WO1992005441A1 - Water insensitive tissue oxygen sensor - Google Patents

Water insensitive tissue oxygen sensor

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Publication number
WO1992005441A1
WO1992005441A1 PCT/US1991/006716 US9106716W WO1992005441A1 WO 1992005441 A1 WO1992005441 A1 WO 1992005441A1 US 9106716 W US9106716 W US 9106716W WO 1992005441 A1 WO1992005441 A1 WO 1992005441A1
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WO
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Application
Patent type
Prior art keywords
dye
polymer
sensor
oxygen
matrix
Prior art date
Application number
PCT/US1991/006716
Other languages
French (fr)
Inventor
Henry W. Oviatt, Jr.
Cary J. Reich
Steven R. Morehead
James R. Lusk
Original Assignee
Baxter International Inc.
Priority date (The priority date 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 date listed.)
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Publication date

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    • GPHYSICS
    • G01MEASURING; TESTING
    • G01NINVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00Investigating or analysing materials by the use of optical means, i.e. using infra-red, visible or ultra-violet light
    • G01N21/75Systems in which material is subjected to a chemical reaction, the progress or the result of the reaction being investigated
    • G01N21/77Systems in which material is subjected to a chemical reaction, the progress or the result of the reaction being investigated by observing the effect on a chemical indicator
    • G01N21/7703Systems in which material is subjected to a chemical reaction, the progress or the result of the reaction being investigated by observing the effect on a chemical indicator using reagent-clad optical fibres or optical waveguides
    • GPHYSICS
    • G01MEASURING; TESTING
    • G01NINVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00Investigating or analysing materials by the use of optical means, i.e. using infra-red, visible or ultra-violet light
    • G01N21/62Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
    • G01N21/63Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
    • G01N21/64Fluorescence; Phosphorescence
    • G01N21/6428Measuring fluorescence of fluorescent products of reactions or of fluorochrome labelled reactive substances, e.g. measuring quenching effects, using measuring "optrodes"
    • GPHYSICS
    • G01MEASURING; TESTING
    • G01NINVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00Investigating or analysing materials by the use of optical means, i.e. using infra-red, visible or ultra-violet light
    • G01N21/62Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
    • G01N21/63Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
    • G01N21/64Fluorescence; Phosphorescence
    • G01N21/6428Measuring fluorescence of fluorescent products of reactions or of fluorochrome labelled reactive substances, e.g. measuring quenching effects, using measuring "optrodes"
    • G01N2021/6432Quenching
    • GPHYSICS
    • G01MEASURING; TESTING
    • G01NINVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00Investigating or analysing materials by the use of optical means, i.e. using infra-red, visible or ultra-violet light
    • G01N21/62Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
    • G01N21/63Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
    • G01N21/64Fluorescence; Phosphorescence
    • G01N21/6428Measuring fluorescence of fluorescent products of reactions or of fluorochrome labelled reactive substances, e.g. measuring quenching effects, using measuring "optrodes"
    • G01N2021/6434Optrodes
    • GPHYSICS
    • G01MEASURING; TESTING
    • G01NINVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00Investigating or analysing materials by the use of optical means, i.e. using infra-red, visible or ultra-violet light
    • G01N21/75Systems in which material is subjected to a chemical reaction, the progress or the result of the reaction being investigated
    • G01N21/77Systems in which material is subjected to a chemical reaction, the progress or the result of the reaction being investigated by observing the effect on a chemical indicator
    • G01N21/7703Systems in which material is subjected to a chemical reaction, the progress or the result of the reaction being investigated by observing the effect on a chemical indicator using reagent-clad optical fibres or optical waveguides
    • G01N2021/7706Reagent provision
    • G01N2021/772Tip coated light guide
    • GPHYSICS
    • G01MEASURING; TESTING
    • G01NINVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00Investigating or analysing materials by the use of optical means, i.e. using infra-red, visible or ultra-violet light
    • G01N21/75Systems in which material is subjected to a chemical reaction, the progress or the result of the reaction being investigated
    • G01N21/77Systems in which material is subjected to a chemical reaction, the progress or the result of the reaction being investigated by observing the effect on a chemical indicator
    • G01N21/7703Systems in which material is subjected to a chemical reaction, the progress or the result of the reaction being investigated by observing the effect on a chemical indicator using reagent-clad optical fibres or optical waveguides
    • G01N2021/7706Reagent provision
    • G01N2021/773Porous polymer jacket; Polymer matrix with indicator
    • GPHYSICS
    • G01MEASURING; TESTING
    • G01NINVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00Investigating or analysing materials by the use of optical means, i.e. using infra-red, visible or ultra-violet light
    • G01N21/75Systems in which material is subjected to a chemical reaction, the progress or the result of the reaction being investigated
    • G01N21/77Systems in which material is subjected to a chemical reaction, the progress or the result of the reaction being investigated by observing the effect on a chemical indicator
    • G01N2021/7769Measurement method of reaction-produced change in sensor
    • G01N2021/7786Fluorescence

Abstract

A dye matrix is provided for use in an optical sensor. In the preferred embodiment sufficient of a gas-sensitive organometallic aromatic-containing fluorescent dye is dissolved in an organosilane polymer permeable to the gas to measure concentrations of oxygen or other gases in bodily tissue. The polymer contains sufficient aromatic substituents to prevent the dye from crystallizing and sufficient crosslinker to prevent an increase in turbidity in the dye matrix in an aqueous environment for up to 72 hours. A reference fluorescent dye can also be dissolved in the dye matrix to aid in screening out the 'noise' introduced by muscle movement when the sensor is used in a tissue probe, such as a tissue oxygen probe.

