removed during sintering.
- the printable paste is deposited onto a conducting substrate by ink-jetting, screen printing or doctor blading.
- the porous nanostructured film of the invention comprises mesopores between 1 and 50nm in size and macropores between 50 and lOOOnm in size.
- the invention also provides a method for detecting an analyte in a test sample comprising the steps of:-
- Fluorescence may alternatively be used as a detection method.
- Fig. 1 is a schematic representation of the functioning of the sensor of the invention
- Fig. 2 are surface and cross sectional scanning electron micrograph (SEM) showing a dense screen printed titania film with pore size of approximately 20 nm;
- Fig. 3 are surface and cross sectional SEM showing a templated, doctorbladed titania films incorporating 100 nm pores;
- Fig. 4 are surface and cross sectional SEM showing a templated, doctorbladed titania films incorporating 400 nm pores
- Fig. 5 are surface and cross sectional SEM showing a templated, doctorbladed titania films incorporating 1000 nm pores
- Fig. 6 is a schematic representation of three nanoparticles having a pore size of less than 50nm in a closely packed structure
- Fig. 7 is a schematic representation of nanoparticles having a pore size of from 1 to 50nm and larger macropores approximately lOOnm in size;
- Fig. 8 is a schematic representation of nanoparticles having a pore size of from 1 to 50nm and larger macropores approximately 400nm in size;
- Fig. 9 is a schematic representation of nanoparticles having a pore size of from 1 to 50nm and larger macropores approximately lOOOnm in size;
- Fig. 10 is a schematic representation of nanoparticles having a pore size of from 1 to 50nm and larger macropores approximately 400nm and lOOnm in size;
- Fig. 11 is a bar graph comparing the IgG loading capacity of standard screen printed films to films incorporating 100 nm pores;
- Fig. 12 is a schematic representation showing the covalent binding of proteins and/or dyes to the titania surface
- Fig. 13 is a schematic representation of the electrochemical cell used with the sensor of the invention.
- Fig. 14 shows the structure of Protoporphyrin IX
- Fig. 15 is a graph showing the dose response to horse radish peroxidase (HRP) (in solution);
- Fig. 16 is a graph showing three traces for potential transients for IgG-HRP covalently bound to the film and three traces for potential transients obtained in the absence of HRP conjugated to the IgG;
- Fig 17 is a graph showing the limits of sensitivity of the hCG assay achieved on the porous nanostructured films of the invention.
- Fig. 18 is a schematic representation of a titania film with dye and antibody attached
- Fig. 19(a) is a graph showing the sensitivity of the sandwich assay to different concentrations of hCG, 0, 25 and 50mIU.
- Fig. 19(b) is a graph showing the potential transients obtained for concentration of hCG at 0, 25 and 50mIU. The tests were carried out in triplicate.
- the invention describes a porous nanostructured film with integrated signal transduction capability where detection of an analyte is via luminescent signal generation. This is achieved by integration of a sensing element and/or a signal detection element into a single porous nanostructured semiconductor metal oxide film surface.
- the invention combines two complementary applications of nanostructured titania films to make an integrated sensing device.
- the invention provides a nanostructured film which comprises not only the molecules necessary to detect an analyte and produce a light signal but also molecules that can harvest the light and turn it into an electrical output thus eliminating the need for external photon measuring instrumentation.
- the invention significantly simplifies and reduces the cost of transducing a luminescent signal.
- the invention also provides a sensor comprising the nanostructured film.
- a sensor (1) of the invention for example an immunosensor, comprising a nanostructured titania film (2) with probe molecules (3) (such as antibodies; IgG, IgM, IgA, IgD, IgE or antibody fragments; Fab, F(ab)'2,
- probe molecules (3) such as antibodies; IgG, IgM, IgA, IgD, IgE or antibody fragments; Fab, F(ab)'2,
- Fv, Fc receptors drug receptors, ligands, enzymes, substrates, aptamers, affibodies, affinity binding agents, proteins, cell or tissue samples, cells, antigen and DNA, an oligonucleotide probe, bacteria, fibrin binding protein, EGF receptor, collagenase, plasminogen, vitamin K, somatostatin receptors, monoamine oxidase, dopamine receptors, prostaglandin synthase or Hydroxy-methyl glutaryl (HMG) Co-
- A immobilised on the film.
- the titania film (2) is positioned on a support (4).
- the bound molecules (3) are capable of recognising and binding the analyte (5) being detected.
- a reporter molecule (6) (for example a secondary antibody), conjugated to an enzyme is used to indicate the presence of the analyte (5) in a sample that has been brought into contact with the sensor (1). If the analyte (5) is present the reporter molecule (6) binds to it and is retained. If the analyte (5) is not present then the reporter molecule (6) will not bind.
