CA2394948C - Screen-printable paste for producing a porous polymer membrane for a biosensor - Google Patents
Screen-printable paste for producing a porous polymer membrane for a biosensor Download PDFInfo
- Publication number
- CA2394948C CA2394948C CA2394948A CA2394948A CA2394948C CA 2394948 C CA2394948 C CA 2394948C CA 2394948 A CA2394948 A CA 2394948A CA 2394948 A CA2394948 A CA 2394948A CA 2394948 C CA2394948 C CA 2394948C
- Authority
- CA
- Canada
- Prior art keywords
- paste
- screen
- polymer
- printable
- weight
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
- C08J5/00—Manufacture of articles or shaped materials containing macromolecular substances
- C08J5/20—Manufacture of shaped structures of ion-exchange resins
- C08J5/22—Films, membranes or diaphragms
-
- 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
- B01D67/0002—Organic membrane manufacture
- B01D67/0009—Organic membrane manufacture by phase separation, sol-gel transition, evaporation or solvent quenching
- B01D67/0011—Casting solutions therefor
-
- 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
- B01D67/0002—Organic membrane manufacture
- B01D67/0009—Organic membrane manufacture by phase separation, sol-gel transition, evaporation or solvent quenching
- B01D67/0013—Casting processes
-
- 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
- B01D69/122—Separate manufacturing of ultra-thin membranes
-
- 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
-
- 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
-
- 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
- B01D71/06—Organic material
- B01D71/08—Polysaccharides
- B01D71/12—Cellulose derivatives
- B01D71/14—Esters of organic acids
- B01D71/16—Cellulose acetate
-
- 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
- C12Q1/002—Electrode membranes
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D2323/00—Details relating to membrane preparation
- B01D2323/06—Specific viscosities of materials involved
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D2323/00—Details relating to membrane preparation
- B01D2323/12—Specific ratios of components used
Abstract
The invention relates to a paste, which can undergo screen printing, for producing a porous polymer membrane. Said paste contains at least one polymer, one or more solvents for the poly-mer having a boiling point of > 100 °C, one or more non-solvents for the polymers (pore-forming agents) having a higher boiling point than that of the solvent(s), and contains a hydrophilic viscosity mod-ifier.
Description
-------------------------------------------------------Screen-printable paste for producing a porous polymer membrane for a biosensor -------------------------------------------------------The present invention relates to a screen-printable paste for producing a porous polymer membrane which can be used in electrochemical sensors, especially in electrochemical biosensors, for integrated preparation of, in particular, whole blood samples.
Biosensors are already in use in a large number of diagnostic methods, for example in the determination of the concentration of various factors in body fluids such as blood. The aim in this connection is to have sensors which require no elaborate processing of the (blood) sample but provide a rapid result simply by applying the body fluid to a test strip. This entails a specific biochemical reaction taking place, such as, for example, the enzymatic conversion of the component to be determined, which then brings about an electron transfer between different electrodes (working and reference electrodes), and this can be determined quantitatively.
The disadvantage of most of the known electrochemical biosensors is that, on application of the blood to the region provided therefor on the test strip, the biochemical reaction which takes place is influenced by other constituents present in the blood, especially the red blood corpuscles (erythrocytes). Thus, for example, when the values of the hematocrit (= volume of the erythrocytes as a proportion of the total amount of blood in vol.wt.%) are high, the value measured for glucose using conventional blood glucose sensors is lower than the actual value. This adverse affect arises from the fact that the erythrocytes influence, through adsorption onto the reactive layer of the biosensor, the diffusion of glucose into the latter and to the electrode and reduce the measured signal.
To solve this problem, various membranes which are put on top of the enzyme layer, which is disposed on the electrodes, of the test strip in order to keep the erythrocytes away from this layer have been proposed.
Thus, for example, U.S. Patent No. 5,658,444 describes an erythrocyte exclusion membrane for a sensor, which consists of a water-insoluble, hydrophobic polymer, of a water-soluble hydrophilic polymer and of an erythrocyte aggregating agent and is produced by spraying onto the surface of the test strip.
One disadvantage of this membrane is that the membrane pore diameter varies as a function of the spraying distance and spray pressure. In addition, the spraying on of the membrane during production of the test strip means an additional operation which is different from the production of the remainder of the test strip and is therefore elaborate, which makes the production process complicated and thus costly.
The present invention seeks to provide a paste for producing a porous membrane which does not have the disadvantages mentioned since it can be applied during the biosensor production process by a method which fits in with the remaining procedure and is therefore cost-effective, and provides a membrane of constant pore size.
In accordance with one aspect of the invention, there is provided a screen-printable paste for producing a porous polymer membrane, comprising at least one polymer, one or more solvents for the polymer with a boiling point of >
100 C, one or more nonsolvent pore formers for the polymer - 2a -with a higher boiling point than the one or more solvents and a hydrophilic viscosity modifier.
In a preferred embodiment, the difference in the boiling points of solvent and pore former is at least 30 C.
In another aspect of the invention, there is provided a method for producing a screen-printable paste, by producing a mixture of one or more solvents for a polymer and one or more nonsolvent pore formers for a polymer, mixing in the polymer until a uniform suspension results, rolling the suspension until a clear gel results, adding a hydrophilic viscosity modifier, and rolling the mixture until the viscosity modifier is uniformly distributed, said one or more solvents having a boiling point of > 100 C, and the one or more nonsolvent pore formers having a higher boiling point than the one or more solvents.
In another aspect of the invention, there is provided the use of the paste of the invention for producing a porous polymer membrane.
In a particular embodiment of this latter aspect of the invention, there is provided the use of the paste of the invention for producing a porous polymer membrane, where the polymer membrane is introduced into a biosensor test strip, for example a biosensor designed for measuring blood glucose concentration or for determining the value of the hematocrit.
In still another aspect of the invention, there is provided a porous polymer membrane produced from the screen-printable paste of the invention.
The invention is explained below by means of the figures, where Figure 1 shows diagrammatically the structure of a test strip with the membrane of the invention, Figure 2 shows the rheological characteristics of the paste of the invention, Figure 3a shows an electron micrograph of a polymer membrane with inadequately developed pore structure, Figure 3b shows an electron micrograph of the polymer membrane of the invention with well developed pore structure, Figure 4 shows the results of measurement with two biosensors, one of them being provided with a membrane of the invention, comparing as the values of the hematocrit increase, Figures 5a to 5d show the clinical performance on comparison of four blood glucose sensors.
Figure 1 depicts the structure of a test strip with the polymer membrane of the invention. An electrode arrangement 2 in the form of a carbon layer, which in turn is partly covered by an insulation 3, is located on a polyester support material 1. An enzyme and mediator layer 4 is disposed on the region of the electrode layer which is left free by the insulation.
In the case of a blood glucose sensor, this layer comprises, for example, the enzyme glucose oxidase and the mediator Fe3+. The polymer membrane 5 of the invention is arranged above the enzyme and mediator layer 4. The whole is covered by an adhesive layer 6 and a cover sheet 7.
In the mass production of biosensors, the screen printing method is used for printing the various layers such as electrode, insulating and enzyme layers. The present invention provides a membrane which can be applied with the same technique. On the one hand, this has the advantage that the same screen printing device can be used for printing the membrane and thus throughout the sensor production process, which involves enormous economic advantages in mass produc-tion. On the other hand, it is possible to produce by the screen printing method reproducibly a membrane of uniform thickness and pore size, which is not ensured with the other methods such as spincoating, dipping or spraying.
For it to be possible to apply the paste used to produce the polymer membrane by screen printing, the solvent(s) present therein for the polymer must have a boiling point which is as high as possible (above 100 C) in order to avoid premature drying of the material in the printing machine. In addition, the paste comprises a nonsolvent for the polymer, which acts as pore former and has a higher boiling point than the solvent(s) used.
