Sensor for non-invasive measurement of carbon dioxide content in the blood of a patient

Abstract

A sensor suitable for non-invasive measurement of carbon dioxide content, particularly in the blood of a patient, is disclosed. It can be used in the diagnosis and adjunctive therapy of diseases associated with respiratory disorders, particularly for prevention of cot death in newborns and infants.

Description

[0001] Sensor for non-invasive measurement of carbon dioxide content in the blood of a patient

[0002] The object of the invention is a sensor suitable for non-invasive measurement of carbon dioxide content, particularly in the blood of a patient. It can be used in the diagnosis and adjunctive therapy of diseases associated with respiratory disorders, particularly for prevention of cot death in newborns and infants.

[0003] In recent years, fibre optic sensors have been increasingly used in many different industries. Compared to traditional electronic sensors, they have numerous advantages that definitely make them preferred for use in specific applications. Above all, they provide significantly higher sensitivity, resolution, and dynamic range. Additionally, wavelengths of light that are typical for medical applications are safe for patients. These are usually wavelengths in the visible range that are encountered on a daily basis and, very importantly, are safe for newborns and young children. Due to the extremely small size of the active part, it is possible to manufacture sensors having a small size.

[0004] The general structure of a fibre optic sensor includes the following basic elements: a light source, e.g. a laser or an LED, an optic fibre for transmitting light, a transducer (a special optic fibre or a special sensing layer) in which the transmitted light interacts quantitatively with an analyte whose change (e.g. absorption of specific wavelengths, change in luminescence, rotation of the polarization plane, etc.) is the basis of the sensor's operation, and a receiver, that is a photodetector, which detects changes in the optical signal.

[0005] In order for the sensor to be sensitive to a specific change, e.g. a specific chemical substance, the transducer must provide selective identification of a particular type of molecule or ion. This can be achieved in various ways, among others by means of a suitable chemical agent bonded to the surface of the optic fibre or located in a cavity closed with a semi-permeable film, allowing the analysed molecules to penetrate into the analytical layer and using a special doping of the optic fibre, e.g. with a fluorescent material.

[0006] In the first case, special fluorescent dyes using ion pairs between the pH-sensitive indicator anion and a quaternary ammonium cation are used to detect carbon dioxide based on the Severinghaus effect. The ion pair is immobilized in various types of matrices - on glass or plastic carriers, on optic fibres, or capillaries. Tetraoctylammonium hydroxide (TOA) is often used as a suitable cation. Deprotonated dye D - is usually contained in an aqueous buffer solution, in which CO2can enter the volume, as a membrane permeable gas. In order to avoid the need for using an aqueous environment, the dye can be located in a hydrophobic matrix, e.g. made of polymer, sol-gel, or ethyl cellulose. [1]

[0007] In the second method, ready-made indicator dyes are used. The principle of operation of these sensors is based on the absorption of light passed through the silica fibre. The outer gel or polymer coating contains active dyes, e.g. methyl red, thymol blue, and phenol red. These substances change their colour when they are exposed to environments with different pH levels, e.g. methyl red changes from yellow to red when the pH drops, phenol red changes from fuchsia to yellow, and thymol blue from blue to yellow. The ranges in which colour changes occur are quite narrow: 4.8-6.0 for methyl red, 6.4-8.0 for phenol red, and 8.0-9.6 for thymol blue. Indicator substances usually work when they are dissolved in the matrix material. The analyte reacts with the indicator inside the sensing layer, which causes the latter to change colour, which in turn causes a change in the colour of light transmitted by the optic fibre. Each pH-sensitive dye has at least two forms specific to a particular type of environment (e.g. acidic and alkaline). Each form of the dye has a different absorption spectrum. Sensors based on such solutions have a much simpler design. Previous studies have shown that the thickness of silica gel coating has a significant impact on sensitivity and response time. The influence of temperature and humidity on the operation of the sensor was also studied. The response times of the reported sensors are very short and range from 2-3 s, while the sensor sensitivity range is 3 to 10 for different coating thicknesses. [2]

[0008] There are also two methods of applying a matrix with a pH-sensitive part: on the section of the optic fibre using the wave reflection phenomenon (external sensors) or applying to the optic fibre using an evanescent wave (internal sensors).