- a chemiluminescent substrate (7) is then added to the sensor (1) and light is emitted when the enzyme conjugated to the reporter molecule (6) reacts with it.
- the light produced is absorbed by a dye (8) which is also bound to the titania surface (2).
- the dye (8) is thus excited to an electronically excited state and injects an electron into the titania film (2).
- the presence of electrons in the titania film are then measured.
- the sensor (1) therefore senses the analyte present in a sample and simultaneously converts the light signal indicating the presence of the analyte to an electrical signal which can be measured.
- the nanostructured films of the invention are meso and macroporous metal oxide films comprising fused nanoscale particles.
- the films provide a recipient surface for the immobilisation of probe molecules employed in the sensor. These films typically possess the following characteristics: high surface area, optical transparency, semi- conductivity and are highly receptive surfaces for biomolecules, for biosensor applications.
- mesoporous is taken to include nanoparticles of between 2 to 50nm in size.
- macroporous is taken to include any particle greater than 50nm in size.
- Nanostructured titania films are deposited by conventional methods either by screen printing, doctor blading or ink-jetting onto a fluorine doped tin oxide (FTO) coated or indium doped tin oxide (ITO) coated substrate.
- FTO and ITO are typically used for glass and plastic substrates.
- ITO is the industry standard however, its properties change at high sintering temperatures (400°C), therefore FTO is more suitable for glass substrates and ITO for plastic substrates.
- the nanoparticles are formulated with solvent and a polymeric binder to make a printable paste. After printing, the films are heated to remove both the solvent and binder and to sinter the particles together and adhere them to the surface below.
- dense metal oxide films such as TiO 2 films are described in detail in WO9835267 and WOO 127690 both of which are herein inco ⁇ orated in full.
- dense films typically comprise mesopores of approximately 2-50nm in size only.
- the properties of the films of the invention may be tailored to the sensor application.
- immunosensors which employ large proteins, such as antibodies
- Pores should also accommodate all of the recognition molecules involved in the sensing event and allow efficient washing where necessary.
- Bimodal pore distributions are possible, the smaller pores being accessible to small molecules such as dyes while the larger pores can accommodate antibodies or other large proteins.
- Bimodal pore distribution is also useful for use in multianalyte assays such as microarrays which may require different pore sizes for loading of different sensing agents.
- Trimodal or polymodal pore distributions are also possible. In this case mesopores are present in addition to two or more sizes of macropores. In this way the pore distribution of the films of the present invention provides a higher loading capacity in comparison to films having a mesopore pore distribution only.
- Film porosity is determined by constituent particle size and by the binders used during formation.
- the particles making up the film can either be single nanocrystallites of the metal oxide in question or can be agglomerates of nanocrystallites, also known as secondary particles. Variation of the above parameters allows control over the porosity of the resulting film. Both unimodal, bimodal, trimodal or polymodal pore distributions may be achieved.
- Another method of preparing films with bimodal pore distributions is to template the nanoparticles around polymer spheres of a defined diameter during the film deposition process. The polymer is then removed during sintering, leaving films with high surface area and pore size corresponding to the diameter of the templating spheres. In this case a bimodal pore distribution is obtained with the size of the larger pores being fully controllable as shown in Figs. 3 to 5 and Figs 11 to 15.
- the loading of large proteins such as antibodies; ; IgG, IgM, IgA, IgD, IgE or antibody fragments; Fab, F(ab)'2, Fv, Fc, receptors, drug receptors, ligands, enzymes, substrates, aptamers, affibodiesTM, affinity binding agents, proteins, cell or tissue samples, cells, antigen and DNA, an oligonucleotide probe, bacteria, fibrin binding protein, EGF receptor, collagenase, plasminogen, vitamin K, somatostatin receptors, Monoamine oxidase, dopamine receptors, prostaglandin synthase or Hydroxy -methyl glutaryl (HMG) Co- A, on nanostructured films with large pores as shown in Fig. 5, is significantly higher than on less porous nanostructured titania films such as those shown in Fig. 2.
- HMG Hydroxy -methyl glutaryl
- the films may also be templated around polymer fibres, surfactants, starches, or other small molecules to produce films with the required properties for a specific application.
- the titania films of the invention are thicker, and are sintered which fuses the nanocrystallites and makes the films conductive.
- the polymer spheres are burnt out during the sintering process and an organic solvent is not needed. Where the film is deposited on a plastic substrate and high temperature sintering is not used, the polymer spheres may be removed using organic solvents.
- the surface is treated with a functional silane such as an amino silane.
- the surface may also be treated with polyions, bifunctional polymers or DNA. This creates a surface with a high density of reactive attachment groups. These groups are then reacted with a bifunctional cross-linking reagent such as glutaric dialdehyde, the free end of which then attaches to functional groups on the antibodies or the dye molecules. For example this may be either the amine moieties on the antibody or the allylic double bonds on the dye molecule.