The paste must moreover have a suitable viscosity (30 000-50 000 cpi) in order to ensure uniform flow through the screen during the printing. The viscosity of the paste is preferably reduced on exposure to shear forces, as depicted in the rheological characteristics in Figure 2.
The polymer preferably used in the paste of the inven-tion is cellulose acetate (50 kDa). It is preferably present in a proportion of about 8% by weight in the screen-printable paste. In addition, a further polymer which may be present is cellulose nitrate in a proportion of up to 10% by weight.
Solvents which can be used for the polymer are, for example, 1,4-dioxane (boiling point 102 C) and/or 4-hydroxymethylpentanone (boiling point 165 C). A
preferred composition comprises 0-20% by weight, more preferably 20% by weight, of 1,4-dioxane and 0-70% by weight, more preferably 56% by weight, of 4-hydroxy-methylpentanone, it being possible alternatively to replace the 4-hydroxymethylpentanone by ethyl acetate or ethylene glycol diacetate.
It has emerged that long-chain alcohols with a boiling point of > 150 C are suitable as pore formers for the screen-printable membrane paste; preference is given to n-octanol, which has a boiling point of 196 C, and/or 2-methyl-2,4-pentanediol (MPD), which has a boiling point of 197 C.
The paste is somewhat more tolerant to evaporation of dioxane on use of 2-metyl-2,4-pentanediol (MPD) as pore former. Moreover the cellulose acetate remains in solution longer, which extends the time during which the paste remains in a printable state. This extended "pot life" makes it possible to produce larger batches of constant quality.
The pore former should be present in a proportion of 5-20% by weight, preferably 12-15% by weight.
The viscosity modifiers used are, for example, hydrophilic silica xerogels or equivalent "fumed silicas", bentonite, clay, Natrosol~ or carbon black.
They should be added in a proportion of from 1 to 10%
by weight to the screen-printable paste. Preference is given to hydrophilic Cab-O-Sils (proprietary name for silica xerogels marketed by the Cabot organization), such as Cab-O-Sil~ M5, Cab-O-Sil~ H5, Cab-O-SiP LM50, Cab-O-SiP LM130, in a proportion of 4% by weight.
It is also possible to add further additives such as Tween'4~20, Triton X*, Silvet~7600 or 7280, lauryl sulfate (SDS), other detergents, and polyols such as glycerol, * trade-mark or hydrophilic polymers such as polyvinylpyrolidone (PVP) or vinylpyrolidone/vinyl acetate copolymers (PVP/VA) to the paste of the invention.
Addition of one or more of these additives is not obligatory for producing the membrane; however it has emerged that they may improve the wetting of the membrane and speed up the sensor response. Preference is given to the use of PVP/VA or PVP in a proportion of 0.1% by weight in the screen-printable paste.
Moreover the addition of the additives Bioterge, poly-ethyleneimine, BSA, dextran, dicyclohexyl phthalate, gelatin, sucrose and/or biuret may improve the separa-tion of erythrocytes and plasma.
It is additionally possible to add enzyme, for example glucose oxidase, even to the cellulose acetate paste so that printing of the enzyme layer can be dispensed with in the biosensor production process.
After application of a uniform layer of the printing paste to a suitable substrate, the membrane is formed during the drying process. There is formation of a porous layer and not of a continuous film, because the solvents used have a lower boiling point than the pore former; the solvents evaporate correspondingly quickly and the cellulose acetate polymer precipitates in the remaining film of the pore former.
However, in connection with a biosensor, it is not permissible to use just a high temperature in the drying process, because the enzymes/proteins used are denatured if the temperatures are too high. The best results were achieved in connection with a biosensor for determining glucose in whole blood with a drying temperature of about 70 C. The boiling points of the solvents and pore formers used should be selected correspondingly.
Biosensors are already in use in a large number of diagnostic methods, for example in the determination of the concentration of various factors in body fluids such as blood. The aim in this connection is to have sensors which require no elaborate processing of the (blood) sample but provide a rapid result simply by applying the body fluid to a test strip. This entails a specific biochemical reaction taking place, such as, for example, the enzymatic conversion of the component to be determined, which then brings about an electron transfer between different electrodes (working and reference electrodes), and this can be determined quantitatively.
The disadvantage of most of the known electrochemical biosensors is that, on application of the blood to the region provided therefor on the test strip, the biochemical reaction which takes place is influenced by other constituents present in the blood, especially the red blood corpuscles (erythrocytes). Thus, for example, when the values of the hematocrit (= volume of the erythrocytes as a proportion of the total amount of blood in vol.wt.%) are high, the value measured for glucose using conventional blood glucose sensors is lower than the actual value. This adverse affect arises from the fact that the erythrocytes influence, through adsorption onto the reactive layer of the biosensor, the diffusion of glucose into the latter and to the electrode and reduce the measured signal.
To solve this problem, various membranes which are put on top of the enzyme layer, which is disposed on the electrodes, of the test strip in order to keep the erythrocytes away from this layer have been proposed.
Thus, for example, U.S. Patent No. 5,658,444 describes an erythrocyte exclusion membrane for a sensor, which consists of a water-insoluble, hydrophobic polymer, of a water-soluble hydrophilic polymer and of an erythrocyte aggregating agent and is produced by spraying onto the surface of the test strip.
One disadvantage of this membrane is that the membrane pore diameter varies as a function of the spraying distance and spray pressure. In addition, the spraying on of the membrane during production of the test strip means an additional operation which is different from the production of the remainder of the test strip and is therefore elaborate, which makes the production process complicated and thus costly.
The present invention seeks to provide a paste for producing a porous membrane which does not have the disadvantages mentioned since it can be applied during the biosensor production process by a method which fits in with the remaining procedure and is therefore cost-effective, and provides a membrane of constant pore size.
In accordance with one aspect of the invention, there is provided a screen-printable paste for producing a porous polymer membrane, comprising at least one polymer, one or more solvents for the polymer with a boiling point of >
100 C, one or more nonsolvent pore formers for the polymer - 2a -with a higher boiling point than the one or more solvents and a hydrophilic viscosity modifier.
In a preferred embodiment, the difference in the boiling points of solvent and pore former is at least 30 C.
In another aspect of the invention, there is provided a method for producing a screen-printable paste, by producing a mixture of one or more solvents for a polymer and one or more nonsolvent pore formers for a polymer, mixing in the polymer until a uniform suspension results, rolling the suspension until a clear gel results, adding a hydrophilic viscosity modifier, and rolling the mixture until the viscosity modifier is uniformly distributed, said one or more solvents having a boiling point of > 100 C, and the one or more nonsolvent pore formers having a higher boiling point than the one or more solvents.
In another aspect of the invention, there is provided the use of the paste of the invention for producing a porous polymer membrane.
In a particular embodiment of this latter aspect of the invention, there is provided the use of the paste of the invention for producing a porous polymer membrane, where the polymer membrane is introduced into a biosensor test strip, for example a biosensor designed for measuring blood glucose concentration or for determining the value of the hematocrit.
In still another aspect of the invention, there is provided a porous polymer membrane produced from the screen-printable paste of the invention.
The invention is explained below by means of the figures, where Figure 1 shows diagrammatically the structure of a test strip with the membrane of the invention, Figure 2 shows the rheological characteristics of the paste of the invention, Figure 3a shows an electron micrograph of a polymer membrane with inadequately developed pore structure, Figure 3b shows an electron micrograph of the polymer membrane of the invention with well developed pore structure, Figure 4 shows the results of measurement with two biosensors, one of them being provided with a membrane of the invention, comparing as the values of the hematocrit increase, Figures 5a to 5d show the clinical performance on comparison of four blood glucose sensors.
Figure 1 depicts the structure of a test strip with the polymer membrane of the invention. An electrode arrangement 2 in the form of a carbon layer, which in turn is partly covered by an insulation 3, is located on a polyester support material 1. An enzyme and mediator layer 4 is disposed on the region of the electrode layer which is left free by the insulation.