Description

WATER INSENSITIVE TISSUE OXYGEN SENSOR

BACKGROUND OF TEE INVENTION Field of the Invention The present invention relates to polymer matrices for fluorescent gas-sensitive dyes, particularly polymer matrices for such dyes that can be used as sensors in fiber optic probes in aqueous environments such as are encountered during in vivo monitoring of the components of tissue or blood, usually oxygen or glucose. Description of the Prior Art

It is often desirable to determine or monitor the concentration of a gas or a gas-forming substance found in an aqueous medium. For instance, physiological oxygen and' glucose measurements are important for many reasons. The advantages of measuring blood oxygen saturation levels during certain medical procedures, such as cardiopulmonary bypass heart surgery, are apparent. Equally important are physiologic measurements of glucose in blood tissue or serum to indicate metabolic malfunctions, such as diabetes.

Fiber optic devices for optical measurement of blood oxygen saturation are well known. For example, in Lubbers et al, U.S. Patent Re. No. 31,879, and in Ostrowski, U.S.

Patent No. 3,807,390, fiber optic catheters, or probes, for in vivo monitoring of blood oxygen saturation in a human blood stream are disclosed. In use, the tip of the catheter, which houses an oxygen sensitive sensor, is inserted into the cardiovascular system of the living body.

In general, such devices include a fiber optic cable extending into the probe itself for the transmission of light to the probe tip. The sensor element in the probe tip contains a fluorescent dye that excites in response to the incoming light and alters the wavelength of emitted light transmitted back to the source for measurement. Fluorescence emitted from the sensor dye is quenched by oxygen from the surroundings in proportion to its partial pressure. Thus, the amount of oxygen present can be measured by the amount of quenching.

Fluorophores display the ability to absorb light at one wavelength or frequency, reach an excited energy state, and subsequently emit light at another light frequency and energy level. The absorption and fluorescence emission spectra are individual for each fluorophore and are often graphically represented as two separate curves which are slightly overlapping. All fluorophores demonstrate the

Stokes shift, a phenomenon characterized by the emitted light having a longer wavelength (and being at a lower energy level) than that of the absorbed light. Moreover, the same fluorescent emission spectrum is observed so long as the wavelength of the exciting light is absorbed by the fluorophore.

Preferred fluorescent dyes are usually aromatic or organometallic, and typical dyes are listed in Marsoner et al, U.S. Patent No. 4,657,736. In order for the probe to be effective, the dye must be relatively immobilized and evenly dispersed at the relevant sections of the probe tip, or sensor. In some cases, as disclosed in Cramp et al, U.S. 4,560,248, the dye is bonded to the optical core. In other cases, it is embedded in a polymer matrix surrounded by a gas permeable casing. Polymers used, as disclosed in Marsoner, supra, U.S. Patents 4,003,707 and 4,643,877 to Lubbers et al. , British Patent 2,132,248A to Bacon, and U.S. Patent 4,200,110 to Peterson, and European Patent Application 0 190 830A to Gould, Inc., among others, include polyvinyl chloride, Teflon, polyethylene, polypropylene, polystyrene, and silicone rubbers. Although such art frequently indicates that "silicone rubbers" can be used as the polymer matrix, an investigation of the actual silicone rubbers used in the examples of Bacon, Marsoner, and Murray indicates that only polydimethylsiloxanes have been used. As explained in Marsoner, the organopolysiloxanes appear to be the most desirable of the above polymers because of their high oxygen permeability and consequent quick response time in a fiber optic oxygen probe. According to Marsoner, the dye is fixed in the polymer matrix by dissolving both the dye and the matrix in the same solvent and then curing. However, the art has experienced a major problem utilizing this technology because the preferred dyes are frequently not soluble in the organopolysiloxane matrices. This is especially true of organometallic dyes, such as ruthenium (II) complex dyes, especially tris 4,7-diphenyl-l,10 phenanthroline (Ruthenium II) dyes. The resultant precipitation, crystallization, and uneven dispersion of the dye is so. pervasive as to be visible to the unaided eye. h e effects of the dye crystallizing within the matrix are undesirable since crystallization effectively reduces the concentration of the dye in the polymer. The ability of the dye to fluoresce is increased when the dye is in solution, particularly when the dye is in solid solution. Any reduction in the amount in solution caused by crystallization reduces the intensity of the fluorescent light emitted. Also, the spectroscopic properties of the dye change when it is a crystalline solid rather than in a solution. As a result, the partial pressure of oxygen or other gas being measured frequently cannot accurately be read.

To alleviate this problem, heretofore only two solutions have been known. The first solution requires using a polymer in which the fluorescent dye has the requisite solubility at the expense of the high oxygen permeability and quick response time provided by known organopolysiloxane matrices. Usually, polyvinyl chloride, which is much less permeable to oxygen than polydimethyl siloxane, is selected to achieve the requisite solubility of the preferred oxygen quenchable dyes. Gould, Inc., supra, attempts to rectify the low response time of the polymer matrix by adding at least 50 weight percent of a plasticizer, such as didecyl phthalate, to the matrix.

A second approach to the problem of achieving stable solubility of the gas sensitive polycyclic, heterocyclic, and homocyclic fluorescent dyes in polymer matrices is provided by Marsoner in U.S. Patent 4,657,736, wherein it is disclosed that solubility of these aromatic dyes can be increased by performing .a Friedel-Crafts alkylation upon the molecule. Thus the chemical structure of the dye is modified to increase its solubility.

An additional problem occurs when planar polycyclic aromatic dyes, such as pyrene, are solubilized into polymer matrices such as polyvinyl chloride or common silicone rubbers, such as polydimethylsiloxane. The molecules of such dyes, when in close proximity, tend to align with each 'Other so as to form exi ers (short for "excited dimers") that transfer energy back and forth to each other. This energy transfer can occur very rapidly between the molecules with the result that the emitted fluorescence is at a longer wavelength than is emitted by molecules of the dye that do not form eximers. Of even more importance, the eximers are not oxygen quenchable. With the use of these dyes, therefore, the attempt to increase the amount of useful fluorescent signal by solubilizing as high a concentration of fluorescent dye as possible only results in reducing the ability of the dye to function as an oxygen indicator.