- a film with either covalently bound antibody and/or dye may be prepared (Fig. 12).
- a polyfunctional cross-linking agent could be used.
- the loading of proteins and/or dye molecules to the film may also be carried out in the absence of a bifunctional or a polyfunctional cross-linking reagent wherein the surface is treated with a functional silane, polyion, bifunctional polymer and the protein is attached directly.
- the functional silanes have the general formula
- R is CH 3 , CH 2 CH 3 ;
- R 1 includes but is not limited to any of NH 2 , NH-NH 2 , CHO, SH, COOH,
- X is -(CH 2 )n, aromatic, and n is 1 or more.
- bi-functional cross linking reagents are compounds having the general formula
- the dye is covalently attached first and then the pendant carboxylate groups of the dye are activated with a compound such as carbodiimide which then attach to amine groups on the antibody.
- the electrodes are then incubated in a solution of blocking agent such as Bovine Serum Albumin (BSA) or casein to block non-specific binding by analyte or secondary antibodies.
- BSA Bovine Serum Albumin
- the films are incubated with an analyte for which the immobilised antibody is specific, washed to eliminate any non-specific binding and then incubated with a labelled secondary antibody, using a label such as horse radish peroxidase (HRP).
- HRP horse radish peroxidase
- the secondary antibody is also specific for the analyte and forms a sandwich complex of the two antibodies with the analyte in the middle.
- the label is an enzyme capable of carrying out organic transformations on small molecules to produce a luminous signal.
- the conducting glass substrate (21) with modified TiO 2 film (22) is used as one electrode and a piece of platinised conducting glass (23) is used as the other electrode as shown in Fig. 13.
- a piece of rubber gasket (24) is cut to size, with a hole in the middle to contain solution. A contact is made between each of these electrodes and a potentiostat in order to measure the open circuit potential.
- the open circuit potential measurement is started and a chemiluminescent substrate in solution such as luminol is injected into the cell, ensuring that no air bubbles are injected.
- a chemiluminescent substrate in solution such as luminol
- HRP chemiluminescent substrate in solution
- light is released and this light is absorbed by the dye molecules on the surface, elevating them to an excited electronic state which then inject electrons into the titania electrode.
- These electrons can be measured as a current, potential or a charge build up.
- the signal produced is proportional to the amount of light produced and the concentration of analyte captured by the sensor.
- the integrated sensor of the invention may form part of an array of such sensors for highly parallel analysis.
- individual sensors may be addressed by direct drive, passive matrix or active matrix electronic circuitry.
- the integrated sensor of the invention has many advantages over currently known sensors.
- sensing elements e.g. antibodies
- photovoltaic elements molecules that turn light into electrons
- the sensor provides a simple alternative to conventional instrumentation and software required to collect and analyse a luminescent signal. It allows for the miniaturisation of instrumentation required to collect and process a luminescent signal and adds the capability to the sensor of transportability providing on-site or in the field analysis.
- the sensor of the invention also presents a significant reduction in the cost of collecting and processing a luminescent signal.
- Nanostructured films as solid phase supports for sensors such as high probe loading due to the high surface area of these materials, scope for miniaturisation, high signal to noise ratios for optical sensors due to optical properties of the materials and the opportunity for integrated readouts due to semiconductive properties of the films etc.
- mesoporous titania films these advantages can only be realised in practice for sensors which use small molecules, i.e. molecules with dimensions smaller than the pore size in the film.
- Nanostructured metal oxide films with variable porosity allow all the advantages of using nanostructured films for biosensor applications to be extended to sensors that involve the use of large and bulky molecules for recognition and detection such as immunosensors.
- the integrated sensor of the invention is applicable to any sensor that emits a luminescent signal such as chemiluminescent gas sensors for the detection of ozone, reactive oxygen species and nitrogen, chemiluminescent sensors for the analysis of solutions such as ethanol or glucose.
- the invention is particularly applicable to biochips where trends are towards highly parallel testing and miniaturisation.
- biochip market is an important and emerging market and has potential in the areas of pharmaceutical research, medical diagnostics for example autoimmune disease and cancer typing, identification of infecting microorganisms, forensics, transplantation, identity testing and environmental testing in the future.
- Biochips require high sensitivity and a capacity for high protein or nucleotide loading making the integrated film and sensor of the invention ideally suited to this format. There are two main types of biochip, depending on the probes attached.
- Nucleic acid biochips which have DNA/RNA attached and protein biochips that have proteins such as antibodies attached.
- Mini-lab chips which incorporate microfluidics in the housing.
- fluorescent probes can be susceptible to photo-bleaching, and the ambient buffer must be carefully chosen so that there are no quenching species present, the solvent polarity must also be considered and fluorescent probes are pH sensitive.
