JPH032533B2 - - Google Patents

Description

Claim 1: A porous coating that is small enough to be inserted into a blood vessel, is liquid-water impermeable and has high oxygen permeability, and is excitable by visible wavelengths and emits visible light having visible wavelengths. A non-toxic dye that can be generated and has luminescence stability, stability over time, and good oxygen quenching sensitivity; a porous dye support with high oxygen permeability that bears exposed dye molecules to allow collisions with oxygen incorporated into the chemical coating;
Porous to optically expose its ends to the dye to transmit excitation visible light to excite the dye within the porous coating and to collect oxygen-quenched luminescence from the dye. the partial pressure of oxygen in the blood and tissues of a living animal, consisting of an optical fiber means hermetically affixed to one end of the covering;
Oxygen partial pressure measuring device with a probe for measuring PO ₂ . 2 The dye is perylene dibutyrate (color index 59075)
The oxygen partial pressure measuring device according to claim 1, characterized in that: 3. The oxygen partial pressure measuring device according to claim 1 or 2, wherein the porous dye support is selected from porous organic polymers. 4. The oxygen partial pressure measuring device according to claim 1, wherein the porous dye support is made of silica gel. 5. The oxygen partial pressure measuring device according to claim 1, wherein the porous dye support is made of a porous adsorbed granular polymer material. 6. The oxygen partial pressure measuring device according to claim 1, wherein the porous dye support is selected from ion exchange resins made of hydrophobic crosslinked polymers. 7. Claim 1, characterized in that the porous coating is formed from a tube-shaped envelope of a porous material.
The oxygen partial pressure measuring device described in . 8. The oxygen partial pressure measuring device according to claim 7, wherein the tube-shaped outer envelope is formed from a porous polypropylene sheet material. 9. Claim 1, characterized in that the porous covering is formed from a porous polypropylene sheet material formed into a tube shape by heat fusion, one end of which is closed, and the closed end has a tapered tip shape. The oxygen partial pressure measuring device described in . 10. The optical fiber means of claim 1, wherein the optical fiber means is formed from at least one strand of transparent plastic fiber, one end of which extends into the porous coating and is optically exposed to the dye. Oxygen partial pressure measuring device. 11. Claims characterized in that the optical fiber means is formed from two strands of flexible transparent plastic fiber extending within a porous coating and having ends optically exposed to the dye. The oxygen partial pressure measuring device according to item 1. 12. The optical fiber means is formed from one strand of clear plastic fiber with one end extending into the porous coating and optically exposed to the dye, and optically coupled to the other end of the plastic fiber. a beam splitting means for forming two separated light beams from the light transmitted through the optical fiber; photoelectric signal generating means for generating a photoelectric signal according to the
and oxygen partial pressure calculation circuit means connected to the output end of the photoelectric signal generating means. 13. The oxygen according to claim 12, characterized in that, between the light beam splitting means and the photoelectric signal generation means, different color filter means are disposed in the optical paths of the two separated light beams. Partial pressure measuring device. 14 One color filter means passes only light of a color corresponding to the luminescence wavelength of the dye, and the other color filter means corresponds to the wavelength of the scattered light reflected from the dye in the scattered light of the incident light exposing the dye. 14. The oxygen partial pressure measuring device according to claim 13, wherein only light of a certain color passes through the oxygen partial pressure measuring device. FIELD OF THE INVENTION The present invention relates to the measurement of oxygen partial pressure, and more particularly to an injectable fiber optic probe device for measuring oxygen partial pressure in blood or tissue. BACKGROUND OF THE INVENTION Physiological oxygen measurements are important for a variety of reasons, including the following. The Γ transfer function (Figure 1) is a fundamental determinant of oxygen transport and distribution. Adsorption of _O2 on Γ heme is the most widely used mechanism of oxygen accumulation and transport in the animal kingdom. The corresponding protein changes (globins) that frame the Γ-heme control its adsorption properties, shape the transfer function, and adapt the heme to the needs of specific species. The Γ globin chain also plays a role in biochemical signals, especially
