CA2015415A1 - Method and material for measurement of oxygen concentration - Google Patents
Method and material for measurement of oxygen concentrationInfo
- Publication number
- CA2015415A1 CA2015415A1 CA002015415A CA2015415A CA2015415A1 CA 2015415 A1 CA2015415 A1 CA 2015415A1 CA 002015415 A CA002015415 A CA 002015415A CA 2015415 A CA2015415 A CA 2015415A CA 2015415 A1 CA2015415 A1 CA 2015415A1
- Authority
- CA
- Canada
- Prior art keywords
- analyte
- species
- output
- indicator
- oxygen
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
Classifications
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
- G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
- G01N21/63—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
- G01N21/64—Fluorescence; Phosphorescence
- G01N21/6428—Measuring fluorescence of fluorescent products of reactions or of fluorochrome labelled reactive substances, e.g. measuring quenching effects, using measuring "optrodes"
- G01N21/643—Measuring fluorescence of fluorescent products of reactions or of fluorochrome labelled reactive substances, e.g. measuring quenching effects, using measuring "optrodes" non-biological material
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B5/00—Measuring for diagnostic purposes; Identification of persons
- A61B5/145—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue
- A61B5/1455—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue using optical sensors, e.g. spectral photometrical oximeters
- A61B5/1459—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue using optical sensors, e.g. spectral photometrical oximeters invasive, e.g. introduced into the body by a catheter
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
- G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
- G01N21/63—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
- G01N21/64—Fluorescence; Phosphorescence
- G01N2021/6417—Spectrofluorimetric devices
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
- G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
- G01N21/63—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
- G01N21/64—Fluorescence; Phosphorescence
- G01N21/645—Specially adapted constructive features of fluorimeters
- G01N2021/6484—Optical fibres
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
- Y10T436/00—Chemistry: analytical and immunological testing
- Y10T436/20—Oxygen containing
- Y10T436/207497—Molecular oxygen
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
- Y10T436/00—Chemistry: analytical and immunological testing
- Y10T436/20—Oxygen containing
- Y10T436/207497—Molecular oxygen
- Y10T436/209163—Dissolved or trace oxygen or oxygen content of a sealed environment
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
- Y10T436/00—Chemistry: analytical and immunological testing
- Y10T436/25—Chemistry: analytical and immunological testing including sample preparation
- Y10T436/25375—Liberation or purification of sample or separation of material from a sample [e.g., filtering, centrifuging, etc.]
- Y10T436/255—Liberation or purification of sample or separation of material from a sample [e.g., filtering, centrifuging, etc.] including use of a solid sorbent, semipermeable membrane, or liquid extraction
Abstract
AN IMPROVED METHOD AND MATERIAL FOR
MEASUREMENT OF OXYGEN CONCENTRATION
Abstract of the Disclosure The method and material for measuring oxygen concentration use indicators, namely polynuclear aromatics, or more specifically, perylene derivatives, together with an appropriate matrix, such as crosslinked polydimethylsiloxane to provide a sensor element for insertion in the blood stream, preferably by means of an appropriate catheter system. By irradiating the resulting matrix with light of a specific wavelength or wavelength range, which may or may not be the wavelength of maximum absorption, while measuring the fluorescent emission over at least two other specific wavelength ranges, different portions of the emission spectrum have been observed to have different sensitivities to oxygen quenching.
MEASUREMENT OF OXYGEN CONCENTRATION
Abstract of the Disclosure The method and material for measuring oxygen concentration use indicators, namely polynuclear aromatics, or more specifically, perylene derivatives, together with an appropriate matrix, such as crosslinked polydimethylsiloxane to provide a sensor element for insertion in the blood stream, preferably by means of an appropriate catheter system. By irradiating the resulting matrix with light of a specific wavelength or wavelength range, which may or may not be the wavelength of maximum absorption, while measuring the fluorescent emission over at least two other specific wavelength ranges, different portions of the emission spectrum have been observed to have different sensitivities to oxygen quenching.
Description
AN IMPROYED ME~HOD AND MATERXAL
FOR MEASUREMENT OF O~XYGEN coNcEN~rRATIoN
BACKG~OUND OF THE INVENTION
Fleld o~ tha Invention This invention is generally related to the measurement of concentrations o~ elements, compounds or other analytes ln a fluid or in a gaseous mixture, and more spacifically, to the measurement of concentrations of oxygen in a fluid or in a gaseous mixture.
Description of the Related Art A number of methods and apparatus have been developad to measure concantration~ of an analyte such as elements or compound~ in a fluid or a gaseous mixture. These measurement methods and apparatus have become particularly important in modern medicina, where blood chemistry and other life-critical diagnostic and monitoring measurements have become increasingly important to the sophisticated treatments available.
Among such measurement methods and appara~us have been those directed to the measurement of the concentration of oxygen in the blood based upon the phenomenon of quenching of the emissions from certain dyes which are used as indicators. Systems incorporating these methods have been incorporated into intravascular catheters which are used to measure concentrations of cxygen in the blood. In such catheters, optical ~ibers are used to conduct excitation light generatad in an external instrument to the sensing element 2 ~ 5 incorporating the indicator at the distal tip of the cathetsr and to transmit the resulting emitted light from the sensing el~ment back to the detection system of the extarnal instrument.
Wh~e such maasurement me~hods have been shown to be quite useful and have acceptable sensitivity and accuracy, the indicated oxygen concentration often tends to drift or otherwis~ show inaccuracies or biases, sinca the intensity of the fluorescence is a ~unction of a number of fac:tors related to the apparatus and dye in addit:ion to the oxygen concentration. These factors include tha power of the excitation light, transmission of the optical fiber, the tsmperature of the sampls, the concentration of the indicator dye, and the local anvironment of the indicator (e.g., changes in the dye-matrix conformation when the dye is immobilized in an analyte permeable matrix). It has besn widely recognized that optical sensors show greatly enhansed performance and/or stability when the system include~ a means for referencing the intensity of the output to a stable independent source. Ideally, the intensity of this second source should illustrate the same variation Ln intensity ~ro~ factors that influence the oxygen sensit~ve component, with the exception of the oxygen sensiti~i~y. In that case, the quotient of ~he two fluorescence~ will yield a ratio which is dependent only upon the concsntration vf oxygen.
A variety of dif~erent approaches have been proposed to provide such reference means, including providing a sample of the indicator which is not exposed to the oxygen, the use of a separate indicator compound or the use of a different chemical form of the indicator. ~11 of these approaches result in a more complex apparatus that may not necessarily provide compensat~on for a variety of allied indicator _ 3 _ 2 0 ~
degradation phenomena, su~h as differential photobleach-in~ or differential leaching of the indicator and reference compounds from the sensing el~m~nt. While it has been suggested that a ~ingle ~hemical compound can be used as both as an indicator and a reference material on the basis of ratioinq the fluorescence and phosphorescence of that compound, the rea~ents developed for such use have not been suitable for the analysis of aqueous and other liquid samples and such a method has been shown to be of limited utility.