In the case of a blood glucose sensor, this layer comprises, for example, the enzyme glucose oxidase and the mediator Fe3+. The polymer membrane 5 of the invention is arranged above the enzyme and mediator layer 4. The whole is covered by an adhesive layer 6 and a cover sheet 7.
In the mass production of biosensors, the screen printing method is used for printing the various layers such as electrode, insulating and enzyme layers. The present invention provides a membrane which can be applied with the same technique. On the one hand, this has the advantage that the same screen printing device can be used for printing the membrane and thus throughout the sensor production process, which involves enormous economic advantages in mass produc-tion. On the other hand, it is possible to produce by the screen printing method reproducibly a membrane of uniform thickness and pore size, which is not ensured with the other methods such as spincoating, dipping or spraying.
For it to be possible to apply the paste used to produce the polymer membrane by screen printing, the solvent(s) present therein for the polymer must have a boiling point which is as high as possible (above 100 C) in order to avoid premature drying of the material in the printing machine. In addition, the paste comprises a nonsolvent for the polymer, which acts as pore former and has a higher boiling point than the solvent(s) used.
The paste must moreover have a suitable viscosity (30 000-50 000 cpi) in order to ensure uniform flow through the screen during the printing. The viscosity of the paste is preferably reduced on exposure to shear forces, as depicted in the rheological characteristics in Figure 2.
The polymer preferably used in the paste of the inven-tion is cellulose acetate (50 kDa). It is preferably present in a proportion of about 8% by weight in the screen-printable paste. In addition, a further polymer which may be present is cellulose nitrate in a proportion of up to 10% by weight.
Solvents which can be used for the polymer are, for example, 1,4-dioxane (boiling point 102 C) and/or 4-hydroxymethylpentanone (boiling point 165 C). A
preferred composition comprises 0-20% by weight, more preferably 20% by weight, of 1,4-dioxane and 0-70% by weight, more preferably 56% by weight, of 4-hydroxy-methylpentanone, it being possible alternatively to replace the 4-hydroxymethylpentanone by ethyl acetate or ethylene glycol diacetate.
It has emerged that long-chain alcohols with a boiling point of > 150 C are suitable as pore formers for the screen-printable membrane paste; preference is given to n-octanol, which has a boiling point of 196 C, and/or 2-methyl-2,4-pentanediol (MPD), which has a boiling point of 197 C.
The paste is somewhat more tolerant to evaporation of dioxane on use of 2-metyl-2,4-pentanediol (MPD) as pore former. Moreover the cellulose acetate remains in solution longer, which extends the time during which the paste remains in a printable state. This extended "pot life" makes it possible to produce larger batches of constant quality.
The pore former should be present in a proportion of 5-20% by weight, preferably 12-15% by weight.
The viscosity modifiers used are, for example, hydrophilic silica xerogels or equivalent "fumed silicas", bentonite, clay, Natrosol~ or carbon black.
They should be added in a proportion of from 1 to 10%
by weight to the screen-printable paste. Preference is given to hydrophilic Cab-O-Sils (proprietary name for silica xerogels marketed by the Cabot organization), such as Cab-O-Sil~ M5, Cab-O-Sil~ H5, Cab-O-SiP LM50, Cab-O-SiP LM130, in a proportion of 4% by weight.
It is also possible to add further additives such as Tween'4~20, Triton X*, Silvet~7600 or 7280, lauryl sulfate (SDS), other detergents, and polyols such as glycerol, * trade-mark or hydrophilic polymers such as polyvinylpyrolidone (PVP) or vinylpyrolidone/vinyl acetate copolymers (PVP/VA) to the paste of the invention.
Addition of one or more of these additives is not obligatory for producing the membrane; however it has emerged that they may improve the wetting of the membrane and speed up the sensor response. Preference is given to the use of PVP/VA or PVP in a proportion of 0.1% by weight in the screen-printable paste.
Moreover the addition of the additives Bioterge, poly-ethyleneimine, BSA, dextran, dicyclohexyl phthalate, gelatin, sucrose and/or biuret may improve the separa-tion of erythrocytes and plasma.
It is additionally possible to add enzyme, for example glucose oxidase, even to the cellulose acetate paste so that printing of the enzyme layer can be dispensed with in the biosensor production process.
After application of a uniform layer of the printing paste to a suitable substrate, the membrane is formed during the drying process. There is formation of a porous layer and not of a continuous film, because the solvents used have a lower boiling point than the pore former; the solvents evaporate correspondingly quickly and the cellulose acetate polymer precipitates in the remaining film of the pore former.
However, in connection with a biosensor, it is not permissible to use just a high temperature in the drying process, because the enzymes/proteins used are denatured if the temperatures are too high. The best results were achieved in connection with a biosensor for determining glucose in whole blood with a drying temperature of about 70 C. The boiling points of the solvents and pore formers used should be selected correspondingly.
A crucial factor for the pore formation is the viscosity modifier used, which forms a gel together with the pore former in order to stabilize the polymer structure. With the substances used, the gel is produced through the interaction between the OH groups of the silica xerogel and the long-chain alcohol (e.g.
octanol). The amount and the distribution of the gel produced during the drying process eventually deter-mines the size and shape of the pores which develop.
Without addition of a viscosity modifier there is formation of an emulsion from the solvent and the pore former, because the pore former is unable on its own to stabilize the polymer skeleton. The result is a white, smooth and unstructured film with entrapped pore former, which does not allow lateral liquid transport.
By comparison, a clear film is obtained when no pore former is used in the paste.
If the amounts of viscosity modifier used are too small (< 1% by weight), the resulting membrane has an only inadequately developed pore structure, as shown in Figure 3a.
Since the various suitable viscosity modifiers have different surface properties, the viscosity modifier can be selected depending on the required membrane or the required biosensor. For example, with high mechanical stress, e.g. with long printing times or on printing of very thin layers with a high squeegee pressure, the Cab-O-SilH5 is "crushed". The surface then shows microscopically sharp fracture edges which may lead to lysis of the red blood cells.
This is an unwanted property for a blood glucose sensor because the basic current of the sensor is increased thereby. On the other hand, this effect can be opti-mized, and the plasma from cells be utilized directly in the sensor for the electrochemical detection. One * trade-mark practical example would be the examination of hemoglobin in erythrocytes. In this case, the mediator of the biosensor, e.g. potassium hexacyanoferrate(III), reacts with the Fe(II) group of the hemoglobin, producing potassium hexacyanoferrate(II) which can be determined directly at the electrode of the biosensor.
An enzyme like that in the case of glucose determination is unnecessary in this case because the mediator reacts directly with the hemoglobin. It is possible in this way in practice to determine the value of the hematocrit for a patient with similar measuring equipment as in the monitoring of blood glucose, making the time-consuming use of capillary tubes and centrifuge unnecessary.
Cab-O-Sil~ LM 150 consists of smaller particles than H5, which are therefore more stable and are not damaged by the mechanical stress during the printing process. This viscosity modifier is therefore most suitable for producing a membrane for blood glucose sensors.
In accordance with the above statement, the difference in boiling points between solvent and pore former is, besides the stabilization of the polymer skeleton by the viscosity modifier, important for the formation of a suitable membrane. The difference should be about C in this case, so that there is formation in the drying process of a film which comprises a sufficiently high concentration of pore former in which the membrane 30 polymer can precipitate. If the boiling point differen-ces are smaller the pore former starts to evaporate before a critical ratio between solvent and pore former is reached, which brings about the precipitation of the membrane polymer.
After the screen-printable paste with the composition described previously has been printed, and the solvent has evaporated, there is formation through deposition of the cellulose esters of a membrane with an average * trade-mark pore size of from 0.1 to 2 m, it being possible to influence the pore size by the amount of long-chain alcohol used. An electron micrograph of the membrane is shown in Figure 3b. Since erythrocytes have an average size of 8 to 10 m, the membrane keeps them away from the enzyme layer, while the plasma can pass through unhindered. In addition, the membrane contributes to the mechanical stability of the enzyme layer and prevents the enzyme being detached from the electrode on application of the blood sample and then no longer being available for the electrochemical reaction.
