WO1990000572A1 - Elements de detection composes de films de colorant sous forme d'hydrogel et leur preparation - Google Patents

Elements de detection composes de films de colorant sous forme d'hydrogel et leur preparation Download PDF

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Publication number
WO1990000572A1
WO1990000572A1 PCT/US1989/003015 US8903015W WO9000572A1 WO 1990000572 A1 WO1990000572 A1 WO 1990000572A1 US 8903015 W US8903015 W US 8903015W WO 9000572 A1 WO9000572 A1 WO 9000572A1
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Prior art keywords
dye
film
hydroxy
azo
amino
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PCT/US1989/003015
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English (en)
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Bernhard J. Boesterling
Daniel M. Chang
Alex M. Madonik
Robert T. Stone
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Nellcor Incorporated
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Publication of WO1990000572A1 publication Critical patent/WO1990000572A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G18/00—Polymeric products of isocyanates or isothiocyanates
    • C08G18/06—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen
    • C08G18/28—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen characterised by the compounds used containing active hydrogen
    • C08G18/30—Low-molecular-weight compounds
    • C08G18/38—Low-molecular-weight compounds having heteroatoms other than oxygen
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G18/00—Polymeric products of isocyanates or isothiocyanates
    • C08G18/06—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen
    • C08G18/08—Processes
    • C08G18/0804—Manufacture of polymers containing ionic or ionogenic groups
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N31/00—Investigating or analysing non-biological materials by the use of the chemical methods specified in the subgroup; Apparatus specially adapted for such methods
    • G01N31/22—Investigating or analysing non-biological materials by the use of the chemical methods specified in the subgroup; Apparatus specially adapted for such methods using chemical indicators
    • G01N31/221—Investigating or analysing non-biological materials by the use of the chemical methods specified in the subgroup; Apparatus specially adapted for such methods using chemical indicators for investigating pH value
    • 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
    • G01N33/52—Use of compounds or compositions for colorimetric, spectrophotometric or fluorometric investigation, e.g. use of reagent paper and including single- and multilayer analytical elements
    • G01N33/525—Multi-layer analytical elements
    • G01N33/526—Multi-layer analytical elements the element being adapted for a specific analyte
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G2210/00—Compositions for preparing hydrogels

Definitions

  • the present invention relates to new hydrogels, azo dyes, and pH sensitive dye films and sensing elements made therefrom. More particularly, it relates to hydrogel dye film sensing elements capable of detecting pH and pCO 2 and to apparatus useful for in vivo measurement of the pH and pCO 2 of body fluids, such as blood.
  • body fluid analyzers are known in the art, presently available analyzers use electro- chemical sensors, also known as electrodes, to measure blood parameters such as pH and pCO 2 . See, e.g., U.S. Patents 3,874,850; 4,097,921; 4,579,641; 4,615,340.
  • Optical sensors provide an alternative to electrochemical sensors, and there is a consequent need for new materials useful for making reliable optical sensing elements which are compatible with available. optical equipment.
  • hydrogels which are compatible with optical dye
  • hydrogels into which dyes may be permanently incorporated and which are suitable for use in optical sensing elements. It is further object to provide hydrogel dye films capable of undergoing an optically detectable, reversible color change as a function of changing pH.
  • a dye-containing sensing element e.g. for use in an apparatus for analyzing body fluids, the apparatus providing for contact between the sensing element and the fluid to be analyzed, and providing optical elements for automatically reading color changes in the sensing elements.
  • the sensing elements according to the present invention are comprised of thin films of a polyurethane or polyacrylamide hydrogel containing one or more azo dye indicators. The azo dye indicators undergo reversible color shifts as a
  • apparatus equipped with the sensing elements of the invention can optically detect such color shifts and calibrate the shifts to give accurate information as to the pH and pCO 2 of the fluid
  • polyurethane or polyacrylamide hydrogels and azo dyes disclosed herein are employed to form the sensing elements of the present invention.
  • FIGURE 1 is a schematic diagram of a fluid analyzer apparatus according to the invention.
  • FIGURE 2 is a sectional plan view of a possible configuration for a sensing cuvette in
  • FIGURE 3 is a sectional plan view of a sensing cell employing a sensing element according to the present invention showing its relationship toward impinging light from the optical components of a fluid analyzer which measures backscattered light.
  • the present invention relates to apparatus for analyzing fluids and to dyes, hydrogels, and dye films useful in the sensing elements in such apparatus.
  • Preferred sensing elements of the present invention are useful for detecting pH or for detecting pCO 2 .
  • Each of the sensing elements comprises one or more thin films.
  • the films are most advantageously deposited in layers on an optically clear substrate and disposed within fluid analyzer sensing cells such that the outermost layer is contacted by the fluid to be analyzed.
  • the sensing elements depend on a dye film layer, which is normally the first layer of the sensing element (i.e., deposited directly on the optically clear substrate).
  • the sensing elements may also include light scattering film layers and light absorbing film layers, to permit the use of optical equipment that measures
  • a gas permeable layer will also be employed.
  • the arrangement of the layers will depend on the configuration of the optical reading elements of the apparatus.
  • the optical reading elements of the apparatus For example, in the preferred embodiment
  • the order of the layers will be as follows: optically clear substrate, dye film layer, light reflective layer, light absorptive layer, gas permeable layer (pCO 2 -detecting elements only) .
  • the optically clear substrate is oriented toward the light source, and the outermost film layer (e.g., the gas permeable layer or the light absorptive layer) communicates with the channel of the sensing cuvette through which the fluid to be measured is made to pass.
  • the outermost film layer e.g., the gas permeable layer or the light absorptive layer
  • the indicator dyes used to produce the pH- detecting dye films of the present invention are azo dyes of the general formula:
  • R 2 represents a phenyl, naphthyl, or a C 2 -C 12 heterocyclic aromatic radical, which may be substituted with one or more groups selected from nitro, cyano, sulfo, carboxy, carboxamido, carboalkoxy, acyl, alkoxy, perfluoroalkyl, or halogen atoms such as bromine, chlorine, fluorine, etc.;
  • R 3 represents a suphonated naphthol
  • R 4 represents a reactive substituent capable of binding the dye molecule to a polymeric substrate without affecting the pH-indicating character of the dye.
  • Preferred dyes have the formula (I):
  • Each R 5 is independently selected from
  • R 6 is amino, carboxamido, acrylamido, -NHCO(CH 3 ) (CH 2 OH) 2 , or -NHCOCH(NR 7 R 8 )CH 2 NR 7 R 8 , wherein R 7 and R 8 are, independently, hydrogen, straight chain or branched alkyl, aminoalkyl, or hydroxyalkyl groups of 1 to 6 carbon atoms (e.g., methyl, ethyl, propyl, t-butyl, isobutyl, isopentyl, aminoethyl, aminopropyl, hydroxyethyl, hydroxypropyl, tris (hydroxymethyl)methyl, and the like), or R 7 and R 8 taken together form the radical -CH 2 CH 2 NR 9 CH 2 CH 2 -, wherein R 9 is hydrogen or any of the aforementioned C 1 -C 6 aminoalykl or hydroxy-alkyl radicals; and
  • E is hydrogen, sodium, lithium, potassium, magnesium or calcium.