In addition to the problems of solubility and eximer formation associated with the dyes, it has been found that the performance of polymer dye matrices rapidly degrades when the sensors are used in an aqueous environment, such as in bodily fluids or tissues. Polymer matrices, especially the dimethyl siloxanes, are subject to a phenomenon known as increased "turbidity" when immersed in an aqueous environment for an extended period of time. Turbidity is the loss of intensity of light passed through a cell containing a solution due to light scattering caused by components of the solution. When the dye matrix of the sensor fails to maintain a constant low turbidity in an aqueous environment, the signal sent to the detector is so attenuated that the sensor becomes useless: The total energy of a fluorescent light signal is always lower than the total energy of the exciting light; therefore transmission losses quickly render the instrument useless in sensors employing fluorescent dyes.

Many gas-sensitive fluorescent dyes are highly sensitive to humidity and yet it is desirable to use sensors in aqueous environments over extended periods of time. In the clinical environment, for instance, gas sensors are used to monitor the partial pressure of oxygen in tissue. Because post operative infections usually develop within 72 hours in tissue having a low concentration of oxygen, tissue oxygen sensors must remain free from increased turbidity in an aqueous environment for at least 72 hours. As another example, the viability of skin flaps used in plastic repair is determined by monitoring the oxygen content of the tissue with a gas sensor over several days.

In view of the above considerations, it can be seen that new and better compositions are needed to provide stable solutions of fluorescent gas-sensitive dyes in polymer matrices that withstand increased turbidity in aqueous environments. It is especially desirable to discover organopolysiloxane polymer dye matrices that experience essentially no increased turbidity in an aqueous environment and can be used as a sensor element in a gas- sensitive probe, such as a fiber optic probe. Brief Description of the Drawings Figure 1 is a schematic diagram of a optical catheter having at its distal end a tissue oxygen probe containing the dye matrix of the invention; Figure 2 is an axial cross sectional view of the optical fiber and sensor associated with the present invention.

SUMMARY OF TEE INVENTION The present invention is an improved composition comprising a polymer matrix within which a 'tfas sensitive fluorescent sensor dye is incorporated in stable liquid or solid solution so as to solve many of the above-mentioned problems. To enhance the solubility of aromatic gas-sensitive dyes, the polymer of the matrix is usually substituted with both alkyl and aromatic substituents. Preferably the polymer has between 40 and 90 weight percent of the monomers dialkyl substituted, with each alkyl group containing from 1 to about 4 carbons, and has from about 10 to 60 percent of the monomers diaro atic substituted, with each aromatic group containing from 6 to about 10 carbons. The most preferred polymer matrix is a dimethyl, diphenyl siloxane copolymer. It has been discovered that aromatic gas-sensitive dyes, such as the planar polycyclic hydrocarbon and the organometallic oxygen-quenchable dyes, can be permanently dissolved in amorphous liquid or solid solution at concentrations of up to about 2 millimoles per kilogram of polymer without the dye crystallizing out. The optimal concentration of dye for making oxygen-sensitive dye matrix sensors has been found to be as little as about 1.6 millimoles. per kilogram of polymer.

To utilize a sensor having a liquid solution of the dye in the copolymer matrix, the dye matrix composition is encapsulated within an oxygen permeable containing envelope, usually polymer, with the indices of refraction of the dye matrix, the containing envelope, and the fiber optic of the probe being selected so as to capture and reflect by total internal reflection all of the beams of fluorescent light generated within the dye matrix sensor. Since the liquid solution gas sensors of this invention are generally sensitive to humidity they cannot be used in an environment in which water vapor is present unless they are intended to be used as humidity sensors. On the other hand, the dye matrix can be rendered free from the effects of humidity upon its ability to transmit light by the method of cross-linking taught herein. The capacity of the dye matrix to maintain a constant turbidity in an aqueous environment for at least 12 hours and preferably up to 72 hours is imparted by the following method of crosslinking the polymer matrix to incorporate the dye in solid solution. Usually the monomers are dissolved in a solvent, for example methylene dichloride, to form a first solution and the dye is dissolved in the same solvent to form a second solution. For a crosslinked polymer with the dye in solid solution, sufficient crosslinker is added to the monomer mixture prior to its dissolution to constitute at least 3 and preferably from about 5 to 10 weight percent. Then the two solutions are mixed together and the solvent is removed by known means, and the polymer is crosslinked, leaving a thoroughly distributed mixture of polymer and dye molecules. If the gas sensor is to be used in a clinical environment, a biocompatible crosslinker is selected and at least 10 weight percent of crosslinker is employed thereby rendering the sensor free from increased turbidity in an aqueous environment for at least 72 hours.

Turbidity as defined herein is a reduction in intensity of light transmitted through a solution caused by light scattering components therein. Turbidity is measured by interposing a turbid solution between a light source and a detector, such as a photocell, and finding the difference in intensity between the input and the output light according to the following equation: I = Io wherein I = intensity of light leaving a cell , l0 = intensity of incident light and 1 =_ length of the cell.

In turbidity, attenuation of the light source is caused by scattering, rather than by absorption. Although the mechanism by which turbidity of a polymer dye matrix increases upon prolonged exposure to an aqueous environment forms no part of this invention and the invention cannot be limited thereto, it is believed that light travelling through the polymer matrix is refracted by multiple transitions through phase changes. A beam of light would be scattered each time it encountered one of these phase changes, thus causing the physical phenomenon of increased turbidity and consequent loss of transmission of light.

It has been discovered that a crosslinked polymer having reduced rate of increase in turbidity in an aqueous environment can be provided by controlling the proportion of crosslinker used in the polymerization step within a

-specified range of from 3 to 20 weight percent of the polymerization mixture. Within this range of crosslinker concentration the interstitial spaces in the crosslinked polymer are large enough for oxygen to permeate therethrough but small enough to prohibit the turbidity effect in the sensor in use.