There remains, therefore, a need for a means of refersncing tha output of indicators which employ the phenomenon of fluorescent quenching which is simple and easily implemented in catheter systems and which provides a means of accurate normalization within a wide variation in the fluorescent emission of the indicator. Furthermore, it would be extremely helpful if such a method could be applied to a variety of indicators and does not require additlonal complex electronics or optics associated with the excitation and measurement scheme.
SUMMARY OF T~E INVENTION
The invention provides a method and apparatus by which a single quantity of a species of indicator may be used as both the indicator and the reference element. certain conventional blood oxygen chemistry sensors utilize as the sp~cies incorporated in the indicator a dye which fluorescss when irradiated with light of a certain wavelength. One particular use for such sensors is the measurement of oxygen concentration in the blood. If the dye is expossd to a fluid containing oxygen, the fluorescence will be quenched Ln proportion to the concentration of oxygen in ~h~
fluid. However, calibration of the output of such a 5 ~ 1 ~
method is not ~imple, and the ~luorescence may degrade without any extrinsic indlcation, thereby causing an undetected error in the measurement.
The present invention use3 approprlate mdicators, namely polynuclear aromatics, or mora speci~ically, perylene derivativles, together with an appropriate matrix, such a~ cross]inXed polydimethyl-siloxane to provide a sensor elament for insertion in~he blood stream, pre~erably by means of an appropriate catheter syste~. ~y irradiating the resulting matrix with light o~ a specific wave!length or wavelength rangs, which may or may not be the wavelength o~
maximum absorption, while measuring the fluorescent emission over at least two other specific wavelength ranges, d~f~erent portions of the emission spectrum have been obsexved to have different sensitivities to oxygen quenching. By choosing certain perylene dQrivatlvQs, dispersed or immobilized in a sillcone matrix, lmportant and unexpected bene~its are derived, in that the normallzation o~ emission of tha dye can ~Q
derived from the emlss~on of the dye itself, rather than from another sample of that dye or a similar one, thereby reducing the complexlty of the sensing method and apparatus, and eliminating the uncertainty of measurement of emission o~ a sa~ple different from that which is maXing the prime measurement. When the same dye is excited in an organic solvent, the sensitivity to oxygen is nearly the same over the entlre emission spectrum and therefore cannot be practically used as a normalization scheme.
Thus, the use of the normalization scheme of the present invention provides a more accurate indication method than previous methods and further results in a far simpler system and apparatus for measurement of the sample containing the analyte.
While the invention has proved to be particularly 2 ~ 1 5 useful for maasurement of oxygsn samplles m tha blood by use o~ a catheter carrying a sensor module incor-porating the indicator, the method should also prove advantageous ~ox any measurement system in which an 5 indicator i5 activated to cause an output, the level o~
which is altered by the presenc~ of a quantity to be measured.
From the above, it may be se2n that the present invention provides a new and use~ul method for measuring concentrations of an analyts in a fluid by ~he use of indi~~ators that emit fluorescence when exposed to external radiation such as light. Other features and advantages o~ the present invention will become apparent from the following detailed description, taken in conjunction with the accompanying drawings, which illustrate, by way of example, the principles of the invention.
BRIEF DESCRIPTION OF THE DRAWINGS
Flgura 1 is a schematic representation of an apparatus according to the present invention, illustrating the relationship between the means of irradiating the sensor and collecting the information for readout of the concentration of oxygen in the sample exposed to the sensor.
Figure 2 is an enlarged cros~ sectional perspective viaw o~ ths arrangement of the components of the sensor system.
Figure 3 is an illustration of the ~uenching of fluorescence which occurs when typical oxygen sensitive dye in either silicone or a typical organic solvent is irradiated in the presence o~ oxygen.
Figure 4 is an illustration of the quenching of fluorescence as a function of frequency when one of the disclosed dyes, dispersed or immobilized in a 2 ~
~ilicone matrix, is irradiat~d in th~ presence of a given concentration of oxygen.
Figure 5 is an illustration of the quenching of fluorescence as a function of` ~requancy of output for one of the disclosed dyes" indica~ing how the output may be ratioed to derive the concentration of oxygen in the sample.
DESCRIPTION OF PREFERRED E~BODIMENT
The present invention is embodied in a system and method that allows the use of a single sa~ple of 3ensor ~aterial to perform both measurement of the analyte and normalization of the fluorescent signal for system perturbations, e.g., changes in excitation intensity, changes in flber transmission, changes in temperature, changes in dye concentration including photodegradation and leaching of the dye.
Sensors which are used to determine the concentration of oxygen in the blood are well known in the art. Among these sensors are systems which utilize a dye which fluoresces when irradiated with light of a certain wavelength. If the dye is also exposed at the same time to concentrations of oxygen, the Pluorescenca w;~l be ~uenched in a predictable way in proportion to the concentration of oxygen in the blood. Furthermore, oxygen quenching of the fluorescence of such dyes is gener~lly uniform across the antire emission band.
The conventional means of normalization of such a system for environmental perturbations involves inclusion of a second dye species which is insensitive to oxygen, but which gives an indicatlon of all changes in fluorescent intensity due to all factors other than a change in oxygsn concentration. Such systems are susceptible to differential degradation or differential 2 ~ 5 le~ching o~ th~ dyas with tha res~lt that the measure-ment method becomes unreliable.
The present in~ention employs the dis~overy that whan certain oxygen indicator dyes are dispersed or immob~lized in a silicona matrix, and are irradiated with l~ht at the frequency of maximum absorption or wlth light at a frequency not at the frequency of maximum absorption, they will emit fluorescence whlch is frequency sensitive to the quenching phenomena. By measuring the fluorescent emission over at least two specific wavalength ranges which have different sensitivities to oxygen quench~ng and by ratioing the output at such fre~uencies, a normalized measurement of fluorescent quenching dua to the presence of oxygen may be measured wi~hout the need for a second, distinct dye ~ample. Thus, the system and apparatus of the present invention provides a more accurate ratiomatric method in that it normaliz~ for dye leaching and/or dye photodsgradation, whereas the two dye method does not.
Figure l illustrates the general arrangement of the components o~ an apparatus according to the pre~ent ~n~ention. A light source 2 provides an output light beam 4 that is focused by a lens system 6 into the connector 8 of an optical fiber lO. Optical fiber lO conducts the light to a sansor module 12 located m a fluid 14 with a concentration of oxygen to be measured. Sensor module 12 incorporates a portion of dye material (in combination with the matrix to immobilize it) genarally indicated 16, surrounding the optical material 18. An output optical fiber 20 carries light from indicator 16 to lens system 22, which focuses the light upon detector array 24, containing two or mors detectors 26, each of which is sensitive to various output frequencies to be measured. In practice, the detectors may all be identical, but be fitted with fil~rs which filter all but the frequency - ~ -to b~ measured by the detector out of the light reaching the detector. The electrical output o~ such detectors i5 fed via a system of cables 28 to a comput~r 30 which calculates the percentage o~ analyte present on the basis of the ratio of signals detected by the indi~idual detectors and al~orithms in the computer representing the sensitivity of the sensor Ln those frequ~ncy bands to the analyte.