  • R 6 are explicitly defined above, also contemplated are other groups which will serve to bind the dye molecules to a substrate without interfering with its pH-indicating properties.
  • hydrocarbons eg., alkylene
  • ether and thioether bridges terminating in a variety of functional groups may also be employed.
  • dyes in which R 5 para to the azo group and on R 5 ortho to the azo group are or cyano nitro are or cyano nitro
  • R 6 is -NHCO(CH 3 ) (CH 2 OH) 2 , -NHCOCH 2 NR 7 R 8 , or -NHCOCH(NR 7 R 8 )CH 2 NR 7 R 8
  • R 7 and R 8 are aminoethyl, aminopropyl, hydroxyethyl, hydroxypropyl, or tris
  • the reactive azo dyes of the present invention exhibit a pH-dependent color change with absorption maxima at wavelengths longer than 500 nm for both the protonated and deprotonated forms of the dye, and there is nearly complete spectral separation of the protonated and the deprotonated forms.
  • a single sharp transition due to a protonated equilibrium is exhibited within the pH-range encountered with physiological fluids such as blood; and the dyes are stable under the variable conditions of the medical environment in which they can be advantageously used (i.e., in terms of stability to heat, light, oxygen, compatability with physiological fluids, stability to sterilization procedures).
  • the dyes are conveniently incorporated into the structure of the polyurethane hydrogels and thereby immobilized, preventing them from leaching or bleeding out of the hydrogel substrate during use.
  • the dyes having the structure of formula (I) have a red to blue transition with increasing pH.
  • the dyes may be advantageously prepared via a coupling reaction between diazonium salts and amides derived from aminonaphthol sulfonic acids.
  • preferred starting materials for the dyes of formula (I) thus include the 2-halo-4, 6-dinitro-phenyldiazonium salts and their analogues (see R 5 in formula (I)).
  • the pK a can be lowered and the water- solubility increased by the introduction of a second sulfonic acid group on the naphthalene ring.
  • amides derived from 3-amino-5-hydroxy-2,7-naphthalenedisulfonic acid or 4-amino-5-hydroxy-2,7-naphthalenedisulfonic acid (H-Acid) may be used as coupling components.
  • interaction of the indicator with the supporting substrate is expected to be prominent.
  • nitro, cyano, sulfo, carbory, carboxamido, carboalkoxy, acyl, methyl- or methoxy-substituted phenyl or naphthyl diazonium reagents may be used.
  • Hydroxy substitution is also possible, however those dyes containing an ortho hydroxy substituent form complexes with heavy metal ions, a characteristic which may render them useless as pH-indicators.
  • the electronegativity of the substituents can be used to adjust the pK a value of the final dye.
  • the actual pK a value may also be further modified by the nature of the reactive group (e.g., R 4 , R 6 , supra) and by subsequent binding of the azo dye to a substrate.
  • derivatives may be prepared by dropwise addition of the acylating agent to an aqueous solution of the azo dye or the starting amino-naphthol (di) sulfonic acid.
  • the pH of the solution can be maintained by addition of a solution of sodium hydroxide or by the presence of sodium hydrogen carbonate resulting in a weakly acidic to weakly alkaline medium.
  • the reaction stoichiometry should be carefully controlled to avoid acylation of the hydroxyl group.
  • Diazonium coupling is carried out using standard methods (see, for example, H. E. Fierz-David and L. Blangey, "Fundamental Processes of Dye
  • pH-indicator dyes are also obtained by coupling ortho or para to the amino substituent, in which case an amino group is left that can be used for subsequent binding of the dye to a substrate.
  • such dyes are readily incorporated into isocyanate-capped polyurethane prepolymers, however this normally results in a radical shift in the optical characteristics of the dye (concommitant with engaging the free amino group) which makes this option somewhat less desirable for end uses such as optical pH or pCO 2 measurement.
  • reactive substituents such as aromatic sulfonyl halides or isocyanates
  • Reactive dyes obtained using these reagents can be bound directly to a substrate that contains nucleophilic substituents, or they can be readily converted into stable derivatives by treatment with suitable nucleophiles such as methylamine, ethanolamine, N-alkylethanolamines, diethanolamine, tris(hydroxymethyl) aminomethane, ethylenediamine, piperazine, and the like.
  • suitable nucleophiles such as methylamine, ethanolamine, N-alkylethanolamines, diethanolamine, tris(hydroxymethyl) aminomethane, ethylenediamine, piperazine, and the like.
  • the addition of substituents bearing hydroxyl or amino functions is most preferred, as it permits ready binding of the dye into the
  • the 2,3-dihalopropanoamide derivatives are readily converted to 2-haloacrylamides at pH 6 or above.
  • Dyes bearing acrylamido or 2-haloacrylamido groups may be linked covalently to a matrix by
  • R 4 may be a substituted amido group such as 2, 2-bis(hydroxymethyl) propanoamido.
  • R 4 is an amide derived from a succinamido substituent, for example an amide formed between an alkanolamine or diamine and the free
  • the dyes can electrostatically bind via their charged substituents.
  • no reactive group R 4 is required unless it is used to introduce additional charged groups for increased affinity to a charged substrate.
  • a charged group may be introduced by reaction of the acylated dye with aspartic acid.
  • the electrostatic binding of the dye may strongly affect the pK-value and can be used to modify the pH-sensitive range for color change after binding to a substrate. Examples are the binding of sulfonated dyes to a quarternarized
  • binding indicator dyes electrostatically via salt bridges is somewhat less desirable than covalent bonding because of the high probability of the
  • a solution of the diazonium salt was obtained by dissolving 2-bromo-4,6-dinitroaniline (6 mmol, 1.57 g) in concentrated sulfuric acid (11 g, 6 ml) followed by addition of nitrosylsulfuric acid (0.76 g, 6 mmol) . The yellow-orange solution was stirred for 1 hour at room temperature.
  • ANS-2-bromoacrylamide (2.38 g, 5 mmol) was dissolved in 100 ml water. The solution was cooled to 0oC by the addition of crushed ice. Approximately 0.5 equivalents of diazonium solution (2.5 ml, 2.5 mmol) was added to the stirred solution. After stirring overnight, the solution was acidified to pH 3. The addition of a sufficient 20% aqueous salt solution gave a 10% salt solution and precipitated the product.
  • the purple-red precipitate was washed with a small amount of water, dried and then taken up in hot methanol. Most of the solvent evaporated.