The polymer dye matrix is made by thoroughly mixing the monomers and the dye together, and crosslinking the mixture using the above described proportion of crosslinker. Usually the monomers are dissolved in a solvent forming a first solution and the dye is dissolved in the same solvent forming a second solution. Then the two solutions are mixed together and the solvent is removed by known means, leaving a homogeneous mixture of prepolymers and dye molecules. Any volatile solvent for silicones that would also dissolve the sensor and reference dyes can be used, for example, chlorinated solvents such as methylene chloride, chloroform, and carbon tetrachloride, or aromatic solvents, such as benzene and toluene. To form a solid solution, sufficient crosslinker to constitute at least about 3, preferably from 10 to 20 weight percent of the mixture is added and the mixture is crosslinked.

The dye matrices of this invention are both non-toxic and dependable in an aqueous environment because the sensor maintains a constant low turbidity for up to 72 hours, depending upon the concentration of crosslinker used. Therefore, these sensors are particularly suited for incorporating an oxygen-quenchable dye and for monitoring oxygen concentrations in bodily fluids and tissues. Commonly the sensors are used at the distal tip of a catheter or probe equipped with an optical fiber for bidirectional transmission of light.

To limit the noise encountered when an optical probe is implanted into the body, the dye matrix of this invention can also incorporate in solution one or more reference aromatic fluorescent dyes that are insensitive to the analyte of interest. For instance, if an oxygen- quenchable dye is used as the sensor dye, the reference dye must be insensitive to oxygen. The fluorescence of such reference dyes can be compared by known means with that of the sensor dye to remove the artifacts from the signal caused by muscle movement, and the like.

DESCRIPTION OF THE PREFERRED EMBODIMENTS The improved gas sensitive fluorescent sensors of the present invention can be employed in a fiber optic probe of the type fully described in copending application Serial No. 07/359,254 assigned to a common assignor, which application is hereby incorporated by reference in its entirety. The probe comprises a sheath defining a cavity having a sensor element located at the distal tip and having an annular recess for receiving a fiber core functioning as an optical waveguide, the distal end of which fiber core abuts against the proximal end of the sensor. The sheath comprises a gas permeable polymer material that permits the passage of oxygen into the sensor. The sensor composition, which comprises a gas sensitive fluorescent dye( i.e. oxygen quenching) is uniformly dissolved in a gas permeable polymer matrix, is disposed within the sensor cavity. Light conducted along the optical iber enters the sensor where it strikes the fluorophores in the sensor, which fluoresce in response thereto with total average intensity which is dependent upon the concentration of oxygen permeated through the sheath into the sensor cavity.

When used invasively for in vivo monitoring of gas concentrations the probe must be of small size and the magnitude of the information signals available for interpretation is, accordingly, relatively low. "Noise" generated by muscle movement and other artifact noise on the other hand, can be relatively high with a consequently low signal-to-noise ratio.

To capture and maintain as much of the incident light introduced into the sensor and the light which is emitted from the sensor, a single fiber optic is used as the waveguide. In addition, the indices of refraction of the optical fiber, the chemical sensor, and the gas permeable sheath are selected to provide the sensor with lightguide properties, including a critical angle which is generally equivalent to the critical angle for the optical fiber. In this way the sensor and fiberoptic can be selected to have total internal reflection.

To further reduce the transmission losses that might occur at the fiber/sensor interface, the index of refraction of the sensor core is generally selected to be equivalent to the index of refraction for the core of the fiber. And finally, the signal-to-noise ratio of the sensor is enhanced by providing a cap at the distal end of the sensor, such as a mirror, for directing toward the optical fiber that portion of the return signal which is travelling distally and therefore would be lost to the measurement process.

In one embodiment of the invention, the probe is a catheter having a gas sensor disposed at its distal tip. The catheter can be inserted into the tissue bed, for instance in the arm of a patient, to measure the concentration of gases such as oxygen and carbon dioxide. In Figure 1, light source 14 and sensor 16 are illustrated. Sensor 16 includes a multiplicity of fluorophores 20. Light from the light source can be generally white light or to achieve light of a desired color or wavelength, it can be passed through means 26 for providing light of specific desired wavelength. The fluorophores 20 respond to the impinging light by fluorescing at a color dependent upon the chemistry of each fluorophore.

For an oxygen sensor, preferably the light is generally blue with a central wavelength of about 480 nanometers and the chemistry of fluorophores 20 is such that some of fluorophores 20 fluoresce with a generally red light having a central wavelength of about 620 nanometers, while others of fluorophores 20 fluoresce with generally green light having a central wavelength of about 530 nanometers.

The fluorescent green and red lights emanating from fluorophores 20 travel back along the fiberoptic catheter 12 to means for splitting the red and green light, such as filter 38 and beam splitter 30. From splitter 30 the green light is directed to detector 54 and the red light is directed to detector 48, which detectors provide an indication of the intensity of the respective red and green components of the return signal. These measurements are related to the intensity with which the respective fluorophores 20 fluoresce and the measurement, therefore provides an indication of the magnitude of that fluorescence.