Figure 4 illustrates by means of a series of measure-ments the fact that at a constant glucose concentration the test strip provided with a membrane of the inven-tion provides, in contrast to a test strip without membrane, constant results as the values of the hema-tocrit increase, whereas the response with the test strip without membrane decreases as the erythrocyte concentration increases. Because of the increased dif-fusion barrier between the enzyme layer and the blood sample, the response overall is somewhat reduced in the case of the sensor with membrane.
The invention is illustrated by means of the following examples.
Production of the printing paste:
In accordance with the ratios of amounts indicated in the following examples, a mixture of the solvent (e.g.
hydroxymethylpenanone, dioxane) and the pore former (e.g. octanol, MPD) is produced to ensure uniform distribution of the two substances. In the next step, all the additives (e.g. PVP/VA) are added and dissolved, if necessary with the aid of ultrasound. The membrane polymer (cellulose actate 50 kDa) is then mixed rapidly with the previously produced solvent until a uniform suspension results. This suspension is rolled for 48 h in a closed container until a clear gel results, and it is possible to add the viscosity modifier (e.g. Cab-O-Sil) to this. The finished printing paste is rolled for a further 24 h in order to ensure uniform distribution of the viscosity modifier.
Example 1 Polymer(s):
Cellulose acetate (Mw 30 000) 7.5% by weight Solvent:
Ethylene glycol diacetate (b.p. 186 C) 65.5% by weight Pore former:
n-Decanol (b.p. 231 C) 25.0% by weight Viscosity modifier:
Cab-O-Sil~ M5 2.0% by weight Example 2 Polymer(s) Cellulose acetate (Mw 50 000) 8.0% by weight Solvents:
1,4-Dioxane (b.p. 102 C) 35.0% by weight Ethyl acetate (b.p. 154 C) 35.0% by weight Pore former:
n-Octanol (b.p. 196 C) 18.0% by weight Viscosity modifier:
Cab-O-Sil''M5 4.0% by weight * trade-mark Example 3 Polymer(s):
Cellulose acetate (Mw 50 000) 8.0% by weight Solvents:
1,4-Dioxane (b.p. 102 C) 20.0% by weight 4-Hydroxymethylpentanone (b.p. 165 C) 56.0% by weight Pore former:
n-Octanol (b.p. 196 C) 12.0% by weight Viscosity modifier:
Cab-O-Sil~ M5 4.0% by weight Additives:
PVP/VA 0.1% by weight Example 4 Polymer(s):
Cellulose acetate (Mw 50 000) 7.4% by weight Solvents:
1,4-Dioxane (b.p. 102 C) 18.5% by weight 4-Hydroxymethylpentanone (b.p. 165 C) 55.6% by weight Pore former:
2-Methyl-2,4-pentanediol 14.8% by weight Viscosity modifier:
Cab-O-Si? M5 3.7% by weight Additives:
PVP/VA 0.1% by weight Figure 5 shows the clinical performance of blood glucose sensors a) without polymer membrane * trade-mark b) with polymer membrane (composition of Example 2) c) with polymer membrane (composition of Example 3) d) with polymer membrane (composition of Example 4).
In the comparative clinical investigations, the results of measurement with the various types of sensors were compared with the results of measurement by the reference method (YSI Model 2300 Stat Plus), and the percentage deviation was plotted against the values of the hematocrit for the individual blood samples. The result in the ideal case is a measurement line hori-zontal to the x axis. The gradient of these measurement lines, which is shown in Table 1, provides information about the interference of the hematocrit with the sensor system used.
Table 1 Gradient of the Gradient in %
measurement lines Type 1 (no membrane) -0.8253 100%
Type 2 (membrane from -0.4681 56%
Example 2) Type 3 (membrane from -0.2946 35%
Example 3) Type 4 (membrane from -0.0273 3.3%
Example 4) The data unambiguously reveal the superior performance of the sensor system with the preferred membrane (com-position of Example 4). This improvement is achieved through the separation of whole blood and plasma directly in front of the electrode, because the Nernst diffusion layer in front of the electrode can no longer be extended into the region with erythrocytes and therefore also can no longer be influenced by different values of the hematocrit.
The following comparative examples describe printing pastes in which there is no suitable accordance between the pore former, the solvents and the viscosity modifier.
Comparative Example 1 Polymer(s):
Cellulose acetate (Mw 50 000) 8.0% by weight Solvent:
Ethylene glycol diacetate (b.p. 186 C) 76.0% by weight Pore former:
n-Octanol (b.p. 196 C) 12.0% by weight Viscosity modifier:
Cab-O-Sil*M5 (hydrophilic) 4.0% by weight Additives:
PVP/VA 0.1% by weight Comparative Example 2 Polymer ( s ) :
Cellulose acetate (Mw 50 000) 8.0% by weight Solvents:
1,4-Dioxane (b.p. 102 C) 20.0% by weight 4-Hydroxymethylpentanone (b.p. 165 C) 56.0% by weight Pore former:
n-Octanol (b.p. 196 C) 12.0% by weight Viscosity modifier:
Cab-O-SiI~ TS720 (hydrophobic) 4.0% by weight Additives:
PVP/VA 0.1% by weight * trade-mark Comparative Example 3 Polymer(s):
Cellulose acetate propionate (Mw 75 000) 8.0% by weight Solvents:
1,4-Dioxane (b.p. 102 C) 20.0% by weight 4-Hydroxymethylpentanone (b.p_ 165 C) 56.0% by weight Pore former:
n-Octanol (b.p. 196 C) 12.0% by weight Viscosity modifier:
Cab-O-Sil~M5 (hydrophilic) 4.0% by weight Additives:
PVP/VA 0.1% by weight In Comparative Example 1 there is no formation of a porous membrane because the difference between the boiling points of the solvent (ethylene glycol diacetate) and pore former (n-octanol) used in the printing paste is too small. If, by contrast, n-decanol is used as pore former (as described in Example 1), a porous membrane is obtained after the drying process because the boiling point between the solvent and the pore former is sufficiently large.
In Comparative Example 2 there is only inadequate gel formation between the pore former and the viscosity modifier, because of the use of hydrophobic Cab-O-Sil*
which is unable to react with the OH groups of the pore former, and thus there is inadequate stabilization of the polymer skeleton. This impedes the formation of a porous membrane.
No porous membrane is formed in Comparative Example 3 either, where the solubility of the polymer used * trade-mark (cellulose acetate propionate) in the pore former is too high.
octanol). The amount and the distribution of the gel produced during the drying process eventually deter-mines the size and shape of the pores which develop.
Without addition of a viscosity modifier there is formation of an emulsion from the solvent and the pore former, because the pore former is unable on its own to stabilize the polymer skeleton. The result is a white, smooth and unstructured film with entrapped pore former, which does not allow lateral liquid transport.
By comparison, a clear film is obtained when no pore former is used in the paste.
If the amounts of viscosity modifier used are too small (< 1% by weight), the resulting membrane has an only inadequately developed pore structure, as shown in Figure 3a.
Since the various suitable viscosity modifiers have different surface properties, the viscosity modifier can be selected depending on the required membrane or the required biosensor. For example, with high mechanical stress, e.g. with long printing times or on printing of very thin layers with a high squeegee pressure, the Cab-O-SilH5 is "crushed". The surface then shows microscopically sharp fracture edges which may lead to lysis of the red blood cells.
This is an unwanted property for a blood glucose sensor because the basic current of the sensor is increased thereby. On the other hand, this effect can be opti-mized, and the plasma from cells be utilized directly in the sensor for the electrochemical detection. One * trade-mark practical example would be the examination of hemoglobin in erythrocytes. In this case, the mediator of the biosensor, e.g. potassium hexacyanoferrate(III), reacts with the Fe(II) group of the hemoglobin, producing potassium hexacyanoferrate(II) which can be determined directly at the electrode of the biosensor.