  • 2-chloro-4,6-dinitroaniline (2.18 g, 10 mmol) was diazotized in concentrated sulfuric acid (10 g) containing nitrosyl-sulfuric acid (1.27 g, 10 mmol) at room temperature. After one hour this solution was diluted with ice (30 g) and poured into a well-stirred slurry of the ANS-2-bromoacrylamide (3.94 g, 10 mmol) in a mixture of ice (50 g), water (25 g) and
  • Diazonium coupling with 2,6-6initro-4-trifluoromethylanilme (A 3 -2-bromoacrylamide); 2,6-dinitroaniline (A 4 -2-bromoacrylamide); 2,4-dinitro-6-trifluoromethylanilme (A 5 -2-bromoacrylamide) and 4-carboxamido-2,6-dinitroaniline (A 6 -2-bromoacrylamide).
  • the methods of Examples 4-6 were used to couple these diazonium components with the ANS-2-bromoacrylamide. All of the resulting dyes were useful pH indicating compounds, capable of further reaction at the 2- bromoacrylamido group, permitting their incorporation into polymeric films. The properties of these dyes are summarized in Table 1, infra.
  • 2,3-dibromopropanoyl chloride (40 mmol, 4.6 ml) was added to a well-stirred solution of 4-amino-5-hydroxy-2,7-naphthalenedisulfonic acid (H-Acid, 40 mmol of the monosodium salt sesquihydrate, 14.73 g) in 150 ml water adjusted to pH 6.5 with IN NaOH over 15 minutes at room temperature. Simultaneously, IN NaOH was added to maintain the pH between 6 and 7. When the reaction was completed (indicated by a stable pH), solid NaOH was added to raise the pH to 12, and the solution was heated briefly to boiling. The mixture was then cooled and acidified to pH 3 with concentrated HCl.
  • H-Acid 4-amino-5-hydroxy-2,7-naphthalenedisulfonic acid
  • Table 4 summarizes examples of pH-indicating dyes prepared from a variety of other coupling components.
  • R and R 1 substituents on the amine are chosen to provide covalent or electrostatic binding of the dye to the hydrogel (covalent linkage is preferred); their choice also influences the solubility of the dye, a significant consideration in the
  • This dye can also be precipitated in two acidified forms. After reaction with N-methylethanolamine as described in Example 20, treatment of the reaction mixture with glacial acetic acid gave a high yield (73%) of a red powder, presumably protonated at the naphthol end but not at the sulfonate end. This form of the dye was poorly soluble in water or organic solvents.
  • Diamino compounds including ethylene diamine, piperazine, and N-2-hydroxyethylpiperazine were added to the reactive dye in aqueous or methanol solution at room temperature, using a four to five-fold excess of the diamine. These reactions were completed within 15 minutes, and the adducts were isolated in high yield (>80%). However, TLC analysis (silica, eluting with BuOH : EtOH: NH 4 OH - - 3 : 2 : 1) revealed a mixture of products . Furthermore, these adducts had significantly lower pK a 's ( ⁇ 7), making them less suitable as physiologic pH indicators.
  • reaction mixture was acidified to pH 3 using
  • the diazonium reagent was prepared as in example 2, from 2-bromo-4, 6-dinitroaniline (20 mmol, 5.24 g) and nitrosylsulfuric acid (20 mmol, 2.54 g) in concentrated sulfuric acid (40 g). Before use, the diazonium solution was diluted with 120 g crushed ice. The resulting yellow solution was added in one portion to the coupling component (ANS-2-bromoacetamide,
  • a diazonium solution was prepared by adding 2-chloro-4, 6-dinitroaniline (2.17 g, 10 mmol) to concentrated sulfuric acid (20 g) containing
  • a diazonium solution was prepared by adding 2-trifluoromethyl-4,6-dinitroaniline (5.02 g, 20 mmol) to concentrated sulfuric acid (40 g) containing nitrosylsulfuric acid (20 mmol, 2.54 g). After stirring for one hour, the dark yellow diazonium solution was diluted with crushed ice (120 g) and poured into a well-stirred slurry containing ANS-2- bromoacetamide (20 mmol, 7.64 g), water (40 ml), crushed ice (80 g), and concentrated sulfuric acid (40 g). After one hour, the solid product was
  • a diazonium solution was prepared by adding 2-amino-3,5-dinitrobenzenesulfonic acid (5.70 g,
  • hydroxyethyl substituents are capable of reaction with isocyanates to form urethane linkages.
  • Table 5 summarizes the properties of the dyes prepared according to Examples 29-37.
  • the reaction mixture was then acidified to pH 0.5 with concentrated HCl and heated at 80oC for 2 hours.
  • High performance liquid chromatography (HPLC) analysis was used to determine when cleavage of the cyclic sulfite was complete.
  • the solution was then filtered while warm using Whatman #54 filter paper and Celite. An HPLC sample was run to determine ANS-BHPA concentration.
  • Examples 40-44 disclose the synthesis of dyes bearing the bis (2-hydroxymethyl)propanoamido group.
  • the diazonium solution was prepared by adding
  • diazonium solution can be stored at -20oC for several days.
  • a diazonium solution was prepared by addition of 2-chloro-4,6-dinitroaniline (25 mmol, 5.44 g) to concentrated sulfuric acid (40 g) containing
  • nitrosylsulfuric acid 25 mmol, 3.18 g
  • ANS-BHPA 25 mmol in 60 ml water
  • the dense red-purple precipitate was collected by filtration overnight on Whatman #54 paper. It was then dispersed in water (300 ml), precipited with 20% aqueous NaCl (300 ml), and filtered on Whatman #54 paper. The resulting cake was washed with water
  • the reguired aniline (4,6-dinitro-2-fluoroaniline) was prepared as described by Schiemann and Miou (Ber. 66, 1179-87 (1933)). It was diazotized on the same scale used in the previous example
  • the aniline (2-bromo-6-cyano-4-nitroaniline) was prepared according to U.S. Patent 3,821,276 (Mrozik and Bochis). Its diazotization on a 40 mmol scale (9.68 g) was carried out in concentrated sulfuric acid (40 g) containing one equivalent of nitrosylsulfuric acid (40 mmol, 5.08 g) at room temperature. Just before use, the diazonium solution was diluted with crushed ice (120 g), and then added to a well-stirred solution of ANS-BHPA (39 mmol in 170 ml water)
  • reaction mixture turned brown. Filtration on Whatman #541 paper, followed by washing with water (150 ml total), afforded a deep red product, which was further purified by slurrying with acetone (300 ml),
  • the film layers utilized in the present invention are comprised of polyurethane or polyacrylamide hydrogels.
  • hydrogel is meant a water-swollen (or swellable) three-dimensional matrix or network of crosslinked, hydrophilic macromolecules. Fully swollen hydro-gels will contain 20% to over 90% water.
  • the polyurethane hydrogels of the present invention are a copolymerization product of alkylene glycols or thioglycols, organic polyisocyanates, and optionally, ionic diols, such as sulfonate diols, quaternary ammonium diols, carboxylate diols, and phosphate diols, or acids corresponding to such diols.