The output of the computer may be provided in the form of a meter 32 or other means to provide a direct indication of the concentration of oxygen m the blood stream. While the above apparatus is illustratad in the form of individual optical fibers for the irradiation and collection of data from the sensor module, those sXilled in the art will appreciate that other methods, including time multiplexing and beam splitting, may be used to simplify or alter this apparatus for certain applications.
The sensor of the present system is ~lustrated in more detail in Figure 2, which shows that thQ light conductor 18 provides a means of irradiating sensor dye 16 which is immobilized in, a matrix surrounding tha light conductor. Appropriate systems for such use include the use of indicators such as dyes derived from perylene dispersad in an appropriate matrix such a crosslinked polydimethyl-siloxane and surrounding the sensor with an oxygen permeable membrane 34 which allows mixing of the oxygen with the dye to promote the quenching by which the measuremant of the concsntration of the oxygen is performed. Those skilled in the art will appreciate that whil~ a sensor has been illustrated ~hat shows the indicator -dispersed around a central light conductor, other systems, such as those in which the light irradiates a capsule of the indicator or a matrix at 2 ~ 5 g end o~ the fiber, are equally adaptable to the invention.
Fi~ure 3 illustrates that quenching, that ls, the dl~erence between the un~uenced output level represented by dotted line 34 and the quenched level represented by solid lino 36, as a function of oxygen concentration is generally constant ovar the entire emission band for one of the family of dyes conven-tionally used for such measurements. since there are no ` regions of the spectrum that show differential quanching to oxygen, a ratiometric scheme using a single dye is not possible. This is the normal mode in which sensors according to the prior art operate. For ratiometric operation, an additional dye species must be introduced, thereby adding a region that exhibits a quenching that is different than the oxygen sensing region. Ideally, the second dye will exhibit no quenching, but thosa exhibitlng a small quenchlng a~feGt are also useabls. However, schemes ~or normalization based on two or more dyes or specles will not normalize for loss of dye due to either photo-degradation or leaching since the two species may degrade or leach at differential rates. Furthermore, the difference between the two rates may not be constant since each will depend upon environmental conditions such as temperature, oxygen environment, excitation power, analyte medium, etc.
By contrast, Flgure 4 illustrates quenching as a function of oxygen concentration ~or certain dyes useful for the present inYention that are dispersed or immob;lized in silicone matrix. In this case, although there is a band at which the indicator is quite sensitive to the presence of oxygen, there will be at least one other band which is relatively insensitive to the concentration of oxygen in the fluid to be measured.
- lo- 2~
Figure 5 ~lustrates the output of such an indicator as a functlon of frequency per unit o~ oxygsn present as an analyte in a fluid to be evaluated~ As can be seen fxom this ~lustratlon, the sensitivity of quenching of tha fluorescence varies with the output frequency for a given concentration of oxygen. By ratioing the output of the band that is relatively sensitive, e.g., 400 nm to 450 nm, to one which is relati~ely insensitive, e.g., 450 nm to 500 nm, a dlrect indication of the actual concentration of the oxygen ~ay be made. As the dye degrades or leaches from ths system the fluorescent intensity of the oxygen-sensitive and the oxygen-insensitive regions of the emission spectrum w~l change by the same propor-tion since they result from the same dye species.Th~refore, the ratio of the two intensities will remain constant. No drift or inaccuracies will be Lntroduced.
For the purpose o~ this description we de~lne this as an lnternal ratio scheme, that is, a scheme where~y a single dye specie~ is used a~ both the indicator and ~he reference compound. It i5 necessary that there exists in the em~ssion spectrum at least two regions -one that shows oxygen quenching and one that shows greatly reduced, or more ideally, essentially no oxygen quenching, The intensity of emission over each of the wavelength ranges is described by the Stern-Volmer expression:
Fo/F = l + K X PO2 where Fo is th~ fluorescent intensity in the absence of oxygen: F- is the fluorescent intensity at some partial pressure of oxygen, P02; and, K is thQ Stern-Volmer constant, which is different substantially for the - 11 2 ~
different emission wavelangth ranges (i.e., ~uenching differs substantially), then the P02 can be calculated so that the calculated valuQ is independent of ~actors other than the partial pressure of oxygen. This ratiometric scheme will normalize for the loss of dyes as well as other perturbations.
The ~ollowing examplas are included to assist in further understanding of the invention. It should be understood that these examples: are included for the purposas of illustration but are in no way intended to ~mit the scope of the present invention.
MEASUREMENTS USING PRIO~ ART DYES
In order to demonstrate the typical performance of an oxygen sensitive dye, a decacyclene/
polydimethylsiloxane matrix was prepared and inserted into the chamber of a fluore~cent spectrophotometer.
When the sample was irradiated with 395 nm light (the maximum absorbanca of the dye), it was observed that the Stern-Volmer X wa~ 0.00~5 torr-l across th~
entire emission spectrum. Furthermore, the Stern-Volmer K was 0.0035 torr-l across tha entire emission spectrum when irradiated by light at a frequency not at the maximum absorbency of the dye.
Thus, it can bs seen that n internal ratio scheme i5 not possible for this m dicator material.
A FIRS~ EX~MPLE OF MEASUREMENTS UTILIZING
THE PRESENT INVENTION
In order to demonstrate the present invention, incorporating the disclosad mternal ratio scheme, a coronene/polydimethylslloxane matrix was prepared and inserted into the chamber of a fluorescent spectrophotometer. When the ~ample was irradiated with - 12 ~
~80 nm light, it was observed that the emission had a wavelength-dependent oxygen sensitivity; the emission at 500 nm had a K value o~ 0.000~4 torr-l while the amission at 420 nm had a K value of 0.010 torr-l.
However, when coronene was dissolved in xylenQ, inssrted into the chamber of a fluorescent spectromater, and irradiated with 380 nm light, it was observed that the emission did not have a wavelength-dependent oxygen sensitivityt the emission had a K
value of 0.010 torr-l in the 500 nm region as w~ll as the 420 nm region.
A SECO~D EXAMPLE OF MEASUREMENTS UTILIZING
THE PRESENT INVENTION
In order to further demonstrate our inventlon, a naphtho ~8,1,2-abc] coronene/polydimethylsiloxane matrix wa preparsd and inserted into the chamber of a fluore~cent spectrophotometer. When the sampls was irradiated with 408 nm light, it was o~served that the emission had a wavelength-dependent oxygen sensitlvity;
the emi3sion at 570 nm had a K value of 0.00044 torr-l while the emission at 480 nm had a X value of 0.01~7 torr- .
From the above examples, it is evident that the present invention provides a means of continuously nor~alizin~ the output of a fluorescent indicator without ths necessity of separate processes or apparatus to perform the ratiometric ~unctlon. While a particular form of the invention has been illustrated and described, it will also be apparent to those sX~lled in the art that various modifications may be made without dsparting from the spirit and scope of the invention. Accordingly, it is not intended ~hat the invention be limlted, except a~ by the appended claims.