In this particular system, the fluorescence of the red fluorophores 20 is quenched in the presence of oxygen, while that of the green fluorophores is not. On the other hand, the fluorescence of both the red and green fluorophores 20 is affected equally by noise artifacts, such as those caused by muscle motion or blood pulsations. Because of these characteristics, signals from the red and green detectors can be combined in an output circuit 56 to provide an indication of the concentration of oxygen in sensor 16 that is free from distortions caused by noise. Output circuits of this type are well known to those skilled in the art. More particularly, as shown in Figure 2, sensor 16 can be provided with a generally cylindrical core 72 and a cladding 74 which surrounds the core except for an angular recess 82, which is configured to receive the distal end of optical fiber 70, as in a friction fit. Fiber 70 is held within recess 82 in order to provide a direct contact and interface 84 between the core 72 of fiber 70 and core 76 of sensor 16. As is explained in detail in copending U.S. Patent application 07/359,254, it is desirable for fiber 70 to have a relatively small critical angle at the interface 84 with core 72 to utilize the principle of physics known as the principle of total internal reflection, thereby reducing the amount of light lost through cladding 74 and maximizing the amount of light retained for contribution to the gas measurement. The indices of refraction at interface 84 are selected using known optical principles so that the maximum amount of incoming light passes into sensor 16 and the maximum of reflected light passes from the sensor 16 to the optical fiber 70. Similarly, sensor 16, including sensor core 76 and cladding 78, is also configured to function as a light guide or fiber, by having the index of refraction of sensor core 76 greater than the index of refraction of cladding 78. In addition, since each fluorophore emits light in all directions, sensor 16 can optionally be provided with end cap 124 in juxtaposition to the distal end of core 76 having properties selected to provide specular reflectance, such as a mirror or metallized ceramic having a porosity of about 20 percent.

The novel compositions of this invention comprise the sensor core of a fiberoptic probe, such as that described above, but the invention is not limited thereto. The improved polymer matrix disclosed herein can be used as well in other types of fiberoptic probes known in the art, such as those that do not utilize the principles of total internal reflection or that coat the polymer matrix on the surface of a distal portion of the fiber optic, as well as in a variety of other types of optical instruments useful for sensing the concentration of oxygen or of oxygen containing molecules in any environment having significant gaseous or liquid components. For instance, the. compositions of this invention can be incorporated into sensors used for measuring the concentration of glucose in such environments by exposing the glucose first to sufficient glucose oxidase in the presence of the sensor and subsequently measuring the steady state of oxygen concentration that has been attenuated by the presence of glucose. The sensor then measures the concentration of oxygen as described above, from which the concentration of glucose can be determined by known methods.

In addition, the polymer matrix disclosed herein can incorporate a single gas sensitive sensor dye, such as an oxygen quenchable dye, without also incorporating therein a second reference dye emitting fluorescent light at a different wavelength.

To assure solubility of the fluorescent dye in the polymer matrix of the sensor, at least about 10 percent, and preferably greater than 10 but not more than 60 percent of the monomer units comprising the polymer matrix are disubstituted with aromatic groups having from 6 to about 10 carbon atoms, for example phenyl, benzyl, methyl phenyl, methylphenethyl substituents, and the like. The aromatic- substituted monomers can also be substituted with heteroaromatic substituents such as pyridyl or pyrimidyl. Most preferably however, the aromatic-substituted monomer units are disubstituted with phenyl groups. It is also preferred that from about 40 to 90 percent of the monomer units comprising the polymer matrix be substituted with substituted or unsubstituted alkyl groups having from 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, or combinations thereof and wherein the substitutions are selected from the group consisting of halogen, amino, nitro and cyano. Preferably the alkyl substituted monomer units are disubstituted with methyl units.

When an organopolysiloxane polymer is employed, the copolymer preferably comprises from about 40 to 90 weight percent of dialkyl substituted, most preferably dimethyl substituted, monomer units, and from 10 to 60 weight percent of diaromatic substituted monomer units, wherein the aromatic groups are selected as described hereinabove. The preferred polymer for the practice of this invention is a dimethyldiphenylsiloxane copolymer having the above described percentages of dimethyl substituted and diphenyl substituted monomer units.

To form a gas sensor dye matrix suitable for use in a fiber optic probe, an aromatic fluorescent dye sensitive to the desired gas is dissolved in the polymer matrix up to the predictable saturation limit in either liquid or solid solution. Although it is sometimes possible to form a solid solution having a concentration of dye up to about 4 millimoles per kilogram of polymer matrix without having the dye crystalize out upon curing, usually it is not possible to form a stable solid solution containing a concentration of dye greater than about 2 millimoles per kilogram of polymer matrix.

While the theory of operation forms no part of this invention, it is believed that nonpolar interaction between the aromatic substituents in the polymer matrix and the dye molecule are responsible for increasing and/or stablilizing the solubility of the dye within the polymer matrix and thereby decreasing the tendencies of the dye to crystallize out or to leach out during use.

Accordingly, the sensor dyes for use in making the compositions of the dye matrix are fluorescent gas sensitive dyes including polycyclic aromatic hydrocarbons, such as unsubstituted or alkyl-εubstituted napthalenes, phenalenes, fluorenes, anthracenes and pyrenes; polycyclic aromatic heterocycles, such as unsubstituted or alkyl substituted phenanthrolines, acridines, quinazolines, or naphthyridines; organometallic complexes of polynuclear heterocycles, such as complexes of phenanthrolines and bipyridines with the Platinum Metals of Group VIII, ie, ruthenium, rhodium, palladium, osmium, iridium and platinum, wherein for any of the above dyes the alkyl substituents have from 1 to 4 carbon atoms; certain cøumarins, and nitrobenzodiazoleε, as well as other hydrophobic dyes that display high organic and low aqueous solubilities. To make an oxygen sensor, the dye is selected to be oxygen-quenchable. These dyes are well known in the literature. Those preferred for use in the polymer dye matrix herein are the mono-, hetero-, and polycyclic aromatic dyes, for example the pyrenes, and the organometallic dyes, for example the ruthenium II complex dyes, most preferably tris 4,7 diphenyl- 1,10 phenanthroline (Ruthenium II) complexes, which are not only highly prized for use in fiber optic oxygen sensors, but possess the additional advantage of being insensitive to, halothane and carbon monoxide, gases often found in the clinical environment.

In addition to the sensor dye, a reference dye can also be εolubilized and evenly dispersed in the dye matrix herein when it is desired to utilize the sensor in fiber optic probes of the type described above or in other devices subject to unwanted signal artifact or noise. The need arises particularly when the emitted fluorescent signal is low in intensity. Preferably, the fluorescent reference dye is an aromatic dye selected to be insensitive to the gas analyte of interest; for instance, in an oxygen sensor, the reference dye is selected to be insensitive to oxygen and any other gases whose presence is likely in the environment to be tested. When excited by the light beam used to excite the sensor dye, the reference dye should fluoresce with light having a central wavelength sufficiently different from that of the sensor dye to facilitate processing of the signals to remove the noise artifact in the manner well known in the art.