  • Preferred hydrogels according to the present invention have a three-dimensional network structure and include polymeric units of the following general formulas:
  • AX represents a urethane derived by the reaction of a polyalkylene glycol or thioglycol (A) of molecular weight 200 to 15,000 (preferably 600 to 3000) with an organic diisocyanate or triisocyanate (X); T represents a trifunctional or tetrafunctional unit derived from an organic polyol or an organic
  • BX represents a unit derived by
  • an organic polyisocyanate (X) with a sulfonate diol, phosphate diol, carboxylate diol, or quaternary ammonium diol; and a, b, and c are integers, a and b being greater than zero, and a, b, and c being selected so that the -(BX)- units make up no more than 40% by weight, preferably 0-20% by weight, of the hydrogel and the molar ratios of A:X:T in the final polymer are from 2:2:1 to 12:12:1, preferably 3:3:1 to 9:9:1.
  • Preferred dye films used herein to detect changes in pH are hydrogels having the aforementioned polymer units and also units of the formula -(DX) d -, wherein D represents an azo dye reacted with X, an organic polyisocyanate, and d is an integer selected to provide 0.1% to 20% by weight in the hydrogel of the dye (D), preferably from about 1.0% to 10% by weight.
  • the structure and chemical composition of the hydrogels of this invention should be adjusted so that the final film is hydrated 20% to 90%, preferably 40% to 80%, with uniform water distribution and elastomeric properties. Special mention is also made of
  • Reactive azo dyes as disclosed herein may also be incorporated into these polymers to produce pH- indicating dye films.
  • Suitable polyalkylene glycols and thioglycols for use in preparing the hydrogels of the invention are poly(C 2 -C 6 ) alkylene glycols and thioglycols such as polyethylene glycol, polypropylene glycol,
  • polytetramethylene ether glycols mixtures of such glycols and their corresponding thioglycols.
  • thioglycols will be from 200 to 15,000, preferably from 600 to 3,000, to obtain the desired hydration.
  • the percent hydration is defined as the weight percent of water in the completely hydrated film.
  • Suitable organic polyisocyanates useful for preparing the hydrogels have the general formula
  • polyisocyanates include tetramethylene diisocyanate, hexamethylene diisocyanate, 1,4-cyclohexane diisocyanate, 1,4-pentane diisocyanate, methylene bis(4-isocyanatoethyl cyclohexane), 1-isocyanato-3,3,5-trimethyl-5-iso-cyanato-methyl
  • cyclohexane 1,4-isocyanatomethyl cyclohexane, 1,4-isocyanatoethyl cyclohexane, 1,3-isocyanatomethyl cyclohexane, 1,3,5-triisocyanato-cyclohexane, diiso-cyanatopentylcyanomethine, 1, 4-diisocanobenzene, 2,6-diisocyanatotoluene, 2,6-diisocyanatotoluene, toluene diisocyanate (2,4- and 2,6-mixtures), 4,4'- dicyanodiphenylmethane, 4,4'-diisocyanodiphenyl propane (2,2), p-xylylene diisocyanate, and the like. Mixtures of such polyisocyanates can also be employed.
  • heteroorganic diols and carboxylate diols can also be used in preparing the hydrogels of the present invention.
  • Urethane hydrogel polymer units may be derived from reacting the
  • the hydrogel may include up to 40% by weight of the diol component, but preferably 20% or less.
  • diol reactants readily copolymerize with the isocyanates to produce hydroxy-terminated
  • polyurethanes which react further with isocyanate-terminated prepolymers. This results in a single polymer population, as determined by gel permeation chromatography, with the diol components being
  • Suitable sulfonate/sufonic acid diols include compounds of the formula:
  • R 1 may be the same or different bivalent
  • Y is nitrogen, carbon, sulfur, silicon, or phosphorus, with any free valencies being taken by hydrogen or halogen atoms
  • Z is a direct bond or R 1
  • E is hydrogen, sodium, lithium, potassium, magnesium or calcium.
  • examples of such compounds include N,N-bis (2-hydroxyethyl)-2-N-methylaminoethane sulfonic acid, 1,4-butanediol-2-sulfonic acid, and salts thereof.
  • polyurethane hydrogels of the present invention are prepared by reacting organic radicals having the polyurethane hydrogels having the present invention.
  • polyisocyanates with polyalkylene glycols and/or triols at an elevated temperature.
  • polystyrene resin different molecular weights can be produced in this manner depending on the stoichiometry.
  • the polyols and polyfunctional isocyanates are used to control the crosslink density and degree of branching.
  • polyurethane hydrogels can be produced to meet various specifications by varying the stiochiometry of the isocyanate and polyol components as well as by including ionic diol groups and dye groups.
  • isocyanates and polyols can be carried out either in bulk or solution.
  • Aprotic solvents such as acetone, methyl ethyl ketone, ethyl acetate, cyclohexanone, DMF, dimethyl sulfoxide (DMSO) N-alkyl-pyrrolidone, and butyrolactone are excellent because they provide dissolution power, chemical stability and temperature control.
  • the polymerization temperature can be varied from 20oC to 190oC depending on individual preparations and the presence of a solvent.
  • the preferred temperature range is from 70oC to 130oC.
  • An inert atmosphere is sometimes required to prevent undesirable side reactions.
  • the isocyanate and polyol reaction temperature is between 70oC to 140oC, preferably between 90oC to 110oC, for a desirable cure rate and film properties.
  • the polyaddition of isocyanate and polyols can also be carried out in the presence of either acidic or basic catalysts.
  • Tertiary amines, carboxylic acids and metal salts are commonly used.
  • Suitable tertiary amines include triethylamine,
  • the metal salt catalysts generally have greater catalytic power than the
  • tertiary amines and preferred examples include tri-n- butyltin acetate, di-n-butyltin diacetate and din- butyltin dilaurate.
  • Formic acid is an excellent acid catalyst.
  • PEG Polyethylene glycol
  • TMP trimethylolpropane
  • TDI toluenediisocyanate
  • the polymer was prepared according to the procedure of Example 45 except a different grade of polyethylene glycol (mol. wt. 600, 84 g, 100 mmol) was used and no DMF was added.
  • the polymer was prepared as in Example 45 except no TMP was added.
  • the polymer was prepared as in Example 43 except cyclohexyldiisocyanate (CHDI) (29 g, 175 mmol) was used instead of TDI.
  • CHDI cyclohexyldiisocyanate
  • PEG1000 100 g, 100 mmol
  • TMP 3.35 g, 25 mmol
  • CHDI 16.60 g, 100 mmol
  • the mixture was allowed to react at 90oC for 3 hours. After cooling, a solid polymer was isolated.
  • the polymer was prepared as in Example 49, except TDI was used. Enough DMF was added to make a 70% solution.
  • the polymer was prepared as in Example 50, except TMP was not used. Enough DMF was added to make a 70% solution.
  • the polymer was prepared as in Example 50, except PEG600 was used. Enough DMF was added to make a 70% solution.