FOR MEASUREMENT OF O~XYGEN coNcEN~rRATIoN
BACKG~OUND OF THE INVENTION
Fleld o~ tha Invention This invention is generally related to the measurement of concentrations o~ elements, compounds or other analytes ln a fluid or in a gaseous mixture, and more spacifically, to the measurement of concentrations of oxygen in a fluid or in a gaseous mixture.
Description of the Related Art A number of methods and apparatus have been developad to measure concantration~ of an analyte such as elements or compound~ in a fluid or a gaseous mixture. These measurement methods and apparatus have become particularly important in modern medicina, where blood chemistry and other life-critical diagnostic and monitoring measurements have become increasingly important to the sophisticated treatments available.
Among such measurement methods and appara~us have been those directed to the measurement of the concentration of oxygen in the blood based upon the phenomenon of quenching of the emissions from certain dyes which are used as indicators. Systems incorporating these methods have been incorporated into intravascular catheters which are used to measure concentrations of cxygen in the blood. In such catheters, optical ~ibers are used to conduct excitation light generatad in an external instrument to the sensing element 2 ~ 5 incorporating the indicator at the distal tip of the cathetsr and to transmit the resulting emitted light from the sensing el~ment back to the detection system of the extarnal instrument.
Wh~e such maasurement me~hods have been shown to be quite useful and have acceptable sensitivity and accuracy, the indicated oxygen concentration often tends to drift or otherwis~ show inaccuracies or biases, sinca the intensity of the fluorescence is a ~unction of a number of fac:tors related to the apparatus and dye in addit:ion to the oxygen concentration. These factors include tha power of the excitation light, transmission of the optical fiber, the tsmperature of the sampls, the concentration of the indicator dye, and the local anvironment of the indicator (e.g., changes in the dye-matrix conformation when the dye is immobilized in an analyte permeable matrix). It has besn widely recognized that optical sensors show greatly enhansed performance and/or stability when the system include~ a means for referencing the intensity of the output to a stable independent source. Ideally, the intensity of this second source should illustrate the same variation Ln intensity ~ro~ factors that influence the oxygen sensit~ve component, with the exception of the oxygen sensiti~i~y. In that case, the quotient of ~he two fluorescence~ will yield a ratio which is dependent only upon the concsntration vf oxygen.
A variety of dif~erent approaches have been proposed to provide such reference means, including providing a sample of the indicator which is not exposed to the oxygen, the use of a separate indicator compound or the use of a different chemical form of the indicator. ~11 of these approaches result in a more complex apparatus that may not necessarily provide compensat~on for a variety of allied indicator _ 3 _ 2 0 ~
degradation phenomena, su~h as differential photobleach-in~ or differential leaching of the indicator and reference compounds from the sensing el~m~nt. While it has been suggested that a ~ingle ~hemical compound can be used as both as an indicator and a reference material on the basis of ratioinq the fluorescence and phosphorescence of that compound, the rea~ents developed for such use have not been suitable for the analysis of aqueous and other liquid samples and such a method has been shown to be of limited utility.
There remains, therefore, a need for a means of refersncing tha output of indicators which employ the phenomenon of fluorescent quenching which is simple and easily implemented in catheter systems and which provides a means of accurate normalization within a wide variation in the fluorescent emission of the indicator. Furthermore, it would be extremely helpful if such a method could be applied to a variety of indicators and does not require additlonal complex electronics or optics associated with the excitation and measurement scheme.
SUMMARY OF T~E INVENTION
The invention provides a method and apparatus by which a single quantity of a species of indicator may be used as both the indicator and the reference element. certain conventional blood oxygen chemistry sensors utilize as the sp~cies incorporated in the indicator a dye which fluorescss when irradiated with light of a certain wavelength. One particular use for such sensors is the measurement of oxygen concentration in the blood. If the dye is expossd to a fluid containing oxygen, the fluorescence will be quenched Ln proportion to the concentration of oxygen in ~h~
fluid. However, calibration of the output of such a 5 ~ 1 ~
method is not ~imple, and the ~luorescence may degrade without any extrinsic indlcation, thereby causing an undetected error in the measurement.
The present invention use3 approprlate mdicators, namely polynuclear aromatics, or mora speci~ically, perylene derivativles, together with an appropriate matrix, such a~ cross]inXed polydimethyl-siloxane to provide a sensor elament for insertion in~he blood stream, pre~erably by means of an appropriate catheter syste~. ~y irradiating the resulting matrix with light o~ a specific wave!length or wavelength rangs, which may or may not be the wavelength o~
maximum absorption, while measuring the fluorescent emission over at least two other specific wavelength ranges, d~f~erent portions of the emission spectrum have been obsexved to have different sensitivities to oxygen quenching. By choosing certain perylene dQrivatlvQs, dispersed or immobilized in a sillcone matrix, lmportant and unexpected bene~its are derived, in that the normallzation o~ emission of tha dye can ~Q
derived from the emlss~on of the dye itself, rather than from another sample of that dye or a similar one, thereby reducing the complexlty of the sensing method and apparatus, and eliminating the uncertainty of measurement of emission o~ a sa~ple different from that which is maXing the prime measurement. When the same dye is excited in an organic solvent, the sensitivity to oxygen is nearly the same over the entlre emission spectrum and therefore cannot be practically used as a normalization scheme.
Thus, the use of the normalization scheme of the present invention provides a more accurate indication method than previous methods and further results in a far simpler system and apparatus for measurement of the sample containing the analyte.
While the invention has proved to be particularly 2 ~ 1 5 useful for maasurement of oxygsn samplles m tha blood by use o~ a catheter carrying a sensor module incor-porating the indicator, the method should also prove advantageous ~ox any measurement system in which an 5 indicator i5 activated to cause an output, the level o~
which is altered by the presenc~ of a quantity to be measured.
From the above, it may be se2n that the present invention provides a new and use~ul method for measuring concentrations of an analyts in a fluid by ~he use of indi~~ators that emit fluorescence when exposed to external radiation such as light. Other features and advantages o~ the present invention will become apparent from the following detailed description, taken in conjunction with the accompanying drawings, which illustrate, by way of example, the principles of the invention.
BRIEF DESCRIPTION OF THE DRAWINGS
Flgura 1 is a schematic representation of an apparatus according to the present invention, illustrating the relationship between the means of irradiating the sensor and collecting the information for readout of the concentration of oxygen in the sample exposed to the sensor.
Figure 2 is an enlarged cros~ sectional perspective viaw o~ ths arrangement of the components of the sensor system.
Figure 3 is an illustration of the ~uenching of fluorescence which occurs when typical oxygen sensitive dye in either silicone or a typical organic solvent is irradiated in the presence o~ oxygen.
Figure 4 is an illustration of the quenching of fluorescence as a function of frequency when one of the disclosed dyes, dispersed or immobilized in a 2 ~
~ilicone matrix, is irradiat~d in th~ presence of a given concentration of oxygen.