PH, 2,3-diphosphoglycerate and _CO2
is part of the control loop for adjusting the curve. Γ Approximately 200 genetic mutations of hemoglobin are known in humans, most of which are harmless, but some are pathological due to altered transport function (such as sickle cell disease). Γ Therefore, direct measurement of oxygen partial pressure PO ₂ is necessary to observe the oxygen transport behavior of individuals in physiological studies. Furthermore, adequate tissue oxygenation is one of the most important and readily available from various surgical and critical care positions that require rapid sampling and continuous monitoring of _PO2 levels. Although several technologies and systems are known,
None of them can be called optimal. For example, Clark electrodes (membrane-diffusion, current) do not contribute to miniaturization. Anything that relies on diffusion is fraught with problems of standardization and deviation. Strictly potentiometric (redox) electrodes are particularly difficult. US Pat. No. 4,201,222 (Haase) discloses an optical fiber-based catheter that can be inserted into a blood vessel in a living body to measure the partial pressure of oxygen gas in a blood stream. This catheter consists of a semipermeable wall member that allows the gaseous portion of the blood to pass through and prevents the liquid portion of the blood from entering. The intensity of the reflected visible light entering the optical fiber, when compared to the intensity of the incident light, is
It corresponds precisely to the partial pressure of oxygen gas in the blood stream. US Pat. No. 3,814,081 (Mori) discloses an optical catheter for measuring the percentage of oxygen content that saturates the blood flow of the body of a living animal. A light emitting optical fiber system and a light receiving system are provided adjacent to each other. Insert the tip of the catheter into the animal's blood-carrying organ. Oxygen saturation is measured by optical absorption spectroscopy of light waves reflected from the blood stream and received by an optical fiber. U.S. Pat. No. 3,807,390 (Ostrowski et al.) discloses a fiber optic catheter for inserting a catheter tip into the cardiovascular system of a living body and monitoring the state of blood oxygen saturation in an active human blood stream. . US Pat. No. 4,033,330 (Willis et al.) shows a generally related matter showing a transcutaneous optical PH measuring device for determining carbon dioxide concentration in blood and blood PH. No. 4,041,932 is of general interest teaching an apparatus for use in measuring and monitoring the concentration and partial pressure of gases such as oxygen and carbon dioxide in arterial blood vessels and the PH of blood over various periods of time. Although there is quite a lot of literature on _PO2 electrodes, there are still no useful electrodes. Measurement of oxygen by luminescence quenching is also taught. Although the idea originated in the 1930s, it has rarely been put to practical use, and oxygen quenching of fluorescent light is widely known to be harmful. US patent
No. 3,612,866 (Stevens) discloses an apparatus for measuring the oxygen-containing concentration of liquids or gases based on the molecular luminescence quenching effect of gaseous oxygen on aromatic molecules, their derivatives, and aliphatic ketones. Other applications of luminescence quenching for oxygen measurements include (1) “Initial observation of the effect of silica gel adsorbed dyes”
H. Kautsky and A. Hirsch Early 1930s, e.g. H. Kautsky and A. Hirsch "Inorganic and General Chemistry" 222 ,
126−34, 1935. (2) “Measurement of O ₂ by illumination of algae”, M. Pollack, P. Pringsheim, D. Terwood,
Journal of Chemical Physics (J.Chem.Phys), 12 , 295
-9, 1944. (3) "Scintillation of Organic Molecules. A Compendium of Oxygen Quenching Sensitivity of Interests," IB Berlman, "Handbook of Fluorescence Spectra of Aromatic Molecules," Academic Press, 1965. (4) “O ₂ measured at 10 ⁻⁵ torr using acriflavin on acrylic sheets”, Gy. Orban, Zs. Szentirmay, J. Patko, “Proc.of
the Intl.Conf.on Luminescence”, 1966.V.1,
611-3, 1968. (5) “Diffusion efficiency of O ₂ in acrylics measured by phosphorescence observation of rods”, G. Shaw, trans. Trans.Faraday Soc. 63 , 2181-9, 1967. (6) " _O2 permeability of acrylic films measured by extinction ratio versus _PO2 ", PF Jones,
Polymer letters 6 , 487
−91, 1968. (7) “PO ₂ measurement device based on fluoranthene adsorbed on plastic film and porous Vycor” I. Bergman, Nature.
