WO2013131637A1

WO2013131637A1 - Photo-acoustic device

Info

Publication number: WO2013131637A1
Application number: PCT/EP2013/000635
Authority: WO
Inventors: Hermann VON LILIENFELFD-TOAL
Original assignee: Elte Sensoric Gmbh
Priority date: 2012-03-05
Filing date: 2013-03-05
Publication date: 2013-09-12
Also published as: DE102012004658B4; DE202013012102U1; DE102012004658A1

Abstract

In many applications of photo-acoustic measurement of a substance in a medium, for example in non-invasive measurement of the glucose concentration in the human body, increased sensitivity and precision are required. The invention achieves this object by means of a photo-acoustic device with an optical source (1) and a photo-acoustic cell (2). The cell has an acoustic resonant frequency in the ultrasonic range, and the optical source is controlled to emit optical radiation in impulses of a repetition frequency that is equal to the resonant frequency of the photo-acoustic cell. The cell preferably has a plurality of resonant frequencies, and the optical radiation consists of radiation components of different optical wavelengths which are irradiated with different impulse repetition frequencies, each corresponding to one of the resonant frequencies of the photo-acoustic cell. Thus, the absorption of the optical radiation can be measured simultaneously at different wavelengths. The photo-acoustic cell contains a hollow space with two windowless openings for the entry of the optical radiation and the exit of the optical radiation. When the device is used to measure the glucose concentration in the body of a patient, the patient places the surface of his hand or finger on the outlet opening.

Description

Photoacoustic device

The invention relates to a photoacoustic device for measuring a chemical substance in a medium, in particular for measuring the concentration of glucose in the body of a patient.

Diabetes patients need to monitor their blood glucose levels regularly. Usually, a blood sample is taken and examined outside the patient's body. Patients themselves monitoring their blood sugar levels use a small finger lance to extract a drop of blood, which they dab on a reagent strip for analysis. This process is uncomfortable and painful. Therefore, alternatives are sought to avoid blood sampling and to monitor blood glucose levels noninvasively in vivo.

One such alternative is the measurement of glucose by infrared spectroscopy using a laser beam that enters the patient's body through the skin. The glucose-specific absorption of the laser beam at certain optical wavelengths is measured.

EP 1 048 265 A1 discloses an apparatus for infrared spectroscopic measurement of glucose using laser light in the mid-infrared range, that is to say at wavelengths in the range from 2.5 μm to 25 μm. Substances like glucose consist of molecules with covalent bonds whose fundamental vibrations have resonance frequencies in the mid-infrared range of the light spectrum. The absorption spectrum of these substances therefore contains particularly narrow-band absorption lines characteristic of the particular substance in the mid-infrared range. By contrast, at shorter wavelengths, for example in the near infrared range of 0.76 to 2.5 pm, the absorption lines are mostly due to harmonics of the vibrating molecular bonds and are wider and overlap more so that they are less likely to be associated with the substance of interest.

In the mid-infrared, however, there is a strong parasitic absorption of the infrared light by water and other components of human tissue. Therefore, the transmitted radiation intensity is very small and hardly accessible to an optical measurement for recording an absorption spectrum. In the prior art according to EP 1 048 265 A1 the optical absorption coefficient is therefore measured via the photoacoustic effect. The optical absorption of the infrared light leads to the excitation of molecular vibrations. such as vibrational modes of C-0 bonds in glucose. The energy thus absorbed is released via non-radiative transitions as heating to the surrounding medium. The material stress and thermal expansion of the matter detected by the heating results in an acoustic wave which is detected by an acoustic sensor.

The sensor is a photoacoustic cell with a gas filled cavity and a microphone for detecting sound waves in the cavity. The photoacoustic cell is placed on the skin surface of the patient, which is then pulsed optically irradiated. The irradiation leads to pulse-like heating according to the optical absorption. The heats trigger acoustic pressure waves in the cavity, which are detected with the microphone. Amplification of the acoustic waves can be achieved by tuning the frequency at which the optical pulses follow one another to the acoustic resonance frequency of the gas-filled cavity. The amplitude of the acoustic signal received by the microphone corresponds to the optical absorption coefficient of the light-irradiated tissue of the patient at the selected optical wavelength. The repetition of the measurement at different optical wavelengths allows the recording of different regions of an absorption spectrum, from which the concentration of the substance of interest, for example glucose can be tapped.

The described prior art allows a quantitative measurement of the glucose concentration, the sensitivity and accuracy of which, however, does not yet reach that of a measurement with the above-mentioned reagent strips.

The invention is therefore based on the object to provide a device with improved sensitivity for measuring a substance in a medium.