An enzyme like that in the case of glucose determination is unnecessary in this case because the mediator reacts directly with the hemoglobin. It is possible in this way in practice to determine the value of the hematocrit for a patient with similar measuring equipment as in the monitoring of blood glucose, making the time-consuming use of capillary tubes and centrifuge unnecessary.
Cab-O-Sil~ LM 150 consists of smaller particles than H5, which are therefore more stable and are not damaged by the mechanical stress during the printing process. This viscosity modifier is therefore most suitable for producing a membrane for blood glucose sensors.
In accordance with the above statement, the difference in boiling points between solvent and pore former is, besides the stabilization of the polymer skeleton by the viscosity modifier, important for the formation of a suitable membrane. The difference should be about C in this case, so that there is formation in the drying process of a film which comprises a sufficiently high concentration of pore former in which the membrane 30 polymer can precipitate. If the boiling point differen-ces are smaller the pore former starts to evaporate before a critical ratio between solvent and pore former is reached, which brings about the precipitation of the membrane polymer.
After the screen-printable paste with the composition described previously has been printed, and the solvent has evaporated, there is formation through deposition of the cellulose esters of a membrane with an average * trade-mark pore size of from 0.1 to 2 m, it being possible to influence the pore size by the amount of long-chain alcohol used. An electron micrograph of the membrane is shown in Figure 3b. Since erythrocytes have an average size of 8 to 10 m, the membrane keeps them away from the enzyme layer, while the plasma can pass through unhindered. In addition, the membrane contributes to the mechanical stability of the enzyme layer and prevents the enzyme being detached from the electrode on application of the blood sample and then no longer being available for the electrochemical reaction.
Figure 4 illustrates by means of a series of measure-ments the fact that at a constant glucose concentration the test strip provided with a membrane of the inven-tion provides, in contrast to a test strip without membrane, constant results as the values of the hema-tocrit increase, whereas the response with the test strip without membrane decreases as the erythrocyte concentration increases. Because of the increased dif-fusion barrier between the enzyme layer and the blood sample, the response overall is somewhat reduced in the case of the sensor with membrane.
The invention is illustrated by means of the following examples.
Production of the printing paste:
In accordance with the ratios of amounts indicated in the following examples, a mixture of the solvent (e.g.
hydroxymethylpenanone, dioxane) and the pore former (e.g. octanol, MPD) is produced to ensure uniform distribution of the two substances. In the next step, all the additives (e.g. PVP/VA) are added and dissolved, if necessary with the aid of ultrasound. The membrane polymer (cellulose actate 50 kDa) is then mixed rapidly with the previously produced solvent until a uniform suspension results. This suspension is rolled for 48 h in a closed container until a clear gel results, and it is possible to add the viscosity modifier (e.g. Cab-O-Sil) to this. The finished printing paste is rolled for a further 24 h in order to ensure uniform distribution of the viscosity modifier.
Example 1 Polymer(s):
Cellulose acetate (Mw 30 000) 7.5% by weight Solvent:
Ethylene glycol diacetate (b.p. 186 C) 65.5% by weight Pore former:
n-Decanol (b.p. 231 C) 25.0% by weight Viscosity modifier:
Cab-O-Sil~ M5 2.0% by weight Example 2 Polymer(s) Cellulose acetate (Mw 50 000) 8.0% by weight Solvents:
1,4-Dioxane (b.p. 102 C) 35.0% by weight Ethyl acetate (b.p. 154 C) 35.0% by weight Pore former:
n-Octanol (b.p. 196 C) 18.0% by weight Viscosity modifier:
Cab-O-Sil''M5 4.0% by weight * trade-mark Example 3 Polymer(s):
Cellulose acetate (Mw 50 000) 8.0% by weight Solvents:
1,4-Dioxane (b.p. 102 C) 20.0% by weight 4-Hydroxymethylpentanone (b.p. 165 C) 56.0% by weight Pore former:
n-Octanol (b.p. 196 C) 12.0% by weight Viscosity modifier:
Cab-O-Sil~ M5 4.0% by weight Additives:
PVP/VA 0.1% by weight Example 4 Polymer(s):
Cellulose acetate (Mw 50 000) 7.4% by weight Solvents:
1,4-Dioxane (b.p. 102 C) 18.5% by weight 4-Hydroxymethylpentanone (b.p. 165 C) 55.6% by weight Pore former:
2-Methyl-2,4-pentanediol 14.8% by weight Viscosity modifier:
Cab-O-Si? M5 3.7% by weight Additives:
PVP/VA 0.1% by weight Figure 5 shows the clinical performance of blood glucose sensors a) without polymer membrane * trade-mark b) with polymer membrane (composition of Example 2) c) with polymer membrane (composition of Example 3) d) with polymer membrane (composition of Example 4).
In the comparative clinical investigations, the results of measurement with the various types of sensors were compared with the results of measurement by the reference method (YSI Model 2300 Stat Plus), and the percentage deviation was plotted against the values of the hematocrit for the individual blood samples. The result in the ideal case is a measurement line hori-zontal to the x axis. The gradient of these measurement lines, which is shown in Table 1, provides information about the interference of the hematocrit with the sensor system used.
Table 1 Gradient of the Gradient in %
measurement lines Type 1 (no membrane) -0.8253 100%
Type 2 (membrane from -0.4681 56%
Example 2) Type 3 (membrane from -0.2946 35%
Example 3) Type 4 (membrane from -0.0273 3.3%
Example 4) The data unambiguously reveal the superior performance of the sensor system with the preferred membrane (com-position of Example 4). This improvement is achieved through the separation of whole blood and plasma directly in front of the electrode, because the Nernst diffusion layer in front of the electrode can no longer be extended into the region with erythrocytes and therefore also can no longer be influenced by different values of the hematocrit.
The following comparative examples describe printing pastes in which there is no suitable accordance between the pore former, the solvents and the viscosity modifier.
Comparative Example 1 Polymer(s):
Cellulose acetate (Mw 50 000) 8.0% by weight Solvent:
Ethylene glycol diacetate (b.p. 186 C) 76.0% by weight Pore former:
n-Octanol (b.p. 196 C) 12.0% by weight Viscosity modifier:
Cab-O-Sil*M5 (hydrophilic) 4.0% by weight Additives:
PVP/VA 0.1% by weight Comparative Example 2 Polymer ( s ) :
Cellulose acetate (Mw 50 000) 8.0% by weight Solvents:
1,4-Dioxane (b.p. 102 C) 20.0% by weight 4-Hydroxymethylpentanone (b.p. 165 C) 56.0% by weight Pore former:
n-Octanol (b.p. 196 C) 12.0% by weight Viscosity modifier:
Cab-O-SiI~ TS720 (hydrophobic) 4.0% by weight Additives:
PVP/VA 0.1% by weight * trade-mark Comparative Example 3 Polymer(s):
Cellulose acetate propionate (Mw 75 000) 8.0% by weight Solvents:
1,4-Dioxane (b.p. 102 C) 20.0% by weight 4-Hydroxymethylpentanone (b.p_ 165 C) 56.0% by weight Pore former:
n-Octanol (b.p. 196 C) 12.0% by weight Viscosity modifier:
Cab-O-Sil~M5 (hydrophilic) 4.0% by weight Additives:
PVP/VA 0.1% by weight In Comparative Example 1 there is no formation of a porous membrane because the difference between the boiling points of the solvent (ethylene glycol diacetate) and pore former (n-octanol) used in the printing paste is too small. If, by contrast, n-decanol is used as pore former (as described in Example 1), a porous membrane is obtained after the drying process because the boiling point between the solvent and the pore former is sufficiently large.
In Comparative Example 2 there is only inadequate gel formation between the pore former and the viscosity modifier, because of the use of hydrophobic Cab-O-Sil*
which is unable to react with the OH groups of the pore former, and thus there is inadequate stabilization of the polymer skeleton. This impedes the formation of a porous membrane.