218, 396, 1968. (8) “Butyric acid used as a probe for intracellular O ₂ measurement”, JA Knopp, IA Longmuir, Biochimica et Biophysica Acta
279, 393-7, 1972. (9) “Measurement of physiological PO ₂ using DMF solutions of pyrenebutyric acid in various membrane-enclosed forms” D.
W. Lubber, N. Opitz,
Z. Naturf, 30c , 532-3,
1975. SUMMARY OF THE INVENTION Accordingly, it is an object of the present invention to overcome the drawbacks of the known techniques as mentioned above. Another object of the invention is to provide improved in vivo _PO2
It is to provide measurements. It is also an object of the present invention to provide an improved PO ₂ measurement device, in particular a device based on oxygen measurement using luminescence quenching and having an optical fiber probe. Furthermore, another object of the present invention is to provide a relatively simple optical system using luminescence quenching as the working principle and combined with an optical magnification tube, and a system which is operated by the optical magnification tube and detected by the optical system. PO ₂ using an optical fiber probe combined with an electronic arithmetic circuit that performs direct analog calculation of PO ₂ based on the luminescence quenching.
The purpose of this invention is to provide a measuring device for A typical fiber optic probe for measuring oxygen partial pressure based on the principle of fluorescence quenching according to the present invention has a diameter of
It consists of two 150 micrometer strands of plastic optical fiber with plastic tube-shaped ends of a porous cross section of 0.6 mm and a length of about 5 mm. The tube contains the dye on an absorbent particulate support. This basic structure is
U.S. Patent 4200110 to Peterson et al.
It is similar to the physiological PH probe disclosed in . In developing the probe of the present invention, it was necessary to solve three main problems not previously encountered in the application of the extinction principle described above. Namely: 1. A dye must be found that has a combination of properties such as suitable oxygen quenching sensitivity (long active state lifetime), fluorescence excitation by visible light, and resistance to fading. Plastic optical fibers that transmit light at wavelengths shorter than 450 nm are not used. Ultraviolet-transparent inorganic fibers are brittle and therefore unsuitable for the present invention. 2. A suitable hydrophobic, high oxygen permeable envelope was required. 3. The adsorptive support needed to maintain moisture resistance and activate the dye. Traditional silica dye supports are not suitable for use in aqueous media. The probe device of the present invention provides a small, low-cost probe suitable for injection into tissue or blood vessels via a skin needle. The optical fiber probe has the following advantages. a Extremely small sizes, such as diameters of 0.5 mm or less, are possible. b. It is flexible and can thread through small blood vessels and enter various tissues. c. It is cheap, disposable, and easy to manufacture. d.Does not cause electrical interference. e Suitable for static measurements compared to dynamic measurements. The reason for choosing luminescence quenching as the mechanism for oxygen measurement is based on the following factors. 1. A reversible indicator is required for the PO ₂ probe. Reversible colorimetric (absorbance) indicators for oxygen are inappropriate. Transition metal complex oxygen adsorbents do not have the necessary stability. 2 Aromatic molecules form charge-transfer complexes with oxygen upon activation by light absorption. This results in an inert fluorescent state mechanism characteristic of oxygen. The molecular activation energy is not required to be high enough to form active oxygen by collisional energy transfer, i.e. the quenching phenomenon can be observed with visible light activation of luminescence. Fluorescence (and phosphorescence) quenching is the result of a non-luminescent decay mode that competes with the luminescent decay of the active molecule, reducing the average lifetime of the active state and reducing the emission intensity. (See Figure 2) With constant illumination, the decay rate of the excited state is the sum of the rates of various decay modes, and the collisional decay rate is proportional to the average lifetime of the active state and the collision rate (approximately,
(comparable to the fluorescence lifetime), the collision rate is proportional to the pressure of the quenching gas. These competing decay rates are determined by the partial pressure of oxygen PO ₂
is the Schüthern-Folmer equation of emission intensity I. I ₀ /I = 1 + PO ₂ /P' (O. Schüthern & M. Follmer, Fujikaritssier, Zeitschrift, 20 , 183-8,