Figure 5 is an illustration of the quenching of fluorescence as a function of` ~requancy of output for one of the disclosed dyes" indica~ing how the output may be ratioed to derive the concentration of oxygen in the sample.
DESCRIPTION OF PREFERRED E~BODIMENT
The present invention is embodied in a system and method that allows the use of a single sa~ple of 3ensor ~aterial to perform both measurement of the analyte and normalization of the fluorescent signal for system perturbations, e.g., changes in excitation intensity, changes in flber transmission, changes in temperature, changes in dye concentration including photodegradation and leaching of the dye.
Sensors which are used to determine the concentration of oxygen in the blood are well known in the art. Among these sensors are systems which utilize a dye which fluoresces when irradiated with light of a certain wavelength. If the dye is also exposed at the same time to concentrations of oxygen, the Pluorescenca w;~l be ~uenched in a predictable way in proportion to the concentration of oxygen in the blood. Furthermore, oxygen quenching of the fluorescence of such dyes is gener~lly uniform across the antire emission band.
The conventional means of normalization of such a system for environmental perturbations involves inclusion of a second dye species which is insensitive to oxygen, but which gives an indicatlon of all changes in fluorescent intensity due to all factors other than a change in oxygsn concentration. Such systems are susceptible to differential degradation or differential 2 ~ 5 le~ching o~ th~ dyas with tha res~lt that the measure-ment method becomes unreliable.
The present in~ention employs the dis~overy that whan certain oxygen indicator dyes are dispersed or immob~lized in a silicona matrix, and are irradiated with l~ht at the frequency of maximum absorption or wlth light at a frequency not at the frequency of maximum absorption, they will emit fluorescence whlch is frequency sensitive to the quenching phenomena. By measuring the fluorescent emission over at least two specific wavalength ranges which have different sensitivities to oxygen quench~ng and by ratioing the output at such fre~uencies, a normalized measurement of fluorescent quenching dua to the presence of oxygen may be measured wi~hout the need for a second, distinct dye ~ample. Thus, the system and apparatus of the present invention provides a more accurate ratiomatric method in that it normaliz~ for dye leaching and/or dye photodsgradation, whereas the two dye method does not.
Figure l illustrates the general arrangement of the components o~ an apparatus according to the pre~ent ~n~ention. A light source 2 provides an output light beam 4 that is focused by a lens system 6 into the connector 8 of an optical fiber lO. Optical fiber lO conducts the light to a sansor module 12 located m a fluid 14 with a concentration of oxygen to be measured. Sensor module 12 incorporates a portion of dye material (in combination with the matrix to immobilize it) genarally indicated 16, surrounding the optical material 18. An output optical fiber 20 carries light from indicator 16 to lens system 22, which focuses the light upon detector array 24, containing two or mors detectors 26, each of which is sensitive to various output frequencies to be measured. In practice, the detectors may all be identical, but be fitted with fil~rs which filter all but the frequency - ~ -to b~ measured by the detector out of the light reaching the detector. The electrical output o~ such detectors i5 fed via a system of cables 28 to a comput~r 30 which calculates the percentage o~ analyte present on the basis of the ratio of signals detected by the indi~idual detectors and al~orithms in the computer representing the sensitivity of the sensor Ln those frequ~ncy bands to the analyte.
The output of the computer may be provided in the form of a meter 32 or other means to provide a direct indication of the concentration of oxygen m the blood stream. While the above apparatus is illustratad in the form of individual optical fibers for the irradiation and collection of data from the sensor module, those sXilled in the art will appreciate that other methods, including time multiplexing and beam splitting, may be used to simplify or alter this apparatus for certain applications.
The sensor of the present system is ~lustrated in more detail in Figure 2, which shows that thQ light conductor 18 provides a means of irradiating sensor dye 16 which is immobilized in, a matrix surrounding tha light conductor. Appropriate systems for such use include the use of indicators such as dyes derived from perylene dispersad in an appropriate matrix such a crosslinked polydimethyl-siloxane and surrounding the sensor with an oxygen permeable membrane 34 which allows mixing of the oxygen with the dye to promote the quenching by which the measuremant of the concsntration of the oxygen is performed. Those skilled in the art will appreciate that whil~ a sensor has been illustrated ~hat shows the indicator -dispersed around a central light conductor, other systems, such as those in which the light irradiates a capsule of the indicator or a matrix at 2 ~ 5 g end o~ the fiber, are equally adaptable to the invention.
Fi~ure 3 illustrates that quenching, that ls, the dl~erence between the un~uenced output level represented by dotted line 34 and the quenched level represented by solid lino 36, as a function of oxygen concentration is generally constant ovar the entire emission band for one of the family of dyes conven-tionally used for such measurements. since there are no ` regions of the spectrum that show differential quanching to oxygen, a ratiometric scheme using a single dye is not possible. This is the normal mode in which sensors according to the prior art operate. For ratiometric operation, an additional dye species must be introduced, thereby adding a region that exhibits a quenching that is different than the oxygen sensing region. Ideally, the second dye will exhibit no quenching, but thosa exhibitlng a small quenchlng a~feGt are also useabls. However, schemes ~or normalization based on two or more dyes or specles will not normalize for loss of dye due to either photo-degradation or leaching since the two species may degrade or leach at differential rates. Furthermore, the difference between the two rates may not be constant since each will depend upon environmental conditions such as temperature, oxygen environment, excitation power, analyte medium, etc.
By contrast, Flgure 4 illustrates quenching as a function of oxygen concentration ~or certain dyes useful for the present inYention that are dispersed or immob;lized in silicone matrix. In this case, although there is a band at which the indicator is quite sensitive to the presence of oxygen, there will be at least one other band which is relatively insensitive to the concentration of oxygen in the fluid to be measured.
- lo- 2~
Figure 5 ~lustrates the output of such an indicator as a functlon of frequency per unit o~ oxygsn present as an analyte in a fluid to be evaluated~ As can be seen fxom this ~lustratlon, the sensitivity of quenching of tha fluorescence varies with the output frequency for a given concentration of oxygen. By ratioing the output of the band that is relatively sensitive, e.g., 400 nm to 450 nm, to one which is relati~ely insensitive, e.g., 450 nm to 500 nm, a dlrect indication of the actual concentration of the oxygen ~ay be made. As the dye degrades or leaches from ths system the fluorescent intensity of the oxygen-sensitive and the oxygen-insensitive regions of the emission spectrum w~l change by the same propor-tion since they result from the same dye species.Th~refore, the ratio of the two intensities will remain constant. No drift or inaccuracies will be Lntroduced.
For the purpose o~ this description we de~lne this as an lnternal ratio scheme, that is, a scheme where~y a single dye specie~ is used a~ both the indicator and ~he reference compound. It i5 necessary that there exists in the em~ssion spectrum at least two regions -one that shows oxygen quenching and one that shows greatly reduced, or more ideally, essentially no oxygen quenching, The intensity of emission over each of the wavelength ranges is described by the Stern-Volmer expression:
Fo/F = l + K X PO2 where Fo is th~ fluorescent intensity in the absence of oxygen: F- is the fluorescent intensity at some partial pressure of oxygen, P02; and, K is thQ Stern-Volmer constant, which is different substantially for the - 11 2 ~
different emission wavelangth ranges (i.e., ~uenching differs substantially), then the P02 can be calculated so that the calculated valuQ is independent of ~actors other than the partial pressure of oxygen. This ratiometric scheme will normalize for the loss of dyes as well as other perturbations.