  • PEG1000 (40.3 g, 40.3 mmol) was charged and dried in a reactor at 100oC vacuum for one hour. The vacuum was broken with dry nitrogen. TDI (9.61 g, 55.89 mmol) was added and the mixture reacted at 100oC for three hours until there was no TDI left, as shown by stabilization of the NCO peak on IR spectrophotometric analysis. 1,4-butanediol-2-sulfonic acid sodium salt (5.163 g, 26.87 mmol) in of DMSO (23.5 g) were added to the isocyanate-terminated prepolymer solution until the isocyanate peak in IR spectrum disappeared. The final polymer product showed one major population distribution with a number average molecular weight at 47,000.
  • N,N-bis(2-hydroxyethyl)-2-aminoethane sulfonic acid sodium salt (BES, Aldrich Chem. Co.) was methylated by the following procedure.
  • PEG1000 21.68 mmol was dried under vacuum for an hour at 100oC in a reactor. The vacuum was broken with dry nitrogen. TDI (5.035 g, 28.91 mmol) was added and reacted at 100oC for two hours until no TDI remained, which yielded an isocyanate-terminated prepolymer. MeBES (3.285 g, 14.47 mmol) was charged to the reactor in DMSO (27.33 g) and reacted one hour until IR analysis showed no isocyanate peak. The resultant polymer showed one major population
  • a thin hydrogel film containing one or more of the aforementioned pH indicator azo dyes is
  • thin hydrogel film is meant a layer of about 0.5 to 50 microns thickness. In preferred embodiments, the film layers will be from about 1-10 microns, most preferably about 2-6 microns, in
  • die film When a thin film compounded with dye (“dye film”) is hydrated it will change color instantaneously as a function of the acidity or basicity of the
  • optical sensor elements for detecting any parameters which are a function of pH.
  • the dye film is formulated so as to provide, in thin layers of 0.5 to 50 microns, sufficient optical density and pH sensitivity to permit optical
  • suitable amounts of the dye component may range from about 0.1-15% by weight, based on the total weight of the dye-containing hydrogel polymer (non-swollen).
  • the amount of dye will be about 1-10% by weight, most preferably about 3-8% by weight.
  • optical sensing elements may include other components, depending on the overall configuration of the optical reader apparatus.
  • a backscattering optical pathway is employed, and, accordingly, the sensing elements of the analyzer will include a light scattering film adjacent to the dye film.
  • the sensing element may also preferably include a light absorbing layer in order to render the optical
  • the multilayer coatings can be fabricated to make pH and pCO 2 sensor devices.
  • a dye film having the following formulation is prepared:
  • the dye and DMF are mixed in a vial and sonicated for 40 minutes. Although a trace of material remains, the dye dissolves well. After centrifuging for 10 minutes, the solution is drawn off and filtered through a 0.2 micron syringe filter. 97% of the solution is recovered. After adjusting for the
  • polyurethane hydrogel is mixed in by shaking and using a vortex mixer.
  • the solution is centrifuged again for 10 minutes and filtered through a 5 micron syringe filter. 11.043 parts by weight of solution is recovered for an 88% overall recovery. A final centrifugation is performed for 10 minutes to remove any air bubbles.
  • hydrogel is added. Before coating, each disc polyester substrate on the vacuum chuck is washed and scrubbed with filtered MeOH. A final film thickness of 8-10 microns is required for an optical density of 0.5 at this dye loading. The discs are cured for 90 minutes at 110oC. Once out of the oven, the films are tacky but become fully cured on standing overnight. Unbound dye is removed by leaving the films for 5 minutes in DMF followed by 5 minutes in MeOH. Both solvents are filtered (0.45 micron). The DMF removes the majority of loose dye and dye impurities while the MeOH mainly serves to rinse out the DMF.
  • Table 8 gives examples of dye-containing hydrogels which were prepared and tested as pH-sensing materials.
  • the diazonium sulfate converted from 2-bromo-4,6-dinitroaniline (550 mg) in Example 15 was added to a slurry prepared from 4-amino-5-hydroxy-1-naphthalene-sulfonic acid (500 mg), water (25 ml), ice (10 g) and H 2 SO 4 (1.5 ml). After completion of the reaction at 20oC, the dye was precipitated by the addition of sodium chloride and subsequently dried. Up to 100 mg of dye was dissolved in dry dimethylsulfoxide. After the addition of the isocyanate terminated polyurethane hydrogel, the dye became bound to the polyurethane. A pH-indicating hydrogel was formed.
  • polymeric pH-indicating material is lyophilyzed and subsequently incorporated in a variety of hydrogel-forming materials by simply admixing before curing.
  • hydrogel-forming materials include isocyanate-terminated polyurethane prepolymers.
  • the polysaccharide acted as the cross- linking reagent. It is also possible to form a
  • PEG1000 (2.53 g) was dried in a reactor under vacuum at 100oC for one hour and the vacuum was broken with dry nitrogen and TDI (0.551 g) was added. The mixture was allowed to react for two hours at 100oC to produce an isocyanate-terminated prepolymer.
  • B 5 MeETA (1g) in dry DMSO (9g) was charged to the reactor. The reaction was completed in thirty minutes as evidenced by IR spectra.
  • the number average molecular weight of the hydroxy-terminated dye prepolymer product was at 13,000 with a broad molecular weight distribution and hydroxyl content of 0.32 meq./gm.
  • the viscous solution was spin coated on a Mylar disk to form a 10 micron-thick film,
  • a dye hydrogel was formulated and cured following the procedures of Example 61, except that a trifunctional isocyanate, Desmodur IL (Mobay
  • the film had only 31% hydration and a pK a of 6.51.
  • a dye hydrogel was prepared following the procedures of Example 61, except the amount of dye was adjusted to make up 8% by weight of the total
  • the film had 56% hydration and a pK a of 6.74.
  • Example 50 The hydroxy-terminated polyurethane prepolymer of Example 50, the diol dye B 5 MeETA, and a mixture of TDI-Desmodur IL in a ratio of 30%-70% (mole) were reacted using the same procedures as in Example 60.
  • the resultant film had a 72% hydration and a pK a of 6.70.
  • the isocyanate-terminated polyurethane hydrogel (1.17 g) PEG1000 (0.26 g) and B 5 -Tris dye
  • the solution is spin-coated and cured on Mylar to form a 5 micron film.
  • the film has a 65% hydration and a pK a of 7.07, and also possesses acceptable optical density.
  • B 5 -Tris dye 0.3 g, 4% by weight
  • the isocyanate-terminated polyurethane hydrogel 7.2 g
  • the solution is spin-coated and cured as in Example 48.
  • the film had a 43%
  • B 5 -Tris dye (0.25 g, 8% by weight) and the isocyanateterminated polyurethane hydrogel (2.875 g) are mixed in DMF (2.66 g).
  • the solution is coated and cured as in Example 65.
  • the film had a 30% hydration and a pK a of 7.3. This is a good film for using as a sensor.
  • B 5 -Tris dye (0.25 g, 10% by weight) and the isocyanateterminated polyurethane hydrogel (0.5 g) are mixed in dry DMF (2.25 g) .
  • the solution is spin coated as in Example 65, to form a 4 micron film.
  • the film had a pK a of 6.72.
  • Desmodur IL (0.052 g) were mixed well. The solution was spin-coated and cured as in Example 65. The film had a 68% hydration and a pK a of 6.72.