(1919), where I ⁰ is the emission intensity in the unquenched state, and P′ is a constant and the pressure in the semi-quenched state. The above equation can be expressed in terms of the observed emission lifetimes, T ₀ and T, since the constant has a corresponding extinction proportionality that refers to the fluorescence lifetime. T ₀ /T=1+PO ₂ /P' Good sensitivity of quenching requires excited states with long mean lifetimes. Phosphorescence, which has an extremely long lifetime (several seconds), is sensitive to quenching, but the intensity is low. Fluorescence is less sensitive to quenching, but has high brightness (high quantum yield). P ¹ is in the pressure class that should be measured to obtain the best compromise between brightness and sensitivity. (See FIG. 3) BRIEF DESCRIPTION OF THE DRAWINGS Other objects and advantages of the invention will become apparent from the following description and claims, and from the accompanying drawings. Incidentally, FIG. 1 is a graph showing the classical relationship between blood oxygen concentration and pressure in the human body. FIG. 2 is a schematic illustration of the competitive mode of inactivation of optically excited molecules. Figure 3 shows P′ and
FIG. 2 is a schematic explanatory diagram showing the relationship between PO ₂ . FIG. 4 is an illustration of an embodiment of a PO ₂ probe according to the invention. Fifth
The figure is a graph comparing typical observed data according to the present invention with theoretical values of Schütern-Folmer. FIGS. 6 and 7 schematically illustrate an electronic computing system for a simple analog device using an optical system and a test probe according to the invention, respectively. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS In the accompanying drawings, particularly in _FIG.
The probe is configured as shown at 8. The PO ₂ probe 8 was created after the already developed PH probe in the process of use. (See US Pat. No. 4,200,110, Peterson et al.) In this PO ₂ probe 8, the dye 15 of the adsorption support 16 is placed inside a polyethylene tube 10 with a porous cross-sectional shape, and is rapidly exchanged with surrounding oxygen. Obtain equilibrium and dye adsorption support 16
protect from contamination. The tube 10 has a distal end 9 at one end which tapers gradually toward the axis of the tube and is closed. The pair of flexible plastic optical fibers 12, 14 are, for example,
Using a 150 micrometer strand of plastic optical fiber, the end of the fiber is attached to the dye 15 in the dye adsorption support 16 at the other end of the tube 10.
to be optically exposed. tube 1
0 consists of a cross-sectional porous polymer tube approximately 5 mm long and 0.6 mm in diameter. Illumination with blue light passes through one optical fiber 12 and excites the dye 15, causing it to fluoresce. The green fluorescent light with the scattered blue light is connected to the other optical fiber 1.
4 and is transmitted to the measuring equipment. (See Figures 6 and 7). The blue light intensity I ₀ is used as a reference value for optical correction, and the green light intensity I indicates a measure of oxygen quenching. The Schüthern-Folmer relationship provides a linear quantitative criterion for measuring _PO2 using extinction. (See Figure 5) The relationship between the curves is widely seen (there are many publications on data blotted based on Schüthern-Folmer),
Oxygen pressure is often indexed to fit experimental data to the equation. Although the theoretical interpretation of this exponential relationship is difficult to understand, the curve data can be properly fitted by an offset constant during intensity measurements, which can be accounted for in the instrumental context and in non-quenched luminescence. However, for equipment design, corrections are made by attaching an index m to the intensity ratio, or by attaching an index n to the difference enclosed in curly brackets [(I blue / I green) - 1]. It is more practical to use a correction formula. PO ₂ =P′ [(I Blue/I Green) ^m − I] _o A simple analog device was constructed to calculate the probe measurements. (See Figures 6 and 7) Measurement of PO ₂ closest to 1 mmHgPO ₂ requires an accuracy of more than 0.1% intensity measurement error. Instrumentally, the limiting factor is the stability of the light source. As mentioned above, there are three features of the system that need to be selected appropriately: the dye 15, the dye support 16, and the tubular coating 10. Suitable dyes 15 have the following properties: a. Excitable by visible wavelengths that can be transmitted by a plastic optical fiber that does not break when bent