These aromatic dyes are sufficiently soluble in the aromatic substituted polymer matrices herein that, even. when the sensor is sized for use in a fiber optic probe, the fluorescent signal produced is strong enough to be utilized for measurement purposes. However, if the sensor is to be used in an aqueous environment for an extended period of time, the polymer must be crosslinked so as to remain penetrable to the gas analyte of interest while maintaining constant turbidity in the aqueous environment for the time required. This result is accomplished by controlling the weight percent of crosslinker used in the polymer mixture. It has been discovered that a crosslinked polymer having substantially no increase in turbidity in an aqueous environment for up to 72 hours can be provided by controlling the proportion of crosslinker used. An increase in turbidity can be forestalled for up to 12 hours by using at least three weight percent of crosslinker and at 10 weight percent of crosslinker the turbidity of the sensor in aqueous environment remains stable for at least 72 hours. It is recommended therefore, that at least 3, and preferably from about 5 to 20 weight percent of crosslinker be contained in the polymer mixture.

When the proportion of crosslinker is limited within this range, it has been found that the interstitial spaces in the crosslinked polymer are large enough for oxygen to permeate therethrough but small enough to prohibit the turbidity effect in the sensor in use. The polymer dye matrix is crosslinked by thoroughly mixing the monomers and the dye together, and-crosslinking the mixture using the above described proportion of crosslinker. Usually the monomers are dissolved in a solvent to form a first solution. For example, a chlorinated solvent can be used such as methylene chloride, chloroform, or carbon tetrachloride, or an aromatic solvent such as benzene or toluene. The dye is then dissolved in the same solvent to form a second solution. Sufficient crosslinker to constitute at least about 10 weight percentt of the mixture is added, the solvent is removed by know means, and the mixture is crosslinked, leaving a thorough mixture of monomer and dye molecules.

The following examples and the other disclosure of this application are provided for illustrative purposes only, and are not intended to limit the scope of the invention, which is as described in the claims below.

Example 1

Ruthenium (II) tris ,7-diphenylphenanthroline dichloride is prepared and purified by elution chromatography on silica gel using a procedure based on the synthesis of N. Sutin et al., Journal of the American

Chemical Society. 98, page 6536 (1976). To- prepare the polymer dye matrix the following procedure was followed.

Two samples were prepared using Ruthenium (II) tris

4,7- diphenylphenanthroline dichloride as the sensor dye, 4-(N,N-dioctyl) amino- 7-nitrobenz-2-oxa-l,3-diazole as the reference dye, polydi ethyldiphenyl siloxane as the polymer, and methylene chloride as the solvent. Sufficient solvent was used to transfer to and homogeneously dissolve in a round-bottomed flask the following: Cone, of Cone, of Sensor dye wt.

Sample Sensor dve Ref. dve per kilo of Polymer

*

1 2.0 mM 0.65 mM 2.3mg 2 1.6 mM 0.65 mM 1.87mg

The solvent was then evaporated using a rotary evaporator and the solution was stored overnight in a vacuum oven at 60-70 degrees Celsius to eliminate any final solvent residues.

To cure the stock mixture, 10% by weight of polydiethoxysiloxane, a crosslinking silicone, and 1.0% by weight of dibutyl tin dilaurate as catalyst were added. The stock mixture and catalyst were thoroughly mixed and degassed by transfer to a vacuum desiccator in which the vacuum was alternately applied and released until bubbling of the mixture ceased. Each sample was then transferred into a disposable syringe from which it was expelled into a sensor mold. A final cure of the polymer was effected by heating the molded samples to 75 ± 1 degrees Celsius for two hours. The total amount of sensor dye in the molded probe tips made from the samples was 7.67 x lθ"8 grams for Sample 1 and 6.82 x lθ"7 grams for Sample 2. After cure the molded probe tips were visually examined to determine whether any crystals of undissolved dye could be observed. Both dyes appeared fully dissolved in the polymer matrix. Example 2

0.05 grams of methyl (-1-pyrenyl)-dimethyl vinyl silane (containing 25% methylpyrene) and 0.95 of 12-15% diphenyl, 85-88% dimethyl siloxane (PDMDPS) (Petrarch Systems, Bristol, Pa.) were added to a test tube and dissolved in 1 ml. of methylene dichloride. The solution was mixed until all pyrene material dissolved and then the methylene dichloride was evaporated under nitrogen flow and allowed to stand overnight. No crystallization of the dye was observed. The solution was then diluted with the above copolymer to make concentrations of 2.5%, 1.0% and 0.2% of pyrene dye in the copolymer. Each of these dilute concentrations was mixed with 5% polyethoxysilane as crosslinker, 5% stannous octoate as catalyst, and 5% glacial acetic acid as inhibitor. Slides and probes were made with these materials for testing of signal strength and monomer to eximer fluorescence signals. The fluorescence was measured with a Perkin Elmer LS-5 spectrofluorometer and a custom made fixture for mounting slides. The results of the tests are summarized in Table 1 below, which also displays for comparison the results of parallel control tests using a non- aromatic dye matrix made by substituting as the polymer a dimethylsiloxane having substantially no aryl substituents into the procedure described above. The concentration of the pyrene dye in all samples is 0.3 weight percent. Table 1

As can be seen by the data summarized in Table 1, there is only one tenth as much eximer fluorescence in the dimethyl diphenyl siloxane matrix at a pyrene concentration of 1.0 weight percent as is found in the dimethyl siloxane matrix at a concentration of 1.2 weight percent. Example 3