  • a pigment-containing hydrogel film may be prepared by mixing a white pigment (Rutile, a crystal form of titanium dioxide, 79.2 g), a hydroxy-terminated polyurethane prepolymer (28.3 g) and cyclohexanone (42.5 g), and dispersing the solution in a ball mill to prepare a mill base. The solution is then compounded with polyurethane (40 g), cyclohexanone (64 g) and TDI (5.42 g) along with a small amount of catalyst such as di-n-butyltin dilaurate and triethylenediamine (1,4-diaza[2.2.2]bicyclcooctane). The resultant coating mix is used to deposit a white reflective layer by spin coating.
  • a pigment-containing hydrogel film may be pepared by mixing a black pigment (carbon black, 28 g), polyurethane prepolymer (23 g) and cyclohexanone
  • the mill base is compounded with polyurethane (55 g), cyclohexanone (120 g) and TDI (7 g), along with a small amount of catalyst as
  • Example 71 The resultant mix is used to deposit a black absorptive layer by spin coating.
  • a pH-indicator dye film and any other necessary layers may be deposited directly on the interior surface of a cuvette cell into which fluids to be analyzed will be introduced; however, for ease of fabrication and replacement, it is much preferred to deposit the layers on an optically-clear support sheet, such as a 5-mil thick polyester film (e.g., Melinex film, ICI Americas Inc., Wilmington, Delaware or Mylar, E. I. DuPont de Nemours, Inc.).
  • an optically-clear support sheet such as a 5-mil thick polyester film (e.g., Melinex film, ICI Americas Inc., Wilmington, Delaware or Mylar, E. I. DuPont de Nemours, Inc.).
  • hydrogel polymer maintain its structural integrity when it is loaded with indicator dyes, pigments or other substances, so that it possesses the appropriate optical and chemical properties in the pH range of interest.
  • a thin reflective film is deposited over the dye film.
  • the reflective film comprises a hydrogel and at least one pigment having a higher refractive index than water, preferably titanium dioxide.
  • the hydrogel may be the same or different than that of the dye film layer, * and in addition to the polyurethane hydrogels discussed above, special mention is made of hydrogels based on polyacrylamides, many of which maintain especially high water contents even with high pigment loadings.
  • a further pigmented film advantageously applied over the reflective film layer is a light absorptive film. This film is similar to the
  • Carbon black is the most preferred pigment for the light absorptive film.
  • the prepolymer is mixed in by stirring or shaking.
  • the solution is again centrifuged to make subsequent filtration through a 1 micron membrane easier. This step removes precipitated material and solids resulting from introduction of the prepolymer.
  • a final centrifugation removes any air bubbles.
  • hydrophilic polyurethane solutions thus formulated are coated either onto an optically clear substrate or directly into the sensing cells of the cuvette (discussed infra) , and then cured.
  • spin coating methods are used.
  • Viscosity is a function of polymer molecular weight, total solids, solvent type, temperature, and the presence of other ingredients which may react with the polymer components. The viscosity also varies
  • the desired viscosity is generally in the range of about 100 to 1,000
  • the dye films are cured, e.g., in a forced air oven. Depending on the formulation, complete curing is usually achieved in two hours at 90 to 110oC.
  • a “reflective” (i.e., backscattering) film formulation may be prepared by blending a pigment such as titanium dioxide (e.g., Kemira rutile) with the polymer used to make the reflective layer, with a solvent if desired. Pigment loading determines how thick the layer needs to be to give satisfactory reflective properties, keeping in mind that thicker layers lead to longer dynamic response times.
  • a pigment such as titanium dioxide (e.g., Kemira rutile)
  • Pigment loading determines how thick the layer needs to be to give satisfactory reflective properties, keeping in mind that thicker layers lead to longer dynamic response times.
  • pigment loadings of about 50-60% by weight are sufficient.
  • the pigment-containing formulations are milled for a long period, e.g., 1-10 days depending on such factors as pigment loading, type of mill, presence of a solvent, etc., until a mill base having the desired particle size and desired viscosity is
  • the mill base is then formulated with additional prepolymers (including polyfunctional crosslinking components) stirred, and filtered (e.g., 5 microns) before coating over the dye film layer.
  • a non-reflective, absorptive film may be prepared in much the same manner as the reflective film.
  • the absorptive layer serves an optical decoupling function, making the measurement of the dye color immune to variations in the reflectivity and/or absorptivity of electromagnetic radiation of the fluid sample to be analyzed.
  • Carbon black e.g., Raven 1040, Columbian Chemical
  • a cured polymer layer can be made which acts as an optical barrier.
  • the absorptive nature of carbon black is such that a 1 micron layer with only a 25% pigment loading by weight is sufficiently opaque.
  • an additional film is used in the multilayered sensing element.
  • a gas- separating membrane is coated over the non-reflective, absorptive film. This allows for effective diffusion rates of water vapor and CO 2 gas, while liquid water and ions are excluded.
  • the membrane can be placed between the dye film and the reflective film which results in shorter response times to pCO 2 changes.
  • the pCO 2 sensor functions by changes in pH, caused by shifts in the pCO 2 -carbonic acid equilibrium, producing differences in the dye absorbance.
  • the population of dye molecules should first be converted to their anionic form before being sealed in their environment with the gas-separating membrane. Soaking the dye-polymer films in aqueous solutions of pH greater than the pKa of the dye can deprotonate the desired amount of dye. Two aspects of this step are important: The percentage of dye converted to its salt must be very reproducible, and the process cannot leave behind any species which interfere with protonation.
  • the films are soaked in buffer solution having high pH (e.g., pH 9-10) which has preferably been filtered (e.g., 0.45 micron) for cleanliness.
  • buffer solution having high pH (e.g., pH 9-10) which has preferably been filtered (e.g., 0.45 micron) for cleanliness.
  • the films are allowed to air dry completely.
  • the gas-permeable layer preferably a silicone membrane, isolates the dye layer from ionic species, specifically hydronium.
  • Polydimethylsiloxane is most preferred for the membrane material because of its high permeability to carbon dioxide and water. Physically, the membrane needs to be thin enough for an acceptable response time while having good integrity so that no bulk fluid can pass through.
  • the silicone membrane is made by spin coating a solution of silicone polymer in a suitable solvent. Silicone elastomers are diluted to an appropriate percent solids level for spin coating thin films. Xylene and polydimethylsiloxane solvents with a b.p.
  • Petrarch Systems SE is 35% solids in a naphtha solvent. After dilution, the silicone solution is mixed by shaking and then is filtered through at least a 1 micron syringe filter to remove particulates.
  • the substrate When coated, the substrate is first flooded with silicone solution to assure that the entire surface is wetted.
  • silicone solution Many commercial silicones (e.g., Petrarch SE) fully cure in a matter of hours upon exposure to moisture.