[0009] The choice of substrate is also an important factor. Both polymers and silica gels have other useful properties. Depending on the subsequent application, the following should be considered: porosity, transparency, quality of the surface (porous for the silica gel or smooth for polymers), mechanical behaviour (flexibility, brittleness), ease and cost of preparation.

[0010] There are also many factors that should be considered in case of sensors containing chemical substances. These include, among others: sensitivity of the substance to the test parameter (e.g. CO2concentration), the effect of the dye concentration, the effect of the active layer thickness on the sensor response, the repeatability of the sensor response, the sensor response time, the effect of temperature, the cross sensitivity to other gases - all processes using CO2inside the sensing layer require the presence of water at the reaction site. Thus, moisture can also affect the operation of the sensor. Carbon dioxide is not the only gas that can affect the pH of the sensing layer. Other ions are also present, e.g. NO2 and SO2 which also react with water and produce H3O+ions.

[0011] The object of the invention is to provide a sensor capable of easy and quick measuring and monitoring of the concentration of carbon dioxide in the blood of a patient, without the need to perform complex procedures and take a blood sample from the patient's body.

[0012] Surprisingly, this goal has been achieved in the present invention.

[0013] The object of the invention is a sensor for measurement of carbon dioxide content, particularly in the blood of a patient, characterised in that it comprises a safe low-voltage light source equipped with a power supply circuit, comprising a light-emitting diode, preferably an LED, and a CO2sensor having a sensing layer consisting of a polymer in which the active dye is dissolved, and also a photodetector having a photodiode which receives light emitted by the active dye in the presence of carbon dioxide, which is connected to a transducer capable of receiving and processing the signal from the photodiode.

[0014] Preferably, the polymer of the sensing layer is bioneutral poly(methyl methacrylate) (PMMA).

[0015] Preferably, the active dye is 4-dimethylaminoazobenzene-2'-carboxylic acid (methyl red).

[0016] Preferably, the sensing layer is obtained by immersing an optically neutral carrier plate in approximately 5 wt% PMMA solution in chloroform comprising approximately 0.1 wt% of methyl red.

[0017] Preferably, the light source comprises a red light emitting diode, preferably a red LED emitting light with a wavelength of 650 nm. Preferably, the sensing layer comprises 0.01 wt% to 0.2 wt% of methyl red, preferably 0.1 wt%.

[0018] As a result of the tests that led to obtaining the invention, thin active sensory sensing layers composed of methyl red were obtained, which allow for non-invasive measurement of pCO2, and a suitable light source was selected.

[0019] The sensor uses the optic fibre pH sensor method and, through active sensory layers, measures pCO2as a result of skin pH changes due to the diffusion process.

[0020] The active dye that has been shown to be compatible, in the context of the physicochemical environment of the probe, is methyl red.

[0021] Optimization of pCO2measurement results was achieved by using a light source in the form of a red diode.

[0022] Thin active sensory coatings that can be used for non-invasive measurement of CO2concentration used in the sensor according to the invention can be used to assess respiratory disorders in children, in the field of prevention, early diagnosis, and treatment.

[0023] The sensor according to the invention, by measuring the gasometric parameter in the form of pCO2, constitutes a decisive measure in the prevention of cot death in newborns and infants.

[0024] To clarify the results of blood gasometry by an important diagnostic parameter, which is CO2, and miniaturization of the device for anthropometric measurements in children is an innovative proposal for the field of medicine dealing with children's health.

[0025] Example 1 . Structure and operation of the sensor

[0026] The structure of the sensor is shown in Fig. 1 .

[0027] In an exemplary embodiment, the sensor according to the invention comprises the following elements: a sensor housing (1), a transducer (2), constituting an electronic circuit for processing the signal from receiving photodiodes, a photodetector (3) comprising a photodiode, an electronic power supply circuit (4) for the light-emitting diodes, a light source (5) comprising an LED, a CO2sensor (6) comprising an optically neutral carrier plate (6a) with an added sensing layer (6b) comprised of a polymer, in which an active dye is dissolved, and a CO2permeable membrane (7).