The solution to this problem is achieved with the device according to claim 1.

While the above-described conventional photoacoustic device outputs optical pulses which follow each other at a pulse frequency of about 100 to about 2,000 Hz to the skin of a patient, the pulse frequency in the invention is in the ultrasonic frequency range, that is more than 16 kHz. It is preferably more than 30 or 40 or 50 kHz. However, the pulse frequency for each of the lower limits should be less than 200 kHz, preferably less than 120 kHz or 90 or 70 kHz. The pulse frequency is also a resonant frequency of the cavity of the photoacoustic cell. As a result, the following effect is achieved. With increasing frequency in the ultrasonic range, the photoacoustic cell is less susceptible to noise. Since a higher resonance frequency is associated with a smaller volume of the cavity, the photoacoustic cell can be built smaller with increasing pulse frequency. A smaller cavity also causes a higher sound pressure of the acoustic wave formed in it, whereby the sensitivity of the device is increased. Exceeding the upper limits of the pulse frequency, however, the sensitivity of the available acoustic transducer for detecting the acoustic wave and output of an electrical measurement signal decreases, since the inertia of the moving parts of the transducer attenuates higher-frequency vibrations. When using the device according to the invention for the non-invasive detection of glucose in vivo, the following special effect also results.

_; In conventional photoacoustic spectroscopy for measuring glucose concentration in vivo, it was attempted to measure glucose-specific optical absorption as deep as possible below the main surface in order to reach blood vessels or vessel-proximal tissue parts. For this purpose, shortwave infrared light and a pulse frequency in the range of a few hundred to about 2000 Hz were used to give the heat wave generated by the absorption of each optical pulse, before the next optical pulse, sufficient time to reach the photoacoustic cell, where it enters heated in the gas-filled cavity, the gas boundary layer and leads to the formation of the acoustic wave. The inventors have now found that this approach is not effective. For even the interstitial fluid in the inner skin layer, called the stratum spinosum, contains a glucose concentration which, with only a slight delay, follows the blood glucose concentration of interest to diabetics. In addition, the stratum corneum called outer skin layer is only a few microns thick. The information on the thickness of the stratum corneum previously published in the scientific community was always too large due to swelling of the stratum corneum during sample preparation. As a result, the clinically relevant glucose concentration can be achieved even with light of relatively low penetration depth in the middle infrared range at the absorption lines of glucose. Thus, the location of the optical absorption is very close to the photoacoustic cell. It can be both the thermal wave resulting from the optical absorption in the interstitial fluid, which is converted into an acoustic wave in the photoacoustic cell, as well as the resulting when the heat wave in the interstitial fluid with the resulting acoustic wave of the photoacoustic see cell be detected. In any case, the thermal or acoustic wave triggered by an optical pulse reaches the transducer very quickly and the next optical pulse can follow already after a short time. At high pulse frequency results in a short time a significant signal.

The dependent claims relate to preferred embodiments of the invention.

Claims 2 to 7 relate to expedient embodiments of the device according to the invention, in particular for the non-invasive measurement of glucose in the body of a patient.

The features of claim 8 allow the detection of the optical absorption at several absorption lines and at least one reference wavelength away from the absorption lines of glucose simultaneously. Therefore, in a short measuring time, a sufficient amount of data can be obtained for a precise measurement.

The features of claims 9 to 11 have the advantage that the amplitude of the measurement signal detected by the photoacoustic cell is relatively independent of fluctuations in the pressure, the temperature and the moisture content of the gas in the cavity of the cell. The optical radiation is incident through a first opening in the cavity of the photoacoustic cell and exits through an opposite second opening again. In the example of measuring glucose in the body of a patient, the patient places a finger or his hand with the skin surface on the second opening. If there is no window to define the cavity, the optical radiation can occur undamped on the skin surface, and the acoustic and thermal wave resulting from absorption by glucose can directly reach the gas in the cavity and cause the acoustic wave there directly and by thermal expansion of the gas. In the prior art, a zinc selenide window for transmitting the mid-infrared optical radiation is provided on the first opening. The omission of such a window slightly widens the acoustic resonance line of the cavity so that the amplitude of the acoustic wave is less affected by slight shifts in the acoustic resonance frequency as may occur with variations in temperature, humidity or pressure of the gas in the cavity of the cell , In addition, the omission of the window on the first opening provides for good ventilation of the cavity and avoids a resonance behavior changing moisture precipitate in the cavity when the patient's skin on the second opening is moist. Preferred embodiments of the invention are illustrated in the drawings. It shows

1 shows the schematic representation of a photoacoustic device according to an embodiment of the invention,

FIG. 2 shows a cross section in the vertical plane through a photoacoustic cell in the exemplary embodiment according to FIG. 1,

FIG. 3 shows a cross section in the horizontal plane through the photoacoustic cell of the device according to FIG. 1,

Figure 4 shows the acoustic resonance spectrum of the photoacoustic cell of the embodiment of Figures 1 to 3, and

Figure 5 is a vertical cross-section through a photoacoustic cell, which is a concrete embodiment of the cell shown in Figure 2.