To compare the solubility of Ruthenium (II) tris 4,7- diphenylphenanthroline dichloride dye in a number of silane polymers having different substituent groups, about 0.5. to 1 mg. of the dye complex was placed in the bottom of small test tubes, the silanes (all purchased from Petrarch Systems, Bristol, Pa.) were added to the test tubes and the test tubes were shaken or stirred with a glass stirring rod or pipet and subjected to visual examination to determine the degree of solubility of the dye. Results of the comparative solubility tests are displayed in Table 2 below:

Table 2 Type of polymer Degree of solubility Diphenylchlorosilane Soluble p-chlorophenyltrimethylsilane Very slightly soluble polydiethoxysilane Very slightly soluble 88-85% dimethyl-12-15%diphenyl insoluble poly siloxane silanol terminated (8000-12000 centistokes)

chlorodimethylphenylsilane soluble 3-chloropropyltrimethoxysilane soluble phenyltriethoxysilane slightly soluble polycyanopropylmethylsiloxane very soluble (tri ethylsilyl terminated (cyanopropyl) ethyl(48-50%) - difficulty soluble methylphenylsiloxane copolymer trimethylsilyl terminated polydiphenylsiloxane silanol soluble terminated

85-88% dimethyl - 12-15% diphenyl soluble siloxane silanol terminated (1500 - 2500 centistokes) A compound determined to be a solvent for the dye was one in which the dye dissolved. Slightly soluble means a red orange solution formed but had undissolved material at the bottom of the test tube. Very slightly soluble means the solution had a faint color but most of the solid did not dissolve. In a solvent in which the dye was insoluble, the solvent remained colorless.

Example 4

To test the effect of various percentages of crosslinker on the turbidity of the dye matrix composition in water an experiment was conducted as follows in which samples of dye matrix containing 3% or 10% of crosslinker were compared. The diphenyldi ethyl siloxane polymer matrix was crosslinked with dibutyl-tin dilaurate and contained the test concentration of Ruthenium (II) tris

4,7-diphenylphenanthroline dichloride as the sensor dye and 4-(N,N-dioctyl)amino- 7-nitrobenz-2-oxa-i,3-diazole as the reference dye. To test each sample, the dye matrix was placed within a probe having a εilastic tube encasing the sensor and attached to a Tissue Oxygen Monitor®, as manufactured by Baxter Healthcare, Deerfield, Illinois. The silastic tube was vented so that fluctuations in pressure above the test fluid are equivalent to the current barometric pressure.

The oxygen monitor was placed into communication with a computer with an RS 232 interface by which data received from the oxygen monitor could be recorded. Bottles of 99.99% pure nitrogen and oxygen were attached to a Corning precision gas mixer manufactured by Corning Glass, Corning, N.Y. via a custom gas accumulator and connected to a custom test chamber via associated fittings and tubing. Temperature in the test chamber was monitored using a calibrated mercury thermometer.

The set up was tested for leaks. The system was allowed to stabilize at the test temperature, and each oxygen probe was sealed into the test chamber and calibrated in a non-aqueous environment over a period of 72 hours using streams of oxygen from the gas mixer at 3% and 21% concentrations of oxygen for a two point calibration, collecting data every 2 minutes and correcting the data for the effects of temperature and barometric pressure. The wavelength of the excitation light was 420-480 nanometers and the wavelength of the emitted fluorescent light from the sensor dye was 600-640 nanometers. The wavelength emitted from the reference dye was 530-540 nanometers.

After calibration each probe was assayed at the same temperature in a temperature controlled water bath and comparative data was collected over time while the probe was exposed to a known concentration of oxygen. The results of the tests are summarized in Table 3 below:

As can be seen from the data summarized in Table 1, with 3% of crosslinker the decay in the signal caused by immersion in water for 52 hours is 148 mmHg, an amount too great to make the sensor useful for extended periods of time. And after 16 hours immersed in water the signal from a sensor containing only 3 percent by weight of crosslinker has decayed by as much as 96 mmHg. On the other hand, the sensors containing 10 percent by weight of crosslinker are stable in water for as long as 72 hours, consistently exhibiting a variance in the partial pressure of oxygen no greater than 5 mmHg.

While presently preferred embodiments of the invention have been illustrated and described, it will be appreciated by one skilled in the art that the invention may be otherwise variously embodied and practiced within the scope of the claims which follow.