[0028] In an exemplary embodiment, the sensor according to the invention is encased in the housing (1) which protects it from the access of light and provides constant operating conditions for the sensor. In order to take the measurement, the sensor is placed directly on the skin of the patient, from which it is separated by the membrane (7) allowing the passage of CO2that is released through the skin. Inside the sensor, the power supply circuit (4) for the light-emitting diodes provides adjustment of the luminous power of the LEDs (5), which emit light with wavelengths reacting with the dye in the PMMA (6b) embedded on the optically neutral carrier plate (6a) and causing the sensing layer to emit light with a different wavelength than the one emitted by the LEDs. The light emitted by the illuminated sensing layer is received by the photodiodes (3) and processed in the transducer (2) which comprises an electrical circuit allowing conditioning of the signal from the photodiodes. The appearance of CO2at the sensing layer in PMMA (6b) causes a change in intensity of the light emitted by the illuminated sensing layer. This change affects the readings of the photodiode (3) and indications after conditioning of the signal in the transducer (2). The measured CO2concentration depends on the luminous intensity of the sensing layer (6b). In a preferred embodiment, in which methyl red is used as the active dye, a red light-emitting diode (wavelength of 650 nm) is used as the light source. The photodiode used in this embodiment should be capable of sensing light with a wavelength in range of 500 nm to 700 nm.

[0029] Example 2. Preparation of the CO2sensor

[0030] In order to obtain the sensor, a glass slide was covered with a layer comprised of a carrier polymer, which is poly(methyl metacrylate) (hereafter PMMA), in which the active dye has been dissolved. As the active dye, 4-dimethylaminoazobenzene-2'-carboxylic acid (hereafter methyl red) was used.

[0031] For this purpose, an optically neutral carrier plate was immersed in a PMMA solution in chloroform comprising methyl red. Solutions with different PMMA concentration were prepared and the amount of methyl red added was varied.

[0032] PMMA solutions in chloroform with PMMA concentration of 1.01 wt%, 2.05wt%, 3.05wt%, 4.03wt%, 4.98wt%, or 6.01wt% by weight of polymer were prepared. Prepared solutions were divided into two portions with a volume of about 35 ml. To the first one the portion of 0.01g of methyl red was added which constitutes 0.01 wt%. To the second one the portion of 0.1 g of methyl red was added ( which constitutes 0.1 wt%. The speed of sample immersion was 50 mm / min.

[0033] After applying the sensing layer, the carrier plate was left for about 48 h for removing the solvent. The active layers obtained in this manner were subjected to optical characterisation.

[0034] The emission spectrum is formed when electrically charged electrons, atoms, particles, or fragments of molecules that make up a given body, when excited, undergo a transition from a state of higher energy to a state of lower energy. This transition is accompanied by the emission of a quantum of electromagnetic radiation with an energy equal to the energy difference of the levels between which the particle transitioned. The emission spectrum is characteristic for the atoms of a given element. Emission spectra were obtained for different excitation wavelengths. A Hitachi F-7000 spectrophotometer and an Agilent Cary 60 UV-VIS were used. The relationship between increasing the wavelength and shifting of the peak maximum in the direction of longer wavelengths can be observed.

[0035] Fig. 2 shows a comparison of emissions for different wavelengths for a sample containing pure PMMA and PMMA with an added dye (methyl red). A distinct increase of emission intensity in the presence of the dye can be observed.

[0036] The studies allowed establishing that the sample made using ~5 wt% PMMA with an addition of 0.1 g of methyl red had the best properties. Example 3, CO2concentration measurement

[0037] The sensor plates obtained as in Example 2 with an applied layer of PMMA with an active dye (methyl red) were used to construct a sensor having a design described in Example 1. CO2 sensor obtained in this way was used to measure the presence of carbon dioxide.