No porous membrane is formed in Comparative Example 3 either, where the solubility of the polymer used * trade-mark (cellulose acetate propionate) in the pore former is too high.
Claims (18)
1. A screen-printable paste for producing a porous polymer membrane, comprising at least one polymer, one or more solvents for the polymer with a boiling point of >
100°C, one or more nonsolvent pore formers for the polymer with a higher boiling point than the one or more solvents and a hydrophilic viscosity modifier.
100°C, one or more nonsolvent pore formers for the polymer with a higher boiling point than the one or more solvents and a hydrophilic viscosity modifier.
2. A screen-printable paste as claimed in claim 1, characterized in that the difference in the boiling points of solvent and pore former is at least 30°C.
3. A screen-printable paste as claimed in claim 1 or 2, characterized in that the paste comprises cellulose acetate as polymer.
4. A screen-printable paste as claimed in claim 3, characterized in that the paste comprises at least one of 1,4-dioxane, 4-hydroxymethylpentanone and ethyl acetate as solvent.
5. A screen-printable paste as claimed in any one of claims 1 to 4, characterized in that the paste comprises a long-chain alcohol as pore former.
6. A screen-printable paste as claimed in claim 5, characterized in that the paste comprises at least one of n-octanol and 2-methyl-2,4-pentanediol as pore former.
7. A screen-printable paste as claimed in claim 6, characterized in that the at least one of n-octanol and 2-methyl-2,4-pentanediol is present in a proportion of 5-20%
by weight.
by weight.
8. A screen-printable paste as claimed in any one of claims 1 to 7, characterized in that the paste comprises hydrophilic silica xerogel as viscosity modifier.
9. A screen-printable paste as claimed in claim 8, characterized in that the silica xerogel is present in a proportion of 1-10% by weight.
10. A screen-printable paste as claimed in any one of claims 1 to 9, characterized in that the paste additionally comprises at least one of vinylpyrolidone/vinyl acetate copolymer (PVP/VA) and polyvinylpyrolidone (PVP).
11. A screen-printable paste as claimed in claim 10, characterized in that the PVP/VA or PVP is present in a proportion of 0.1% by weight.
12. A screen-printable paste as claimed in any one of claims 1 to 11, characterized in that the paste additionally comprises one or more enzymes.
13. A method for producing a screen-printable paste, by producing a mixture of one or more solvents for a polymer and one or more nonsolvent pore formers for a polymer, mixing in the polymer until a uniform suspension results, rolling the suspension until a clear gel results, adding a hydrophilic viscosity modifier, and rolling the mixture until the viscosity modifier is uniformly distributed,said one or more solvents having a boiling point of > 100°C, and the one or more nonsolvent pore formers having a higher boiling point than the one or more solvents.
14. The use of the paste as claimed in any one of claims 1 to 12 for producing a porous polymer membrane.
15. The use as claimed in claim 14, where the polymer membrane is introduced into a biosensor test strip.
16. The use as claimed in claim 15, characterized in that the biosensor is designed for measuring blood glucose concentration.
17. The use as claimed in claim 15, characterized in that the biosensor is designed for determining the value of the hematocrit.
18. A porous polymer membrane produced from the screen-printable paste as claimed in any one of claims 1 to 12.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE10052066A DE10052066A1 (en) | 2000-10-19 | 2000-10-19 | Screen printable paste for the production of a porous polymer membrane for a biosensor |
| DE10052066.9 | 2000-10-19 | ||
| PCT/EP2001/012073 WO2002032559A1 (en) | 2000-10-19 | 2001-10-18 | Paste, which can undergo screen printing, for producing a porous polymer membrane for a biosensor |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2394948A1 CA2394948A1 (en) | 2002-04-25 |
| CA2394948C true CA2394948C (en) | 2010-04-20 |
Family
ID=7660463
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA2394948A Expired - Lifetime CA2394948C (en) | 2000-10-19 | 2001-10-18 | Screen-printable paste for producing a porous polymer membrane for a biosensor |
Country Status (18)
| Country | Link |
|---|---|
| US (1) | US6719923B2 (en) |
| EP (1) | EP1246688B1 (en) |
| JP (1) | JP3939651B2 (en) |
| KR (1) | KR100830855B1 (en) |
| AT (1) | ATE266461T1 (en) |
| AU (1) | AU780195B2 (en) |
| CA (1) | CA2394948C (en) |
| CZ (1) | CZ20022136A3 (en) |
| DE (2) | DE10052066A1 (en) |
| DK (1) | DK1246688T3 (en) |
| DZ (1) | DZ3245A1 (en) |
| ES (1) | ES2218465T3 (en) |
| IL (1) | IL150175A (en) |
| MX (1) | MXPA02006101A (en) |
| PT (1) | PT1246688E (en) |
| RU (1) | RU2225249C1 (en) |
| TR (1) | TR200401526T4 (en) |
| WO (1) | WO2002032559A1 (en) |
Families Citing this family (78)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6036924A (en) | 1997-12-04 | 2000-03-14 | Hewlett-Packard Company | Cassette of lancet cartridges for sampling blood |
| US6391005B1 (en) | 1998-03-30 | 2002-05-21 | Agilent Technologies, Inc. | Apparatus and method for penetration with shaft having a sensor for sensing penetration depth |
| US20050103624A1 (en) | 1999-10-04 | 2005-05-19 | Bhullar Raghbir S. | Biosensor and method of making |
| US8641644B2 (en) | 2000-11-21 | 2014-02-04 | Sanofi-Aventis Deutschland Gmbh | Blood testing apparatus having a rotatable cartridge with multiple lancing elements and testing means |
| GB0030929D0 (en) | 2000-12-19 | 2001-01-31 | Inverness Medical Ltd | Analyte measurement |
| US9795747B2 (en) | 2010-06-02 | 2017-10-24 | Sanofi-Aventis Deutschland Gmbh | Methods and apparatus for lancet actuation |
| AU2002312521A1 (en) | 2001-06-12 | 2002-12-23 | Pelikan Technologies, Inc. | Blood sampling apparatus and method |
| US9226699B2 (en) | 2002-04-19 | 2016-01-05 | Sanofi-Aventis Deutschland Gmbh | Body fluid sampling module with a continuous compression tissue interface surface |
| US7025774B2 (en) | 2001-06-12 | 2006-04-11 | Pelikan Technologies, Inc. | Tissue penetration device |
| US7344507B2 (en) | 2002-04-19 | 2008-03-18 | Pelikan Technologies, Inc. | Method and apparatus for lancet actuation |
| US7981056B2 (en) | 2002-04-19 | 2011-07-19 | Pelikan Technologies, Inc. | Methods and apparatus for lancet actuation |
| WO2002100461A2 (en) | 2001-06-12 | 2002-12-19 | Pelikan Technologies, Inc. | Method and apparatus for improving success rate of blood yield from a fingerstick |
| US9427532B2 (en) | 2001-06-12 | 2016-08-30 | Sanofi-Aventis Deutschland Gmbh | Tissue penetration device |