Claims

WHAT IS CLAIMED IS:
1. A composition comprising: a fluorescent dye sensitive to a selected gas in an amount sufficient to allow detection of the presence of the gas; a polymer permeable to the selected gas-mixed with the dye and having up to about 2 millimoles of the dye per kilogram of the polymer dissolved therein; wherein transmittance of fluorescent light through the composition remains substantially constant for up to 72 hours in an aqueous environment.
2. A composition according to claim 1 wherein the dye is homogeneously dispersed as a solid solution.
3. A composition according to claim 2 and wherein said gas is oxygen and the polymer is crosslinked so that the interstices of the polymer remain large enough to allow passage of oxygen molecules therethrough, but small enough to substantially prevent an increase in turbidity for up to 72 hours in an aqueous environment.
4. A composition according to claim 3 and wherein said polymer is an organopolysiloxane and wherein from 10 to 60 percent of the monomer units are substituted with aromatic groups containing from 6 to 10 carbons.
5. A composition according to claim 4 and wherein said organopolysiloxane contains from 40 to 90 percent of the monomer units disubstituted with substituted or unsubstituted alkyl groups having from 1 to about 4 carbons wherein the substituted groups are selected from the group consisting of halogen, amino, nitro and cyano.
6. A composition according to claim 5 and wherein said organopolysiloxane contains from about 70 to 90 percent of the monomer units disubstituted with methyl and from about 30 to 10 percent of the monomer units are disubstituted with aromatics.
7. A composition according to claim 6 and wherein said aromatic groups are phenyl groups.
8. A composition according to claim 1 and wherein said dye is an oxygen sensitive aromatic dye having a concentration of from about 1.6 to 2 millimoles per kilogram.
9. A composition according to claim 8 and wherein said dye is a planar, polycyclic hydrocarbon and eximer formation in the composition is minimized.
10. A composition according to claim 9 and wherein said dye is pyrene.
11. A composition according to claim 8 and wherein said dye is an organometallic dye.
12. A composition according to claim 11 and wherein said dye is a complex of Ruthenium(II) .
13. A composition according to claim 12 and wherein said dye is tris 4,7 diphenyl-1,10 phenanthroline (Ruthenium II).
14. A composition according to claim 1 and wherein the composition further comprises a second fluorescent dye emitting fluorescent light at a wavelength other than that at which the sensor dye emits light.
15. A composition comprising: a fluorescent dye sensitive to a selected gas in an amount sufficient to allow detection of the presence of the gas; a polymer permeable to the selected gas mixed with the dye and having from about 40 to 90 percent of the monomers alkyl substituted, with each alkyl group having from l to 4 carbons and from about 10 to 60 percent of the monomers aromatic substituted, with each aromatic group containing from 6 to about 10 carbons; wherein the fluorescent dye is substantiallyhomogeneouslydispersedwithoutcrystallization;
and wherein tranε ittance of luorescent light through the composition remains substantially constant for at least 72 hours in an aqueous environment.
16. A composition according to claim 15 wherein the dye is homogeneous dispersed within a liquid polymer matrix.
17. A composition according to claim 15 wherein the dye is homogeneously dispersed as a solid solution within the polymer.
18. A composition according to claim 17 and wherein said gas is oxygen.
19. A composition according to claim 15 and wherein said polymer is an organopolysiloxane and wherein from 70 to 90 percent of the monomer units are disubstituted with methyl and from 10 to 30 percent of the monomers units are disubstituted with aromatics and wherein the concentration of the dye iε from about 1.6 to 2 millimoleε per kilogram.
20. A compoεition according to claim 19 and wherein said aromatic groups are phenyl groups.
21. A composition according to claim 15 and wherein said dye is an aromatic dye.
22. A composition according to claim 21 and wherein εaid dye iε a planar, polycyclic hydrocarbon and eximer formation in the composition is minimized.
23. A composition according to claim 22 and wherein said dye is pyrene.
24. A composition according to claim 23 and wherein said dye is an organometallic dye.
25. A composition according to claim 24 and wherein said dye is a complex of Ruthenium(II) .
26. A composition according to claim 25 and wherein said dye is tris 4,7 diphenyl-1,10 phenanthroline (Ruthenium II).
27. A composition according to claim 15 and wherein the composition further comprises a second fluorescent dye emitting fluorescent light at a wavelength other than that at which the sensor dye emits light.
28. A dye matrix composition for sensing gas concentration in tissue comprising: an aromatic fluorescent dye sensitive to a selected gas in an amount sufficient to allow detection of the presence of the gas; a polymer permeable to the selected gas and having from about 40 to 90 percent of the monomers disubstituted with alkyl, acyl, or alkoxy groups having from 1 to about 4 carbons and also having from about 10 to 60 percent of the monomers disubεtituted with aromatic groups; wherein the fluorescent dye is substantially evenly dispersed throughout the composition and wherein transmittance of fluorescent light through the composition remains substantially constant for at least 72 hours in bodily tissue.
29. A compoεition according to claim 28 wherein the dye is evenly dispersed as a solid solution within the polymer at a concentration of at least 2 millimoles per kilogram of polymer.
30. A composition according to claim 29 and wherein said gas is oxygen and the polymer is crosslinked so that the interstices of the polymer remain large enough to allow passage of oxygen molecules therethrough, but small enough to substantially prevent an increase in turbidity for up to 72 hours in an aqueous environment.
31. A composition according to claim 29 and wherein said organopolysiloxane contains from 70 to 90 percent of the monomer units disubstituted with methyl and from 30 to 10 percent of the monomer units are disubstituted with aromatics.
32. A composition according to claim 31 and wherein said aromatic groups are phenyl groups and wherein the polymer contains about 10 weight percent of crosslinker.
33. A composition according to claim 28 and wherein said dye is an aromatic dye.
34. A composition according to claim 33 and wherein said dye is a planar, polycyclic hydrocarbon and eximer formation in the composition is minimized.
35. A composition according to claim 34 and wherein said dye is pyrene.
36. A composition according to claim 33 and wherein said dye is an organometallic dye.
37. A composition according to claim 36 and wherein said dye is a complex of Rutheniu (II) .
38. A method for making the composition of claim l, 3, 9, 13, 15, 24, 27, 28, 35 or 37 comprising dissolving the polymer in a solvent to form a first solution, dissolving the dye in the solvent to form a second solution, and then mixing the solutions, removing the solvent, and crosslinking the polymer.
39. A method for making a composition comprising: dissolving at least 2 millimoles per kilogram of dye matrix of a gas-sensitive aromatic fluorescent dye in a solvent to form a first solution; dissolving a mixture of polymer permeable to the gas and at least 3 weight percent of the mixture of a crosslinker for the polymer in said solvent to form a second solution; mixing together the first and second solutions to form, a dye matrix solution; removing the solvent; crosslinking the polymer; and recovering a gas permeable dye matrix containing at least about 1.6 millimoles per kilogram of the dye in homogeneous solid solution in the polymer.
40. The method of claim 39 wherein sufficient dye and crosslinker are added so that the dye matrix contains from about 5 to 10 weight percent of crosslinker and from about 1.6 to 2 millimoles per kilogram of an aromatic oxygen sensitive fluorescent dye.
41. The method of claim 40 wherein the dye matrix contains at least 10 weight percent of crosslinker and the dye matrix maintains substantially constant turbidity in an aqueous environment for at leaεt 72 hourε.
PCT/US1991/006716 1990-09-17 1991-09-17 Water insensitive tissue oxygen sensor WO1992005441A1 (en)

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