[0038] Suitability of the developed sensing layer containing methyl red for measuring changes in CO2concentration was tested under laboratory conditions. The sensing layers prepared according to the procedure described in Example 2, containing 0.01 wt% and 0.1 wt% of methyl red, respectively, were placed in a laboratory test system consisting of a light source, a set of mechanical manipulators that allow positioning the active layer relative to the light source, and an optical power meter. The active layer was placed in a shield that provided it with insulation from the external environment and at the same time allowed it to be illuminated. The chamber was connected to a CO2source (gas mixer enabling the CO2concentration to be changed with an accuracy of 0.1 vol%). A dye laser with a wavelength of 650 nm and a spectral width of 5 nm was used as a light source. The sensing layer was illuminated at an angle of 75°. Luminescence changes were measured with the Thorlabs PM100D standard optical power meter equipped with the S120C silicon measuring head (Thorlabs). The measuring head was placed directly behind the sensing layer, parallel to it. Changes in luminescence were measured in the range of CO2concentration of 0 to 30 vol%. Measurements performed for layers containing 0.01 wt% and 0.1 wt% of the dye showed a linear change (decrease) in luminescence with increasing CO2concentration, whereas for concentrations above 10 vol% a loss of luminescence was observed in the layer containing 0.01 wt% of the dye. For a layer containing 0.1 wt%, luminescence loss was observed at CO2concentration of 30 vol%.

[0039] The results are shown in Fig. 3, which illustrates the loss / quenching of luminescence depending on the CO2concentration.

[0040] Preliminary studies examined the effect of the amount of supplied carbon dioxide on the intensity of light emitted by the sensing layer. The test was carried out using exhaled air and using a gas cylinder. The amount of carbon dioxide and the distance from the measuring part were varied. In each case, changes in emissions were observed, which is promising with the use of plates as thin active sensory layers for CO2in sensors. A red light-emitting diode (wavelength of 650 nm) was used as a light source.

[0041] In the next step, using the sensor according to the invention, measurements of carbon dioxide concentration in the blood were performed. The measurement was performed by placing the sensor (the carbon dioxide permeable membrane) on the patient's skin. The obtained results confirm the possibility of performing such measurements using the sensor according to the invention for the full range of carbon dioxide concentrations observed in the blood.

[0042] References:

[0043] [1] G. Gerlach, W. OelBner, Opto-Chemical CO2Sensors, Carbon Dioxide Sensing: Fundamentals, Principles, and Applications, First Edition. Edited by Gerald Gerlach, Ulrich Guth, and Wolfram OelBner; 2019 Wiley-VCH Verlag GmbH & Co. KGaA. Published 2019 by Wiley-VCH Verlag GmbH & Co. KGaA. [2] K. Wysokihski, M. Napierala, T. Stahczyk, S. Lipinski, T. Nasitowski, Study on the Sensing Coating of the Optical Fibre CO2Sensor, Sensors 2015, 15, 31888-31903

Claims

Claims1. A sensor for measurement of carbon dioxide content, particularly in the blood of a patient, characterised in that it comprises a light source (5) equipped with a power supply circuit (4), comprising a light-emitting diode, preferably an LED, and a CO2sensor (6) having a sensing layer (6b) consisting of a polymer in which the active dye is dissolved, and also a photodetector (3) having a photodiode which receives light emitted by the active dye in the presence of carbon dioxide, which is connected to a transducer (2) capable of receiving and processing the signal from the photodiode.

2. The sensor according to claim 1 , characterised in that the polymer of the sensing layer is poly(methyl methacrylate) (PMMA).

3. The sensor according to claim 1 , characterised in that the active dye is 4- dimethylaminoazobenzene-2'-carboxylic acid (methyl red).

4. The sensor according to claim 1 , characterised in that the sensing layer is obtained by immersing a glass slide (6a) in approximately 5 wt% PMMA solution in chloroform comprising approximately 0.1 wt% of methyl red.

5. The sensor according to claim 1 , characterised in that the light source (5) comprises a red light emitting diode, preferably a red LED emitting light with a wavelength of 650 nm.

6. The sensor according to claim 1 , characterised in that the sensing layer comprises 0.01 wt% to 0.2 wt% of methyl red, preferably 0.1 wt%.

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