| EP1404233B1 (en) | 2001-06-12 | 2009-12-02 | Pelikan Technologies Inc. | Self optimizing lancing device with adaptation means to temporal variations in cutaneous properties |
| US8337419B2 (en) | 2002-04-19 | 2012-12-25 | Sanofi-Aventis Deutschland Gmbh | Tissue penetration device |
| WO2002100254A2 (en) | 2001-06-12 | 2002-12-19 | Pelikan Technologies, Inc. | Method and apparatus for lancet launching device integrated onto a blood-sampling cartridge |
| US7033371B2 (en) | 2001-06-12 | 2006-04-25 | Pelikan Technologies, Inc. | Electric lancet actuator |
| US7892183B2 (en) | 2002-04-19 | 2011-02-22 | Pelikan Technologies, Inc. | Method and apparatus for body fluid sampling and analyte sensing |
| US8784335B2 (en) | 2002-04-19 | 2014-07-22 | Sanofi-Aventis Deutschland Gmbh | Body fluid sampling device with a capacitive sensor |
| US7892185B2 (en) | 2002-04-19 | 2011-02-22 | Pelikan Technologies, Inc. | Method and apparatus for body fluid sampling and analyte sensing |
| US7648468B2 (en) | 2002-04-19 | 2010-01-19 | Pelikon Technologies, Inc. | Method and apparatus for penetrating tissue |
| US8360992B2 (en) | 2002-04-19 | 2013-01-29 | Sanofi-Aventis Deutschland Gmbh | Method and apparatus for penetrating tissue |
| US7976476B2 (en) | 2002-04-19 | 2011-07-12 | Pelikan Technologies, Inc. | Device and method for variable speed lancet |
| US7909778B2 (en) | 2002-04-19 | 2011-03-22 | Pelikan Technologies, Inc. | Method and apparatus for penetrating tissue |
| US7371247B2 (en) | 2002-04-19 | 2008-05-13 | Pelikan Technologies, Inc | Method and apparatus for penetrating tissue |
| US9248267B2 (en) | 2002-04-19 | 2016-02-02 | Sanofi-Aventis Deustchland Gmbh | Tissue penetration device |
| US8267870B2 (en) | 2002-04-19 | 2012-09-18 | Sanofi-Aventis Deutschland Gmbh | Method and apparatus for body fluid sampling with hybrid actuation |
| US8702624B2 (en) | 2006-09-29 | 2014-04-22 | Sanofi-Aventis Deutschland Gmbh | Analyte measurement device with a single shot actuator |
| US7291117B2 (en) | 2002-04-19 | 2007-11-06 | Pelikan Technologies, Inc. | Method and apparatus for penetrating tissue |
| US7229458B2 (en) | 2002-04-19 | 2007-06-12 | Pelikan Technologies, Inc. | Method and apparatus for penetrating tissue |
| US8221334B2 (en) | 2002-04-19 | 2012-07-17 | Sanofi-Aventis Deutschland Gmbh | Method and apparatus for penetrating tissue |
| US7674232B2 (en) | 2002-04-19 | 2010-03-09 | Pelikan Technologies, Inc. | Method and apparatus for penetrating tissue |
| US9314194B2 (en) | 2002-04-19 | 2016-04-19 | Sanofi-Aventis Deutschland Gmbh | Tissue penetration device |
| US7717863B2 (en) | 2002-04-19 | 2010-05-18 | Pelikan Technologies, Inc. | Method and apparatus for penetrating tissue |
| US7713214B2 (en) | 2002-04-19 | 2010-05-11 | Pelikan Technologies, Inc. | Method and apparatus for a multi-use body fluid sampling device with optical analyte sensing |
| US9795334B2 (en) | 2002-04-19 | 2017-10-24 | Sanofi-Aventis Deutschland Gmbh | Method and apparatus for penetrating tissue |
| US8579831B2 (en) | 2002-04-19 | 2013-11-12 | Sanofi-Aventis Deutschland Gmbh | Method and apparatus for penetrating tissue |
| US7547287B2 (en) | 2002-04-19 | 2009-06-16 | Pelikan Technologies, Inc. | Method and apparatus for penetrating tissue |
| US7901362B2 (en) | 2002-04-19 | 2011-03-08 | Pelikan Technologies, Inc. | Method and apparatus for penetrating tissue |
| US7491178B2 (en) | 2002-04-19 | 2009-02-17 | Pelikan Technologies, Inc. | Method and apparatus for penetrating tissue |
| US7331931B2 (en) | 2002-04-19 | 2008-02-19 | Pelikan Technologies, Inc. | Method and apparatus for penetrating tissue |
| US7232451B2 (en) | 2002-04-19 | 2007-06-19 | Pelikan Technologies, Inc. | Method and apparatus for penetrating tissue |
| US7297122B2 (en) | 2002-04-19 | 2007-11-20 | Pelikan Technologies, Inc. | Method and apparatus for penetrating tissue |
| AU2003276413B2 (en) * | 2002-10-30 | 2007-12-13 | Lifescan Scotland Limited | Apparatus and method for controlling registration of print steps in a continuous process for the manufacture of electrochemical sensors |
| US7244264B2 (en) | 2002-12-03 | 2007-07-17 | Roche Diagnostics Operations, Inc. | Dual blade lancing test strip |
| US8574895B2 (en) | 2002-12-30 | 2013-11-05 | Sanofi-Aventis Deutschland Gmbh | Method and apparatus using optical techniques to measure analyte levels |
| DE602004028463D1 (en) | 2003-05-30 | 2010-09-16 | Pelikan Technologies Inc | METHOD AND DEVICE FOR INJECTING LIQUID |
| US7462265B2 (en) * | 2003-06-06 | 2008-12-09 | Lifescan, Inc. | Reduced volume electrochemical sensor |
| US7850621B2 (en) | 2003-06-06 | 2010-12-14 | Pelikan Technologies, Inc. | Method and apparatus for body fluid sampling and analyte sensing |
| US20040251132A1 (en) * | 2003-06-06 | 2004-12-16 | Leach Christopher Philip | Reduced volume strip |
| WO2006001797A1 (en) | 2004-06-14 | 2006-01-05 | Pelikan Technologies, Inc. | Low pain penetrating |
| EP1635170B1 (en) | 2003-06-19 | 2012-09-26 | ARKRAY, Inc. | Analysis implement with opening in insulation film |
| PT1639352T (en) | 2003-06-20 | 2018-07-09 | Hoffmann La Roche | Method and reagent for producing narrow, homogenous reagent strips |
| US8282576B2 (en) | 2003-09-29 | 2012-10-09 | Sanofi-Aventis Deutschland Gmbh | Method and apparatus for an improved sample capture device |
| EP1680014A4 (en) | 2003-10-14 | 2009-01-21 | Pelikan Technologies Inc | Method and apparatus for a variable user interface |
| US7822454B1 (en) | 2005-01-03 | 2010-10-26 | Pelikan Technologies, Inc. | Fluid sampling device with improved analyte detecting member configuration |
| EP1706026B1 (en) | 2003-12-31 | 2017-03-01 | Sanofi-Aventis Deutschland GmbH | Method and apparatus for improving fluidic flow and sample capture |
| EP1751546A2 (en) | 2004-05-20 | 2007-02-14 | Albatros Technologies GmbH & Co. KG | Printable hydrogel for biosensors |
| EP1765194A4 (en) | 2004-06-03 | 2010-09-29 | Pelikan Technologies Inc | Method and apparatus for a fluid sampling device |
| US9775553B2 (en) | 2004-06-03 | 2017-10-03 | Sanofi-Aventis Deutschland Gmbh | Method and apparatus for a fluid sampling device |
| US7569126B2 (en) | 2004-06-18 | 2009-08-04 | Roche Diagnostics Operations, Inc. | System and method for quality assurance of a biosensor test strip |
| CA2973124C (en) | 2004-10-12 | 2020-01-07 | Ascensia Diabetes Care Holdings Ag | Concentration determination in a diffusion barrier layer |
| JP4643222B2 (en) * | 2004-10-27 | 2011-03-02 | 日機装株式会社 | Biosensor and manufacturing method thereof |
| US8652831B2 (en) | 2004-12-30 | 2014-02-18 | Sanofi-Aventis Deutschland Gmbh | Method and apparatus for analyte measurement test time |
| US8744546B2 (en) * | 2005-05-05 | 2014-06-03 | Dexcom, Inc. | Cellulosic-based resistance domain for an analyte sensor |