Figure 1 shows an embodiment of a photoacoustic device for measuring a chemical substance in a medium which is particularly suitable for non-invasive measurement of the concentration of glucose in the body of a patient.

The device comprises an optical source 1, a concave mirror 4, a photoacoustic cell 2 and a control circuit 3.

The optical source 1 includes (not shown) six quantum cascade lasers for emitting optical radiation 5 focused from the mirror 4 into the photoacoustic cell 2 from below and incident on the skin surface of a finger (not shown) on top of the photoacoustic cell 2 impinging on a patient's hand. The optical radiation 5 contains six components, one of each of which is emitted by one of the quantum cascade lasers. The components of five of the quantum cascade lasers are mid-infrared radiation at wavelengths at which absorption maxima in the absorption spectrum of glucose in the body of a patient occur, for example at wavenumbers of 1151, 1105, 1080, 1036 and 992 cm-. The component of the sixth quantum cascade laser is infrared radiation of a wavelength at an absorption minimum of glucose in the body of the patient, for example at a wavenumber of 1170, 1140, 1094, 1066, 1014 or 960 cm- ¹ . The quantum cascade lasers are driven by the control circuit 3 for the simultaneous delivery of these radiation components in pulses according to the following scheme:

Two quantum cascade lasers are driven to emit their two radiation components in pulses of a repetition frequency of 56 kHz and with a phase difference of 90 ° between the components. Two more The quantum cascade lasers are driven to emit their two radiation components in pulses of a repetition frequency of 60 kHz and with a phase difference of 90 °. The two other quantum cascade lasers are driven to deliver their two radiation components in pulses of a repetition frequency of 64 kHz and a mutual phase difference of also 90 °. The control takes place via control signals 6 from the control circuit 3 to the optical source. 1

The photoacoustic cell 2 outputs an electrical measurement signal 7 to the control circuit 3, which contains six Meßsignalkomponenten corresponding to the number of optical radiation components. The frequency and phase of a respective measurement signal component correspond to the pulse frequency and phase of the optical radiation component, the absorption of which in the skin of the patient causes the measurement signal component. The amplitude of the measurement signal component corresponds to the absorption coefficient of the irradiated tissue of the patient at the wavelength of the optical radiation component.

In the control circuit 3, the six measuring signal components, for example, by means of six lock-in amplifiers or a correspondingly programmed signal processor (not shown) using the control signals 6 as a reference from each other and separated from any noise and the six amplitudes of the Meßsignalkomponenten won. The amplitude values represent measurements of the absorption spectrum at the five absorption lines used and the absorption minimum of the glucose. The ratio of the amplitude values at the absorption lines to the amplitude value at the absorption minimum is a measure of the observed glucose concentration in the interstitial fluid in the stratum spinosum of the irradiated skin of the patient.

Figures 2 and 3 illustrate views of the photoacoustic cell in cross section along vertical and horizontal planes. The photoacoustic cell 2 has a body 20 of aluminum or stainless steel in which a cavity 21 is located. The cavity 21 is shaped as a Helmholtz resonator with a bulbous main chamber 22 and a channel 23 branching therefrom. At the end remote from the main chamber 22 of the channel 23, a microphone 24 is arranged as an acoustic transducer for detecting an acoustic wave formed in the cavity 21 and for delivering the electrical measurement signal 7.

The main space 22 has on the underside of the body 20 an inlet opening 25 for the entry of the focused optical radiation 5 and on the upper side of the body 20. side of the body 20 an outlet opening for the exit of the optical radiation 5. In operation, the patient places his or her palm on the exit port 26 so that it is completely covered by the skin 100 of the patient. The inlet opening 25 may be closed with a zinc selenide window 27, which is permeable to medium infrared radiation. For the reasons mentioned above, however, it is advantageous to omit the window 27.

The cavity 21 is connected through the openings 25, 26 with the environment, and therefore air-filled.

In the example illustrated in FIGS. 2 and 3, the body 20 of the photoacoustic cell 2 contains a further cavity 28 with the same shape and dimensions as the cavity 21. The further cavity 28 is provided with a further microphone 29. In this embodiment, the control circuit 3 subtracts the output of the other microphone 29 from the measurement signal 7 to reduce any noise due to ambient noise contained therein.