- the integrated system of the invention overcomes these problems.
- biochip applications recent developments in microfluidic technologies have enabled on chip fluid handling and integration of all the steps necessary in an analytical procedure to be performed on the chip.
- the present invention enables standard luminescent detection and signal processing to be also integrated on the chip.
- the integrated sensor of the invention is applicable to a wide range of assay types and formats on the biochip.
- the system has been established in an immunoassay but is applicable to all protein assays including, antibody specificity, receptor-ligand binding assay and enzyme-substrate assay, protein-protein interactions, protein- RNA, protein-DNA, protein-drug interactions.
- the system is compatible with DNA assays encompassing gene expression analysis and DNA analysis such as SNP detection.
- the water in aliphatic amine white polystyrene latex microspheres of required diameter in surfactant-free de-ionised water at 4% w/v is removed by sublimation using a freeze-dryer.
- the resultant latex is ground to a fine powder with a pestle and mortar. This is added to a standard "in-house" TiO 2 paste at a ratio of 60:100, latex beads: TiO 2 particles. For example for a 10% TiO 2 paste; for every 10 grams of paste 0.6g of latex is added. The mixture is stirred overnight and deposited onto
- Example 2 Determination of the potential transients for different concentrations of IgG-HRP in solution. 04/011672
- FIG. 13 A standard "in-house” TiO 2 doctor bladed film as illustrated in Fig. 2 was prepared. The film was silanised, treated with glutaraldehyde and IgG immobilised on it. The film was then dyed in Protoporphyrin IX (Fig. 14), and blocked with BSA. An electrochemical cell as shown in Fig. 13 was assembled and different concentrations of IgG HRP in luminol solution injected. For each injection the open circuit potential was monitored for at least 1500 sees. Between injections the cell was washed and dried thoroughly before reassembly. The highest concentration HRP shows the biggest potential change as shown in Fig. 15.
- Porous titania films having 400 and 100 nm pores were heated to 110°C, cleaned with UN-ozone and silanised with aminopropyl silane. The films were heated to
- Fig. 13 Each film was assembled into a 2 electrode cell as shown in Fig. 13, an open circuit potential measurement taken and luminol solution injected into the cell. The open circuit potential measurement was continued for 1500 seconds.
- Fig. 16 shows the potential transients obtained. The three thicker lines indicate films with IgG attached while the three thinner lines indicate film with IgG-HRP attached.
- Example 4 Comparison of detection limits achieved for hCG assay on porous titanium oxide films Latex-templated titanium dioxide films were silanated with amino silane, and reacted with gluteraldehyde.
- the films were blocked with 3% bovine serum albumen in phosphate buffered with 0.05% Tween-20 (PBS-tween) for 2 hours on an orbital shaker at 50rev/min followed by two 15min washes in PBS- tween.
- the films were incubated with different concentrations of hCG (diluted in PBS-tween) for one hour and washed twice in PBS-tween for 15 min. Subsequently, the films were incubated with the secondary antibody, monoclonal anti-hCG IgG conjugated to Horse Radish Peroxidase and washed two times in PBS-tween for 15 min. Finally, the films were incubated with precipitating 3,3'5,5-
- TMB Tetramethylbenzidine
- Fig. 17 shows the limits of sensitivity of the hCG assay achieved on the porous nanostructured films.
- Titania films were prepared by doctor blading, using a single layer of Scotch-tape as a spacer. They were allowed to dry and then heated at 450°C for 45 minutes.
- the titania films were coated in amino silane by immersing in a solution (1% aminopropyltriethoxysilane in a 95:5 mixture of ethanol/water) for 1 hour. The films were removed from the silane solution, rinsed twice in pure ethanol and then heated to 110°C for 20 minutes. The films were then placed in a solution of glutaraldehyde (1% in PBS (phosphate buffered saline)) for 1 hour, rinsed twice in water and allowed to dry.
- PBS phosphate buffered saline
- the films were then placed in a solution of protoporphyrin IX [5mM in phosphate buffer (50mM, pH 10.6)] for three hours and washed thoroughly in phosphate buffer (50mM, pH 10.6) and then water.
- the porphyrin molecule attaches to the silane film due to the reaction between one of its pendant double bonds and an /011672
- the films were then blocked by placing in a solution of BSA (3% in PBS/Tween) overnight.
- a standard hCG assay was then performed as in example 4, using concentrations of 0, 25 and 50 mlU of hCG.
- the film was assembled into the 2- electrode cell shown in Fig. 13 and an open circuit potential measurement started when luminol was injected into the cell.
- Fig. 19(a) shows the results of an integrated sensor and its sensitivity over a concentration range which is industrially applicable.
- Fig. 19(b) shows the potential transients obtained for the different concentrations of hCG. Each assay was carried out in triplicate.
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Abstract
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