Chemical apparatus and process disinfecting – deodorizing – preser – Analyzer – structured indicator – or manipulative laboratory... – Means for analyzing liquid or solid sample
Reexamination Certificate
1997-10-03
2001-04-17
Snay, Jeffrey (Department: 1743)
Chemical apparatus and process disinfecting, deodorizing, preser
Analyzer, structured indicator, or manipulative laboratory...
Means for analyzing liquid or solid sample
C422S082080, C436S166000
Reexamination Certificate
active
06217828
ABSTRACT:
FIELD
The present invention relates generally to sensors for measuring the concentration of an analyte of interest. In a preferred embodiment, the present invention relates to sensors for monitoring blood gas concentrations (e.g., carbon dioxide). The present invention also relates to methods of making stable and reproducible water in oil emulsions comprised of a dispersed aqueous phase and a hydrophobic continuous phase.
BACKGROUND
It is sometimes necessary or desirable for a physician to determine the concentration of certain gases, e.g., oxygen and carbon dioxide, in blood. This can be accomplished utilizing an optical sensor which contains an optical indicator responsive to the component or analyte of interest. The optical sensor is exposed to the blood, and excitation light is provided to the sensor so that the optical indicator can provide an optical signal indicative of a characteristic of the analyte of interest. For example, the optical indicator may fluoresce and provide a fluorescent optical signal or it may function on the principles of light absorbance.
The use of optical fibers has been suggested as part of such sensor systems. The optical indicator is placed at the end of an optical fiber which is placed in contact with the medium to be analyzed. This approach has many advantages, particularly when it is desired to determine a concentration of analyte in a medium inside a patient's body. The optical fiber/indicator combination can be made sufficiently small in size to easily enter and remain in the cardiovascular system of the patient.
Optical fluorescence CO
2
sensors commonly utilize an indirect method of sensing based on the hydration of CO
2
to form carbonic acid within an optionally buffered aqueous compartment containing a pH sensitive dye. The aqueous compartment is encapsulated in a barrier material which is impermeable to hydrogen ions but permeable to CO
2
. An optically interrogated pH change in the internal aqueous compartment can then be related to the partial pressure of CO
2
in the monitored sample. Ionic isolation of the internal aqueous phase may be achieved by directly dispersing aqueous droplets throughout the isolating matrix. Alternatively, the aqueous phase may be sorbed into porous particles which are then dispersed throughout the isolating matrix. The isolation matrix or “barrier” is typically a crosslinked silicone polymer.
Unfortunately, prior attempts to provide stable and reproducible emulsions of an aqueous phase dispersed in a polymeric precursor have yielded poor results. In some cases, the emulsions exhibited unexplained lot-to-lot variability that frustrate attempts to perform quantitative experiments correlating sensor performance to the particular sensor formulation. Variability within lots has also been observed. This variability frustrates attempts to uniformly produce sensors, e.g., by coating a sheet of sensor precursor and converting the sheet into individual sensor elements. In other cases, the emulsoids formed from the emulsions are adversely affected by heat (e.g., during autoclaving) and the sensor's performance is thereby compromised. Also unfortunately, prior attempts to make sensors that respond to CO
2
in the “dry” state, i.e., not in contact with liquid water, have yielded poor results. Traditional two-phase sensors dehydrate when stored in ambient conditions and lose intensity. Even when intensity is maintained in the dry state, the sensor may not respond to CO
2
.
It would be desirable to provide a stable and reproducible sensor which has a fast response time and which is easily manufactured. It would also be desirable to provide a CO
2
sensor that provides a stable and effective signal that does not require that it be held in a condition of equilibrium with liquid water or saturated water vapor.
SUMMARY
We have discovered a stable and reproducible sensor. This sensor employs the preparation of stable water in oil emulsions comprised of a dispersed aqueous phase and a hydrophobic continuous phase. More specifically, this invention provides a novel method of preparing aggregation and coalescence resistant emulsions for use as blood gas sensor compositions, and further discloses novel emulsion compositions suitable for use in consistently and uniformly manufacturing precision coated blood gas sensors.
In one embodiment, the invention provides a gas sensing composition, comprising a dispersed first phase comprising droplets which are substantially smaller in at least one dimension than the thickness of the sensing composition and a hydrophobic second phase which is permeable to the analyte and impermeable to ionized hydrogen. The first phase contains at least one substantially water soluble emulsification enhancement agent and at least one water soluble indicator component effective to provide a signal in response to the concentration of a gas in a medium to which the sensing composition is exposed. The second phase contains at least one substantially water insoluble emulsification enhancement agent. Preferably the water soluble emulsification enhancement agent comprises a nonionic, amphipathic copolymer containing both hydrophilic and hydrophobic moieties, and the water insoluble emulsification enhancement agent comprises a plurality of dispersed hydrophobic particles.
The improved sensor compositions exhibit superior dry web sensor performance, enhanced sensor consistency for transparent sensor calibration, improved autoclave stability and rapid rehydration of the sensor.
The improved sensors may be used to sense the concentration of an analyte of interest in a medium. More particularly, the improved sensors may be used to sense carbon dioxide in blood. The invention also relates to sensor apparatus or systems and methods for sensing the concentration of other analytes of interest in industrial settings and environments (e.g., ammonia, CO
2
, SO
2
, or NO
2
).
Precision coated blood gas sensors are provided which exhibit improved coating uniformity and consistent sensor performance from lot to lot, thereby increasing the yield of usable sensors and permitting transparent calibration of the sensors independent of coating time or lot. By transparent calibration we mean the designation of a sensor web lot by the manufacturer according to its calibration parameters (slope and/or intercept) achieved by a web sampling plan. Transparent calibration allows the user to use a constant set of calibration parameters and significantly reduces the calibration time required by the user. It is dependent on consistent performance across and down sensor webs.
In another embodiment, the present invention provides a “dry” gas sensing composition, comprising a dispersed first phase containing a humectant (preferably glycerol) and at least one soluble indicator component; and a hydrophobic second phase which is permeable to the analyte and impermeable to ionized hydrogen. The first phase optionally contains a water soluble emulsification enhancement agent as described above. The second phase optionally, and preferably, contains at least one substantially water insoluble emulsification enhancement agent. The sensing composition of this embodiment provides an effective signal in response to the gas without the necessity that it be held in a condition of equilibrium with liquid water or water vapor prior to use.
In yet another embodiment, the present invention provides a precision coated blood gas sensor which exhibits improved autoclave stability, and preferably also exhibits improved dry web shelf stability. Most preferred blood gas sensors also exhibit rapid rehydration rates.
RELATED APPLICATIONS
Of related interest are copending U.S. patent application Ser. No. 08/375,304, now U.S. Pat. No. 5,607,645 “Sensor with Improved Drift Stability”; Ser. No. 08/159,799, now U.S. Pat. No. 5,508,509 “Sensing Elements and Methods for Making Same”; Ser. No. 08/136,967, now U.S. Pat. No. 5,462,879 “Emission Quenching Sensors”; and Ser. No. 08/137,289, now U.S. Pat. No. 5,409,666 “Sensors and Methods for Sensing,” the disclosures of
Baker James A.
Bretscher Kathryn R.
Hamer Monica A.
Nguyen Mai T.
Rueb Christopher J.
Burns Doane , Swecker, Mathis LLP
Snay Jeffrey
Terumo Cardiovascular Systems Corporation
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