  • Cured silicone elastomers are known for their inertness and low surface energy. Coating or painting silicone materials is customarily difficult because of this very low surface energy. Since there is no surface pretreatment, the coating quality is very poor when the reflective film is spincoated onto the
  • Plasma activation of the silicone surface may be used to both increase the wettability so that acceptable coatings can be made and to enhance the adhesion to these subsequent layers. Plasma activation by exposure to radio frequency discharge of a selected gas is a chemically complex process and will not be discussed here in detail.
  • a preferred body fluid analyzer is
  • hydrogels and dyes already disclosed, will be described with reference to the drawings. It will be understood that the hydrogels and dyes, dye films and sensing elements prepared therefrom, may be employed for purposes radically different the uses described herein design without departing from the scope of this invention. Similarly, the following description illustrates a preferred embodiment and is not provided to in any way limit the present invention.
  • the body fluid analyzer described hereinafter is only one example of a multitude of possible designs which will be apparent to those familiar to this art.
  • analyzing apparatus is comprised of several linked sub-units, shown as separated structures (1, 2, 3, 5).
  • a monitoring unit 1 is provided which is capable of data signal evaluation and data display. Depending on the particular design of the analyzer, its power requirements, and the particular optical
  • a signal preamplification unit 2 may be provided to boost the photoreceptor data signal corresponding to the optical measurement of pH in the sensing cells (described infra).
  • a cuvette housing 3 is provided incorporating optical measurement components including an electromagnetic radiation source (“light source”) and photodetectors (not shown) aligned so as to obtain color measurements of samples placed in a sensing cuvette 5 and having a slot 4 adapted for receiving the sensing cuvette 5.
  • the sensing cuvette 5 is preferably equipped with tubing adapters 6 which permit introduction of a fluid to be measured into an interior channel (not shown) running through the cuvette 5 where the fluid contacts the sensing elements (not shown) of the apparatus.
  • Through optically clear windows 7 and 8, located on one side of the cuvette 5, color changes reflecting pH and pCO 2 changes can be measured by optical measuring components in cuvette housing 3.
  • the cuvette has one or more sensing cells, each in open communicaton at one end with the channel in the cuvette interior and being closed at the other end by optically clear windows 7 and 8, which windows 7 and 8 come into alignment with the measuring optics of the cuvette housing 3 when the cuvette 5 is properly inserted in the slot 4.
  • FIG. 2 a cross-sectional view of a possible sensing cuvette 5 is shown. Optically clear windows 7 and 8 are shown forming the closed ends of two sensing cells 13 and 13A, into which
  • multilayered sensing elements have been inserted.
  • two sensing cells are shown, having sensing elements for optical measurement of pH (13) and pCO 2 (13A) however, it will be seen that numerous additional cells may be fabricated in the body of the cuvette 5 (for pH, pCO 2 , or other measurements)
  • the sensing cuvette 5 is provided with inlet and outlet tubing 6 providing access to a channel 15 which provides a passageway through the cuvette 5.
  • Sensing cells 13 and 13A open on the channel 15 to afford contact of the multilayered sensing elements with any fluid samples introduced into the channel 15.
  • the sensing elements are comprised of a dye film 9 and other layers which adapt the sensing elements to the particular optics and design of the cuvette 5 and the analyzer as a whole.
  • the sensing elements are adapted to permit optical measurement of light transmitted and backscattered through the dye film 9, which dye film changes color as a function of pH.
  • the sensing cell 13 adapted to detect pH of a solution passing through the channel 15 features an optically clear window 7 which will come into line with the particular optic components of the cuvette housing (item 3 in Fig. 1).
  • the pH-indicator dye film 9 may be coated directly on the window 7, but preferably the film 9 (and other layers) will be deposited on an optically clear substrate 16, such as polypropylene or a polyester film (e.g., 10 mil Mylar). Many suitable substrates will suggest themselves to the practitioner.
  • a dye film 9 is deposited (e.g., spin coated) on a clear polymeric substrate 16.
  • the optically clear substrate 16 adjacent the optically clear window 8 is coated with a dye film 9, a reflective film 10 and an absorptive film 11, and also a gas permeable silicone layer 12.
  • the gas-separating film 12 may be positioned elsewhere, for instance between layers 9 and 10, if desired.
  • the inner dimensions of the cuvette 5 are preferably adapted to minimize the volume of fluid needed for analysis while providing sufficient volume to ensure contact with the sensing elements and completion of the protonation reaction with the indicator dyes.
  • the cuvette may be about 40 mm high and about 20 mm wide, and the channel 15 may be about 9 mm in diameter.
  • water and ions in the fluid diffuse freely through the hydrogel layers of the sensing cell 13 and contact the pH indicator dye in the dye film 9, which undergoes a shift of the protonation equilibrium, resulting in a shift in the wavelength of absorbance of light passing through the dye film.
  • water vapor and CO 2 gas from the fluid diffuse through the gas-separating membrane 12. The water vapor hydrates the dye film in the presence of the CO 2 gas, resulting in the formation of carbonic acid which subsequently dissociates, altering the protonation equilibirium of the dye.
  • the cuvette 5 is shown in relation to a light source 18 and an optical receptor 20, which would be contained in the analyzer housing (3 in Fig. 1).
  • the light source 17 directs light (arrowed lines) toward the sensing cell 13.
  • Light passes through the window 7, the clear film substrate 16 and the dye film 9, and then is backscattered off the reflective film 10.
  • Photoreceptor 21 is positioned to accept the returned light emanating from the cell 13.
  • the backscattered light differs from the source light directed as a function of the color of the dye film, and therefore gives an indication of the pH of the solution passing through the cuvette channel 15 in contact with the cell 13.
  • the photoreceptor 20 emits an electronic data signal which is passed along to preamplification and data evaluation equipment (Fig. 1).
  • Diazonium Comp. coupling Comp. Yield acid base pka 4-NO 2 -1-naphthyl 4-(NHCOCBrCH 2 ) 67% red- purple 10.0

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Abstract

On a mis au point de nouveaux colorants azo réactifs, des hydrogels, des films de colorant, et des éléments de détection comprenant lesdits films. Les éléments de détection sont utiles par exemple dans des dispositifs d'analyse de fluides, où ils sont capables de fournir des informations précises sur le pH ou pCO2 de fluides tels que le sang.