The ~ollowing examplas are included to assist in further understanding of the invention. It should be understood that these examples: are included for the purposas of illustration but are in no way intended to ~mit the scope of the present invention.
MEASUREMENTS USING PRIO~ ART DYES
In order to demonstrate the typical performance of an oxygen sensitive dye, a decacyclene/
polydimethylsiloxane matrix was prepared and inserted into the chamber of a fluore~cent spectrophotometer.
When the sample was irradiated with 395 nm light (the maximum absorbanca of the dye), it was observed that the Stern-Volmer X wa~ 0.00~5 torr-l across th~
entire emission spectrum. Furthermore, the Stern-Volmer K was 0.0035 torr-l across tha entire emission spectrum when irradiated by light at a frequency not at the maximum absorbency of the dye.
Thus, it can bs seen that n internal ratio scheme i5 not possible for this m dicator material.
A FIRS~ EX~MPLE OF MEASUREMENTS UTILIZING
THE PRESENT INVENTION
In order to demonstrate the present invention, incorporating the disclosad mternal ratio scheme, a coronene/polydimethylslloxane matrix was prepared and inserted into the chamber of a fluorescent spectrophotometer. When the ~ample was irradiated with - 12 ~
~80 nm light, it was observed that the emission had a wavelength-dependent oxygen sensitivity; the emission at 500 nm had a K value o~ 0.000~4 torr-l while the amission at 420 nm had a K value of 0.010 torr-l.
However, when coronene was dissolved in xylenQ, inssrted into the chamber of a fluorescent spectromater, and irradiated with 380 nm light, it was observed that the emission did not have a wavelength-dependent oxygen sensitivityt the emission had a K
value of 0.010 torr-l in the 500 nm region as w~ll as the 420 nm region.
A SECO~D EXAMPLE OF MEASUREMENTS UTILIZING
THE PRESENT INVENTION
In order to further demonstrate our inventlon, a naphtho ~8,1,2-abc] coronene/polydimethylsiloxane matrix wa preparsd and inserted into the chamber of a fluore~cent spectrophotometer. When the sampls was irradiated with 408 nm light, it was o~served that the emission had a wavelength-dependent oxygen sensitlvity;
the emi3sion at 570 nm had a K value of 0.00044 torr-l while the emission at 480 nm had a X value of 0.01~7 torr- .
From the above examples, it is evident that the present invention provides a means of continuously nor~alizin~ the output of a fluorescent indicator without ths necessity of separate processes or apparatus to perform the ratiometric ~unctlon. While a particular form of the invention has been illustrated and described, it will also be apparent to those sX~lled in the art that various modifications may be made without dsparting from the spirit and scope of the invention. Accordingly, it is not intended ~hat the invention be limlted, except a~ by the appended claims.
Claims (26)
1. An analyte sensing system which comprises:
a species which displays an output when exposed to external excitation, said output quenched by the presence of an analyte, said species exhibiting a level of said quenching in output varying with the frequency of output;
an analyte permeable matrix in which said species is dispersed or immobilized, said permeable matrix exposed directly or indirectly to a sample containing an analyte to be measured;
a means to excite said species at a first frequency;
a means to measure the output of said species at a plurality of frequencies; and a means to ratio said output in said plurality of frequencies to thereby measure the level of analyte in said sample.
a species which displays an output when exposed to external excitation, said output quenched by the presence of an analyte, said species exhibiting a level of said quenching in output varying with the frequency of output;
an analyte permeable matrix in which said species is dispersed or immobilized, said permeable matrix exposed directly or indirectly to a sample containing an analyte to be measured;
a means to excite said species at a first frequency;
a means to measure the output of said species at a plurality of frequencies; and a means to ratio said output in said plurality of frequencies to thereby measure the level of analyte in said sample.
2. The sensing system of Claim 1 wherein the species is a polynuclear aromatic hydrocarbon based fluorescent dye selected from the group consisting essentially of perylene and derivatives thereof.
3. The sensing system of Claim 1 wherein the species is coronene.
4. The sensing system of Claim 1 wherein the species is naphtho [8,1,2-abc] coronene.
5. The sensing system of Claim 1 wherein the analyte permeable matrix in which the species is dispersed or immobilized is crosslinked polydimethylsiloxane.
6. The sensing system of Claim 1 wherein the analyte permeable matrix in which the species is dispersed or immobilized is a crosslinked derivative or copolymer of polydimethylsiloxane.
7. The sensing system of Claim 1 in which said analyte to be sensed is oxygen.
8. The sensing system of Claim 1 m which said analyte to be sensed is an anesthetic agent.
9. A method of sensing the concentration of analyte in a fluid medium which comprises:
exposing a sample of an indicator which displays a variation in output as a function of frequency when exposed to an analyte, to said fluid;
activating said indicator with radiation;
measuring the output of said indicator at a plurality of frequencies; and determining the concentration of said analyte on the basis of the ratio of said plurality of outputs of said indicator.
exposing a sample of an indicator which displays a variation in output as a function of frequency when exposed to an analyte, to said fluid;
activating said indicator with radiation;
measuring the output of said indicator at a plurality of frequencies; and determining the concentration of said analyte on the basis of the ratio of said plurality of outputs of said indicator.
10. The method of Claim 9 wherein the indicator consists of a polynuclear aromatic hydrocarbon based fluorescent dye selected from the group consisting essentially of perylene, and derivatives thereof, said indicator dispersed or immobilized in an analyte permeable matrix.
11. The method of Claim 10 wherein the dye is coronene.
12. The method of Claim 10 wherein the dye is naphtho [8,1,2-abc] coronene.
13. The method of Claim 9 wherein the analyte permeable matrix is crosslinked polydimethylsiloxane.
14. The method of Claim 9 wherein the analyte permeable matrix is a crosslinked derivative or copolymer of polydimethlsiloxane.
15. The method of Claim 9 wherein the analyte to be sensed is oxygen.
16. The method of Claim 9 wherein the analyte to be sensed is an anesthetic agent.
17. An analyte sensing apparatus which comprises;
a species which produces an output when exposed to external excitation, said output varying as a function of the concentration of an analyte exposed to said species, said species further including a variation in output as a function of the frequency of said output when said species is exposed to a given concentration of said analyte;
means to constrain a quantity of said species, said constraining means further providing means to expose at least a portion of said species to said analyte;
means to excite said species;
means to measure the output of said species at a plurality of frequencies of said output; and means to derive the concentration of said analyte from said measurements.
a species which produces an output when exposed to external excitation, said output varying as a function of the concentration of an analyte exposed to said species, said species further including a variation in output as a function of the frequency of said output when said species is exposed to a given concentration of said analyte;
means to constrain a quantity of said species, said constraining means further providing means to expose at least a portion of said species to said analyte;
means to excite said species;
means to measure the output of said species at a plurality of frequencies of said output; and means to derive the concentration of said analyte from said measurements.