| WO2009126900A1 (en) | 2008-04-11 | 2009-10-15 | Pelikan Technologies, Inc. | Method and apparatus for analyte detecting device |
| US20090294302A1 (en) * | 2008-05-28 | 2009-12-03 | John Pasqua | Use of Alginate to Reduce Hematocrit Bias in Biosensors |
| US9375169B2 (en) | 2009-01-30 | 2016-06-28 | Sanofi-Aventis Deutschland Gmbh | Cam drive for managing disposable penetrating member actions with a single motor and motor and control system |
| US20100273249A1 (en) * | 2009-04-24 | 2010-10-28 | Lifescan Scotland Limited | Analytical test strips |
| US8025788B2 (en) * | 2009-04-24 | 2011-09-27 | Lifescan Scotland Limited | Method for manufacturing an enzymatic reagent ink |
| KR101239219B1 (en) * | 2009-10-15 | 2013-03-06 | 한국전자통신연구원 | The bio chip and the sensing method thereof |
| US8965476B2 (en) | 2010-04-16 | 2015-02-24 | Sanofi-Aventis Deutschland Gmbh | Tissue penetration device |
| WO2012055107A1 (en) * | 2010-10-28 | 2012-05-03 | 深圳智慧天使投资有限公司 | Water-in-oil emulsion ink composition and use thereof |
| US8486717B2 (en) | 2011-01-18 | 2013-07-16 | Symbolics, Llc | Lateral flow assays using two dimensional features |
| US20150004686A1 (en) | 2012-02-02 | 2015-01-01 | Corning Incorporated | Automatic continuous perfusion cell culture microplate consumables |
| US9874556B2 (en) | 2012-07-18 | 2018-01-23 | Symbolics, Llc | Lateral flow assays using two dimensional features |
| CN108051590B (en) | 2013-09-13 | 2020-12-11 | Symbolics有限责任公司 | Lateral flow assay using two-dimensional test and control signal readout modes |
| JP7184240B2 (en) * | 2018-07-04 | 2022-12-06 | デュラルクローム アーゲー | Creating a direct-to-mesh screen |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4425263A (en) | 1981-06-03 | 1984-01-10 | E. I. Du Pont De Nemours & Co. | Flexible screen-printable conductive composition |
| US5607566A (en) * | 1989-06-23 | 1997-03-04 | The Board Of Regents Of The University Of Michigan | Batch deposition of polymeric ion sensor membranes |
| GB9309797D0 (en) | 1993-05-12 | 1993-06-23 | Medisense Inc | Electrochemical sensors |
| US5378408A (en) * | 1993-07-29 | 1995-01-03 | E. I. Du Pont De Nemours And Company | Lead-free thick film paste composition |
| US5556576A (en) * | 1995-09-22 | 1996-09-17 | Kim; Yong C. | Method for producing conductive polymeric coatings with positive temperature coefficients of resistivity and articles made therefrom |
| US5886059A (en) * | 1997-07-08 | 1999-03-23 | Memtec America Corporation | Highly asymmetric polyethersulfone filtration membranes |
| US6134461A (en) * | 1998-03-04 | 2000-10-17 | E. Heller & Company | Electrochemical analyte |
-
2000
- 2000-10-19 DE DE10052066A patent/DE10052066A1/en not_active Ceased
-
2001
- 2001-10-18 TR TR2004/01526T patent/TR200401526T4/en unknown
- 2001-10-18 PT PT01987692T patent/PT1246688E/en unknown
- 2001-10-18 RU RU2002119393/04A patent/RU2225249C1/en not_active IP Right Cessation
- 2001-10-18 CZ CZ20022136A patent/CZ20022136A3/en unknown
- 2001-10-18 EP EP01987692A patent/EP1246688B1/en not_active Expired - Lifetime
- 2001-10-18 DZ DZ013245A patent/DZ3245A1/en active
- 2001-10-18 KR KR1020027007799A patent/KR100830855B1/en active IP Right Grant
- 2001-10-18 IL IL15017501A patent/IL150175A/en not_active IP Right Cessation
- 2001-10-18 JP JP2002535792A patent/JP3939651B2/en not_active Expired - Lifetime
- 2001-10-18 WO PCT/EP2001/012073 patent/WO2002032559A1/en active IP Right Grant
- 2001-10-18 DE DE50102260T patent/DE50102260D1/en not_active Expired - Lifetime
- 2001-10-18 MX MXPA02006101A patent/MXPA02006101A/en active IP Right Grant
- 2001-10-18 CA CA2394948A patent/CA2394948C/en not_active Expired - Lifetime
- 2001-10-18 US US10/168,876 patent/US6719923B2/en not_active Expired - Lifetime
- 2001-10-18 ES ES01987692T patent/ES2218465T3/en not_active Expired - Lifetime
- 2001-10-18 AU AU21701/02A patent/AU780195B2/en not_active Ceased
- 2001-10-18 AT AT01987692T patent/ATE266461T1/en active
- 2001-10-18 DK DK01987692T patent/DK1246688T3/en active
Also Published As
| Publication number | Publication date |
|---|---|
| RU2225249C1 (en) | 2004-03-10 |
| CZ20022136A3 (en) | 2003-01-15 |
| RU2002119393A (en) | 2004-01-10 |
| JP2004511791A (en) | 2004-04-15 |
| CA2394948A1 (en) | 2002-04-25 |
| US6719923B2 (en) | 2004-04-13 |
| ATE266461T1 (en) | 2004-05-15 |
| EP1246688A1 (en) | 2002-10-09 |
| JP3939651B2 (en) | 2007-07-04 |
| DE10052066A1 (en) | 2002-05-29 |
| ES2218465T3 (en) | 2004-11-16 |
| DZ3245A1 (en) | 2002-04-25 |
| DK1246688T3 (en) | 2004-08-30 |
| PT1246688E (en) | 2004-09-30 |
| IL150175A (en) | 2005-12-18 |
| US20030125403A1 (en) | 2003-07-03 |
| TR200401526T4 (en) | 2004-09-21 |
| MXPA02006101A (en) | 2004-08-23 |
| AU780195B2 (en) | 2005-03-10 |
| DE50102260D1 (en) | 2004-06-17 |
| EP1246688B1 (en) | 2004-05-12 |
| IL150175A0 (en) | 2002-12-01 |
| WO2002032559A1 (en) | 2002-04-25 |
| AU2170102A (en) | 2002-04-29 |
| KR100830855B1 (en) | 2008-05-21 |
| KR20020081226A (en) | 2002-10-26 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CA2394948C (en) | Screen-printable paste for producing a porous polymer membrane for a biosensor | |
| JP5912213B2 (en) | Size self-regulating composition and test apparatus for measuring analytes in biological fluids | |
| US4824639A (en) | Test device and a method for the detection of a component of a liquid sample | |
| US5658444A (en) | Electrochemical sensors | |
| Mizutani et al. | Amperometric L-lactate-sensing electrode based on a polyion complex layer containing lactate oxidase. Application to serum and milk samples | |
| EP0079502B1 (en) | Multilayer enzyme electrode membrane, method of making same and polarographic cell structure | |
| JP2614277B2 (en) | sensor | |
| JPH0210902B2 (en) | ||
| JPS6358149A (en) | Biosensor | |
| US5520788A (en) | Support layer for enzyme electrode laminated membranes | |
| US5160436A (en) | Asymmetric sandwich membrane system having reduced ascorbate interference | |
| US6706532B2 (en) | Membrane for chemical and biosensors | |
| EP1712635B1 (en) | Water-miscible conductive ink for use in enzymatic electrochemical-based sensors | |
| US6020052A (en) | Laminated membrane structure for polarographic measurement and methods of making said structures | |
| JP2001519896A (en) | Analysis method and device | |
| EP0857107B1 (en) | Improved laminated membrane structure for polarographic measurement and methods of making said structures | |
| JPS6264941A (en) | Enzyme immobilized membrane for biosensor | |
| JPS59228160A (en) | Amylase analyzing method | |
| AU1802888A (en) | Improvements in diagnostic test strips | |
| JPS58129245A (en) | Selective membrane permeable to hydrogen peroxide |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| MKEX | Expiry |
Effective date: 20211018 |