at an acute angle, has high flexibility, and has a shape that allows easy optical coupling by baking etc. In addition, it must be possible to generate visible light having visible wavelengths. b. Must be stable to light and have adequate resistance over time. c. Must not be toxic. d Must have sufficient oxygen quenching sensitivity (long average lifetime of excited states) to make measurements closest to 1 mmHgPO ₂ . The problem with selecting dye 15 is that many UV-excited dyes have high quenching sensitivities (benzene is one of the highest), and the requirement for visible light excitation makes it difficult to select dyes that meet this requirement. Make it more difficult to find. A preferred dye is perylene dibutyrate. Another desirable dye is Pylan Products LX7878. Dyes that are not optimal but can be used are Terasil Brilliant Flavine
8GFF, Nylosan Brilliant Flavine, Acridine Yellow, Brilliant Sulfaflavine, 2,
7-dichlor fluorescein, Acridine Orange, Coumarin 34, Coumarin 6, sodium fluorescein (Auranine), and certain rhodamines. Others are described in the references cited above. Regarding the preferred dye support 16, a quenching effect has traditionally been observed in silica gel, and high sensitivities are obtained with this support. A dye adsorption support with high oxygen permeability is necessary to expose individual dye molecules to oxygen bombardment. Dye solutions in liquids or solids are not photosensitive due to the low oxygen permeability of these materials. The problem with inorganic adsorbents is that the quenching is sensitive to humidity, and the quenching and/or fluorescence is destroyed at 100% humidity, which is the physiological measurement condition. Organic adsorbents such as porous polymers avoid this moisture problem at the expense of quenching sensitivity.
It is desirable to select polymers that can be determined by repeated testing of this description. Porous polymer, product name of ion exchange resin “Amberlite XAD4” (Rohm & Haas “Amberlite
A nonionic hydrophobic polymer is a preferred support 16. Another example is Gas Chrom Q
Q), Amberlite XAD2,
XAD8, Dow XFS 4022, Johns
Johns-Manville Cromosorb
Chromosorb) Nos, 10, 102, 103, 104, 105,
106, 107, 108, Waters Porapak Nos.N, P, PS, Q, R,
S, QS, T; Hamilton Co.PRP
-1. In the illustrated embodiment of the PO ₂ probe 8, a high oxygen permeability liquid-water impermeable container is required for the high oxygen permeability porous coating 10 of this embodiment.
It is preferable to use a porous polypropylene sheet material manufactured by Celanese Co., Ltd. under the trade name Celanese "Celgard" which is heat-sealed to form a tube shape. The above examples were carried out in aqueous media as well as in gaseous systems and worked satisfactorily in test animals. The combined use of fiber optics and luminescence quenching for oxygen measurements is believed to be new and superior. As mentioned above, important features of the invention are the use of porous polymeric supports, the appropriate selection of dyes, and the use of porous coatings or envelopes. The use of a porous polymer as the dye support 16 is one of the most important requirements for oxygen partial pressure measurement. As mentioned above, the preferred coating 10 is formed from Celgard;
Other porous materials can also be used. Various embodiments are possible, including reducing the size of the tip by using other methods of making the tip, such as a single fiber rather than two optical fibers, and appropriate equipment modifications. Can be done. In the typical optical system of FIG. 7, the optical output of fiber 14 is
is transmitted to a two-color filter 19 tilted at 45 degrees. The transmitted light component passes through a blue filter 20,
The first optical magnification tube 21 is reached. The reflected light component passes through the green filter 22 and reaches the second optical magnification tube 23.
As shown in FIG. 6, the output currents from the optical magnification tubes 21 and 23 are respectively
5, and the obtained voltage signals are passed through active filters 26 and 27, respectively, and the quotient (I blue/I blue/I
a division circuit 28 having means for giving an index m to (green)
becomes the input. The output of the circuit 28 is sent to the final calculation circuit 2.
9 to calculate the PO ₂ analog value. That is, the arithmetic circuit 29 subtracts the quantity 1 from the input signal,
Add a coefficient P' as shown in FIG. It will be obvious to those skilled in the art that various modifications can be made without departing from the scope of the invention and that the invention is not limited to what is shown in the drawings or described in the specification.