18. The analyte sensing apparatus of Claim 17 wherein said means to constrain said species includes an analyte permeable matrix in which said species is immobilized or dispersed.
19. The analyte sensing apparatus of Claim 17 wherein the species is polynuclear aromatic hydrocarbon based fluorescent dye selected from group consisting essentially of perylene and derivatives thereof.
20. The analyte sensing apparatus of Claim 17 wherein said species is coronene.
21. The analyte sensing apparatus of Claim 17 wherein said species is naphtho [8, 1, 2 - abc]
coronene.
coronene.
22. The analyte sensing apparatus of Claim 18 in which said matrix is crosslinked polydimethylsiloxane.
23. The analyte sensing apparatus of Claim 18 in which said matrix is a crosslinked derivative or copolymer of polydimethylsiloxane.
24. The analyte sensing apparatus of Claim 17 in which said analyte to be sensed is oxygen.
25. The analyte sensing apparatus of Claim 17 in which said analyte to be sensed is an anesthetic agent.
26. An apparatus for sensing the concentration of analyte in a fluid medium which comprises:
(a) means for exposing a sample of an indicator which displays a variation in output as a function of frequency when exposed to an analyte, to said fluid;
(b) means for activating said indicator with radiation;
(c) means for measuring the output of said indicator at a plurality of frequencies; and (d) means for determining the concentration of said analyte on the basis of the ratio of said plurality of outputs of said indicator.
(a) means for exposing a sample of an indicator which displays a variation in output as a function of frequency when exposed to an analyte, to said fluid;
(b) means for activating said indicator with radiation;
(c) means for measuring the output of said indicator at a plurality of frequencies; and (d) means for determining the concentration of said analyte on the basis of the ratio of said plurality of outputs of said indicator.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US343,423 | 1989-04-26 | ||
| US07/343,423 US5094959A (en) | 1989-04-26 | 1989-04-26 | Method and material for measurement of oxygen concentration |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2015415A1 true CA2015415A1 (en) | 1990-10-26 |
Family
ID=23346059
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002015415A Abandoned CA2015415A1 (en) | 1989-04-26 | 1990-04-25 | Method and material for measurement of oxygen concentration |
Country Status (4)
| Country | Link |
|---|---|
| US (1) | US5094959A (en) |
| EP (1) | EP0454886B1 (en) |
| JP (1) | JPH0363550A (en) |
| CA (1) | CA2015415A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5409666A (en) * | 1991-08-08 | 1995-04-25 | Minnesota Mining And Manufacturing Company | Sensors and methods for sensing |
Families Citing this family (34)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1991018549A1 (en) * | 1990-05-29 | 1991-12-12 | Yue Samuel K | Fetal probe apparatus |
| US5155046A (en) * | 1990-08-10 | 1992-10-13 | Puritan-Bennett Corporation | System and method for measuring oxygen in the presence of halothane |
| US5358876A (en) * | 1991-07-17 | 1994-10-25 | Mitsubishi Gas Chemical Company, Inc. | Oxygen indicator |
| SE9103427D0 (en) * | 1991-11-20 | 1991-11-20 | Pharmacia Biosystems Ab | PROCEDURES FOR QUANTIFYING A SUBSTANCE WITH FLUORESCENCE |
| US5335305A (en) * | 1991-12-19 | 1994-08-02 | Optex Biomedical, Inc. | Optical sensor for fluid parameters |
| WO1994010553A1 (en) * | 1992-10-23 | 1994-05-11 | Optex Biomedical, Inc. | Fibre-optic probe for the measurement of fluid parameters |
| US5322794A (en) * | 1993-02-16 | 1994-06-21 | Lesley Davenport | Fluorescent phospholipid analogs and fatty acid derivatives |
| DE4325529C2 (en) * | 1993-07-29 | 1996-11-28 | Pulsion Verwaltungs Gmbh & Co | Device for determining the concentration of substances in the blood |
| US5462880A (en) * | 1993-09-13 | 1995-10-31 | Optical Sensors Incorporated | Ratiometric fluorescence method to measure oxygen |
| US5577137A (en) * | 1995-02-22 | 1996-11-19 | American Research Corporation Of Virginia | Optical chemical sensor and method using same employing a multiplicity of fluorophores contained in the free volume of a polymeric optical waveguide or in pores of a ceramic waveguide |
| DE19524207A1 (en) * | 1995-07-03 | 1996-06-13 | Kurt Schwabe Inst Fuer Mes Und | Light extinction measuring fibre optic probe for pH measurement of watery solution |
| US5839439A (en) * | 1995-11-13 | 1998-11-24 | Nellcor Puritan Bennett Incorporated | Oximeter sensor with rigid inner housing and pliable overmold |
| US5863460A (en) * | 1996-04-01 | 1999-01-26 | Chiron Diagnostics Corporation | Oxygen sensing membranes and methods of making same |
| US7335164B2 (en) | 1996-07-15 | 2008-02-26 | Ntc Technology, Inc. | Multiple function airway adapter |
| US6815211B1 (en) | 1998-08-04 | 2004-11-09 | Ntc Technology | Oxygen monitoring methods and apparatus (I) |
| US6325978B1 (en) | 1998-08-04 | 2001-12-04 | Ntc Technology Inc. | Oxygen monitoring and apparatus |
| US20070225612A1 (en) * | 1996-07-15 | 2007-09-27 | Mace Leslie E | Metabolic measurements system including a multiple function airway adapter |
| EP0988517A4 (en) * | 1997-06-10 | 2003-03-19 | Calspan Corp | Detection of chemical agent materials using a sorbent polymer and fluorescent probe |
| US6436717B1 (en) | 1998-05-13 | 2002-08-20 | Yellow Springs Optical Sensor Co. Pll | System and method for optical chemical sensing |
| ES2306525T3 (en) | 1998-08-26 | 2008-11-01 | Sensors For Medicine And Science, Inc. | OPTICAL-BASED DETECTION DEVICES. |
| US6300638B1 (en) | 1998-11-12 | 2001-10-09 | Calspan Srl Corporation | Modular probe for total internal reflection fluorescence spectroscopy |
| WO2000042418A1 (en) * | 1999-01-11 | 2000-07-20 | Lightsense Corporation | Method and material for ratiometric fluorescent determination of analyte concentration |
| US6400974B1 (en) | 2000-06-29 | 2002-06-04 | Sensors For Medicine And Science, Inc. | Implanted sensor processing system and method for processing implanted sensor output |
| US7135342B2 (en) * | 2001-05-04 | 2006-11-14 | Sensors For Medicine And Science, Inc. | Electro-optical sensing device with reference channel |