PCT/US1989/003015 1988-07-11 1989-07-10 Elements de detection composes de films de colorant sous forme d'hydrogel et leur preparation WO1990000572A1 (fr)

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US5063178A (en) * 1990-03-19 1991-11-05 Medex, Inc. Freeze-dried blood gas sensor
EP0675362A2 (fr) * 1994-03-30 1995-10-04 Johnson & Johnson Clinical Diagnostics, Inc. Minimiser l'interférence dans des analyses immunologiques chimiluminescentes en couches minces
US5536783A (en) * 1993-06-10 1996-07-16 Optical Sensors Incorporated Fluorescent polymers useful in conjunction with optical PH sensors
WO1997047966A1 (fr) * 1996-06-12 1997-12-18 Novartis Ag Systeme de capteur optique pour determiner le ph independamment de la force ionique, au moyen d'une fluoresceine liee a un polymere par un groupe urethane et/ou uree
WO1999050361A1 (fr) * 1998-03-31 1999-10-07 Avecia Limited Polyurethannes colores
WO1999050326A1 (fr) * 1998-03-31 1999-10-07 Avecia Limited Polyurethannes colorees
US5978691A (en) * 1996-07-19 1999-11-02 Mills; Alexander Knight Device and method for noninvasive continuous determination of blood gases, pH, hemoglobin level, and oxygen content
EP0980518A1 (fr) * 1998-02-10 2000-02-23 Daedalus I, LLC APPAREIL POUR LA DETERMINATION DU pH, pCO2, DE L'HEMOGLOBINE ET DE LA SATURATION EN OXYGENE DE L'HEMOGLOBINE
EP1004017A1 (fr) * 1997-02-25 2000-05-31 Lockheed Martin Idaho Technologies Company Systemes retroreflechissants pour detection a distance
US6139799A (en) * 1997-12-16 2000-10-31 Optical Sensors Incorporated Membranes and optical sensors made therewith having improved barrier properties
US6694157B1 (en) 1998-02-10 2004-02-17 Daedalus I , L.L.C. Method and apparatus for determination of pH pCO2, hemoglobin, and hemoglobin oxygen saturation
DE10239204B3 (de) * 2002-08-21 2004-06-09 Frank Dipl.-Ing. Zahn Ionenstärke-Sensor
GB2408330A (en) * 2003-11-22 2005-05-25 Advanced Gel Technology Ltd Polymeric materials for assessing pH
WO2006138685A2 (fr) * 2005-06-17 2006-12-28 The Sherwin-Williams Company Dispersions de colorant en phase gel pour compositions de revetement
JP2007510141A (ja) * 2003-10-20 2007-04-19 サイファージェン バイオシステムズ インコーポレイテッド 反応性ポリウレタンベースのポリマー
GB2468682A (en) * 2009-03-18 2010-09-22 Univ Dublin City pH sensor device comprising an ionogel
CN108178735A (zh) * 2017-12-27 2018-06-19 北京化工大学 双反应性重氮化合物试剂及制备方法、tmv基水凝胶及应用和相转变调节方法

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Cited By (29)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5063178A (en) * 1990-03-19 1991-11-05 Medex, Inc. Freeze-dried blood gas sensor
US5536783A (en) * 1993-06-10 1996-07-16 Optical Sensors Incorporated Fluorescent polymers useful in conjunction with optical PH sensors
EP0675362A2 (fr) * 1994-03-30 1995-10-04 Johnson & Johnson Clinical Diagnostics, Inc. Minimiser l'interférence dans des analyses immunologiques chimiluminescentes en couches minces
EP0675362A3 (fr) * 1994-03-30 1996-03-06 Johnson & Johnson Clin Diag Minimiser l'interférence dans des analyses immunologiques chimiluminescentes en couches minces.
US6090568A (en) * 1994-03-30 2000-07-18 Clinical Diagnostic Systems, Inc. Format for minimizing interferences in chemiluminescent thin-film immunoassays
WO1997047966A1 (fr) * 1996-06-12 1997-12-18 Novartis Ag Systeme de capteur optique pour determiner le ph independamment de la force ionique, au moyen d'une fluoresceine liee a un polymere par un groupe urethane et/ou uree
US5978691A (en) * 1996-07-19 1999-11-02 Mills; Alexander Knight Device and method for noninvasive continuous determination of blood gases, pH, hemoglobin level, and oxygen content
EP1004017A1 (fr) * 1997-02-25 2000-05-31 Lockheed Martin Idaho Technologies Company Systemes retroreflechissants pour detection a distance
EP1004017A4 (fr) * 1997-02-25 2000-05-31 Lockheed Martin Idaho Tech Co Systemes retroreflechissants pour detection a distance
US6159536A (en) * 1997-12-16 2000-12-12 Optical Sensors Incorporated Method for making an optical sensor having improved barrier properties
US6441057B1 (en) 1997-12-16 2002-08-27 Optical Sensors Incorporated Optical sensor membranes having improved barrier properties
US6139799A (en) * 1997-12-16 2000-10-31 Optical Sensors Incorporated Membranes and optical sensors made therewith having improved barrier properties
US6162494A (en) * 1997-12-16 2000-12-19 Optical Sensors, Inc. Method for making an optical sensor having improved barrier properties
EP0980518A1 (fr) * 1998-02-10 2000-02-23 Daedalus I, LLC APPAREIL POUR LA DETERMINATION DU pH, pCO2, DE L'HEMOGLOBINE ET DE LA SATURATION EN OXYGENE DE L'HEMOGLOBINE
US6694157B1 (en) 1998-02-10 2004-02-17 Daedalus I , L.L.C. Method and apparatus for determination of pH pCO2, hemoglobin, and hemoglobin oxygen saturation
EP0980518A4 (fr) * 1998-02-10 2000-05-03 Daedalus I Llc APPAREIL POUR LA DETERMINATION DU pH, pCO2, DE L'HEMOGLOBINE ET DE LA SATURATION EN OXYGENE DE L'HEMOGLOBINE
WO1999050361A1 (fr) * 1998-03-31 1999-10-07 Avecia Limited Polyurethannes colores
US6632858B1 (en) 1998-03-31 2003-10-14 Avecia Limited Colored polyurethanes
WO1999050326A1 (fr) * 1998-03-31 1999-10-07 Avecia Limited Polyurethannes colorees
DE10239204B3 (de) * 2002-08-21 2004-06-09 Frank Dipl.-Ing. Zahn Ionenstärke-Sensor
JP2007510141A (ja) * 2003-10-20 2007-04-19 サイファージェン バイオシステムズ インコーポレイテッド 反応性ポリウレタンベースのポリマー
GB2408330A (en) * 2003-11-22 2005-05-25 Advanced Gel Technology Ltd Polymeric materials for assessing pH
WO2005052572A1 (fr) * 2003-11-22 2005-06-09 Agt Sciences Limited Materiaux polymeres incorporant un colorant indicateur de ph
GB2408330B (en) * 2003-11-22 2008-12-03 Advanced Gel Technology Ltd Polymeric materials comprising pH indicators for use in wound dressings
WO2006138685A2 (fr) * 2005-06-17 2006-12-28 The Sherwin-Williams Company Dispersions de colorant en phase gel pour compositions de revetement
WO2006138685A3 (fr) * 2005-06-17 2007-06-07 Sherwin Williams Co Dispersions de colorant en phase gel pour compositions de revetement
GB2468682A (en) * 2009-03-18 2010-09-22 Univ Dublin City pH sensor device comprising an ionogel
GB2468682B (en) * 2009-03-18 2012-08-15 Univ Dublin City pH sensor device comprising an ionogel
CN108178735A (zh) * 2017-12-27 2018-06-19 北京化工大学 双反应性重氮化合物试剂及制备方法、tmv基水凝胶及应用和相转变调节方法

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EP0406334A4 (en) 1991-11-13
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