| MXPA05001481A (en) * | 2002-08-06 | 2005-06-06 | Univ California | Tear film osmometry. |
| WO2013023697A1 (en) * | 2011-08-17 | 2013-02-21 | Luxcel Biosciences Limited | Tool and method for validating operational performance of a photoluminesence based analytical instrument |
| WO2014086411A1 (en) | 2012-12-05 | 2014-06-12 | Luxcel Biosciences Limited | Individually and flexibly deployable target-analyte sensitive particulate probes and method of making and using |
| CA2939975C (en) * | 2014-02-17 | 2022-05-10 | Eaton Limited | Oxygen sensor comprising a tip coated optical fibre with a large diameter |
| BR112017005121A2 (en) | 2014-09-23 | 2018-07-31 | Tearlab Res Inc | systems and methods for integrating microfluidic tear collection and lateral flow analysis of analytes of interest. |
| CN104372424B (en) * | 2014-10-20 | 2016-08-17 | 宜宾丝丽雅股份有限公司 | A kind of heat energy reuse method being applicable to plastify overflow water |
| US20200166529A1 (en) | 2017-05-10 | 2020-05-28 | Agilent Technologies, Inc. | Real-Time Cellular or Pericellular Microenvironmental Oxygen Control |
| CN110621586A (en) | 2017-05-16 | 2019-12-27 | 安捷伦科技有限公司 | Headspace-eliminating microtiter plate cover and method for optically measuring the oxygen concentration of a well through the cover |
| WO2023196546A1 (en) | 2022-04-08 | 2023-10-12 | Agilent Technologies, Inc. | Headspace eliminating microtiter plate lid |
| WO2023196547A1 (en) | 2022-04-08 | 2023-10-12 | Agilent Technologies, Inc. | Microtiter plate lid and magnetic adapter |
Family Cites Families (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3612866A (en) * | 1969-07-08 | 1971-10-12 | Brian Stevens | Instrument for determining oxygen quantities by measuring oxygen quenching of fluorescent radiation |
| DD106086A1 (en) * | 1973-07-16 | 1974-05-20 | ||
| DE2508637C3 (en) * | 1975-02-28 | 1979-11-22 | Max-Planck-Gesellschaft Zur Foerderung Der Wissenschaften E.V., 3400 Goettingen | Arrangement for the optical measurement of blood gases |
| US4075493A (en) * | 1976-12-16 | 1978-02-21 | Ronald Alves | Optical temperature measurement technique utilizing phosphors |
| DE2720370A1 (en) * | 1977-05-06 | 1978-11-16 | Max Planck Gesellschaft | OPTODE WITH AUXILIARY INDICATOR |
| US4399099A (en) * | 1979-09-20 | 1983-08-16 | Buckles Richard G | Optical fiber apparatus for quantitative analysis |
| US4476870A (en) * | 1982-03-30 | 1984-10-16 | The United States Of America As Represented By The Department Of Health And Human Services | Fiber optic PO.sbsb.2 probe |
| US4548907A (en) * | 1983-09-14 | 1985-10-22 | Allied Corporation | Fluorescent fluid determination method and apparatus |
| DE3583197D1 (en) * | 1984-09-19 | 1991-07-18 | Siemens Ag | METHOD AND ARRANGEMENT FOR QUICKLY DETERMINING THE PARAMETERS OF A SAMPLING MEDIUM. |
| US4849172A (en) * | 1986-04-18 | 1989-07-18 | Minnesota Mining And Manufacturing Company | Optical sensor |
| US4824789B1 (en) * | 1986-10-10 | 1996-08-13 | Minnesota Mining & Mfg | Gas sensor |
| EP0243116A3 (en) * | 1986-04-18 | 1990-01-24 | Minnesota Mining And Manufacturing Company | Optical sensor |
| US4833091A (en) * | 1987-02-06 | 1989-05-23 | Shiley Incorporated | Sensor system |
| AT393326B (en) * | 1988-08-02 | 1991-09-25 | Avl Verbrennungskraft Messtech | INDICATOR SUBSTANCE FOR A MEASURING DEVICE FOR THE OPTICAL DETERMINATION OF INTERESTING PARAMETERS OF A SAMPLE AND MEASURING PROCEDURE THEREFOR |
-
1989
- 1989-04-26 US US07/343,423 patent/US5094959A/en not_active Expired - Fee Related
-
1990
- 1990-04-25 CA CA002015415A patent/CA2015415A1/en not_active Abandoned
- 1990-04-26 JP JP2111579A patent/JPH0363550A/en active Pending
- 1990-05-02 EP EP90108333A patent/EP0454886B1/en not_active Expired - Lifetime
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5409666A (en) * | 1991-08-08 | 1995-04-25 | Minnesota Mining And Manufacturing Company | Sensors and methods for sensing |
| US5498549A (en) * | 1991-08-08 | 1996-03-12 | Minnesota Mining And Manufacturing Company | Sensors and methods for sensing |
Also Published As
| Publication number | Publication date |
|---|---|
| US5094959A (en) | 1992-03-10 |
| JPH0363550A (en) | 1991-03-19 |
| EP0454886A1 (en) | 1991-11-06 |
| EP0454886B1 (en) | 1995-12-27 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CA2015415A1 (en) | Method and material for measurement of oxygen concentration | |
| US4833091A (en) | Sensor system | |
| US5093266A (en) | Sensor system | |
| AU711444B2 (en) | A method and apparatus to perform trans-cutaneous analyte monitoring | |
| JP3764482B2 (en) | Simultaneous double excitation / single emission fluorescence sensing method for pH and pCO 2 | |
| EP0760093B1 (en) | Emission quenching sensors | |
| US5012809A (en) | Fiber optic catheter system with fluorometric sensor and integral flexure compensation | |
| AU614649B2 (en) | Optical fiber distribution system for an optical fiber sensor | |
| US4861727A (en) | Luminescent oxygen sensor based on a lanthanide complex | |
| EP0283289A2 (en) | Excitation and detection apparatus for remote sensor connected by optical fiber | |
| WO1997010495A9 (en) | SIMULTANEOUS DUAL EXCITATION/SINGLE EMISSION FLUORESCENT SENSING METHOD FOR pH AND pCO¿2? | |
| Vander Donckt et al. | Fibre-optic oxygen sensor based on luminescence quenching of a Pt (II) complex embedded in polymer matrices | |
| US5155046A (en) | System and method for measuring oxygen in the presence of halothane | |
| EP0471861B1 (en) | Optical probe | |
| Walt | Fiber-optic sensors for continuous clinical monitoring | |
| Kieslinger et al. | Capillary waveguide optrodes for medical applications | |
| CA2079987A1 (en) | Sensors and methods for sensing | |
| CA1326772C (en) | Sensor system | |
| WO1992005441A1 (en) | Water insensitive tissue oxygen sensor | |
| Walt et al. | Preparation of small diameter sensors for continuous clinical monitoring | |
| Walt | Continuous clinical monitoring using fiber optic sensors | |
| Healey et al. | Development of the indicator-photopolymer chemistries for multianalyte sensor arrays |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FZDE | Discontinued |