FIG. 4 shows the acoustic resonance spectrum of the Helmholtz resonator formed from the cavity 21 of the photoacoustic cell 2. Plotted is the achievable intensity over the frequency of the acoustic wave in the cavity 21. The acoustic resonance spectrum has three main maxima at the frequencies 56, 60 and 64 kHz. Major maxima are those maxima where the photoacoustic intensity is at least twice the intensity at any other maximum. At these frequencies, the photoacoustic cell particularly intensifies the acoustic wave forming in the cavity. Therefore, these three resonance frequencies were selected as the repetition frequencies of the pulses of the quantum cascade lasers. The number and position of the main maxima can be freely influenced by changing the dimensions of the Helmholtz resonator.

In the present embodiment, the optical source 1 includes six quantum cascade lasers for simultaneously measuring the glucose-specific absorption at six optical wavelengths of the absorption spectrum of glucose. The quantum cascade lasers are operated with pulses of two different phase positions and three different repetition frequencies in order to be able to separate the respective components caused by them in the photoacoustic measuring signal. The exact number is not essential. It is advantageous only if the photoacoustic cell has several main maxima in the ultrasonic range of its acoustic resonance spectrum and the pulse frequencies of the various quantum cascade lasers coincide with the different acoustic resonance frequencies at the main maxima. Instead of different quantum cascade lasers for different optical wavelengths, it is also possible to use a quantum cascade laser, which is tuned successively to the optical wavelengths. Instead of the quantum cascade lasers, other narrow-band radiation sources in the mid-infrared range can also be used. Preferably, the quantum cascade lasers or other radiation sources within each pulse are operated in CW operation without any pulse falling into sub-pulses with radiationless gaps in between. Thus, the entire pulse duration can be used to deliver optical energy and the amount of harmonics in the photoacoustic response, which would be disregarded due to the deviations from the pulse frequencies, can be reduced. The pulse duration is about 0.1 to 1 ps to most efficiently use the energy of the radiation source.

Figure 5 shows a photoacoustic cell which is a concrete embodiment of the cell of Figure 2. The photoacoustic cell is shown enlarged in FIG. 5 and provided with dimensions in mm. It is shown in cross-section along the same plane as in Figure 2 and the same elements as in Figure 2 are provided with the same reference numerals.

The photoacoustic cell shown in FIG. 5 has no window 27. The openings 25, 26 are thus windowless and unlocked, so that the cavity 21 is ventilated through these openings and result in the aforementioned advantages for the resonance behavior of the cell.

As can be seen from Figures 2, 3 and 5, the main space 22 has a cylindrical shape and the two openings 25, 26 are located in the two opposite end faces of the cylindrical shape. The inlet opening 25 has the same diameter as the main chamber 22. In the case of the photoacoustic cell shown in FIG. 5, the diameter of the outlet opening 26 is approximately one third of the diameter of the cylindrical main chamber 22. Preferably, the diameter of the outlet opening 26 is one-tenth to one-half the diameter of the cylindrical main chamber 22. In this area, on the one hand, a ensures sufficient planar irradiation of the patient on the outside of the outlet opening 26 laid finger or the palm and on the other hand prevents the skin of the patient can bulge so far into the cavity 21 that its geometry and acoustic properties are changed.

Claims

claims

1. Device for measuring a substance in a medium by means of photoacoustic spectroscopy, comprising:

an optical source (1) for emitting optical radiation (5) onto the medium at a wavelength at which absorption of the optical radiation by the substance occurs,

a photoacoustic cell (2) for detecting an acoustic wave which occurs upon irradiation of the medium with the optical radiation, and with an acoustic transducer (24) for converting the acoustic wave into an electrical measurement signal (7), and

a control circuit (3) for controlling the optical source and for receiving the measurement signal,

characterized in that

the cell (2) has an acoustic resonance frequency in the ultrasonic range and the control circuit (3) is arranged to control the optical source (1) for emitting the radiation in pulses of a repetition frequency corresponding to the resonance frequency of the cell in the ultrasonic range.

2. Device according to claim 1, wherein the resonance frequency is more than 16 kHz, preferably more than 30, 40 or 50 kHz.

3. Apparatus according to claim 1 or 2, wherein the resonant frequency is less than 200 kHz, preferably less than 120, 90 or 70 kHz.

4. Device according to one of the preceding claims, wherein the wavelength of the optical radiation in the mid-infrared range, in the range of 2.5 m to 25 pm.

5. Device according to one of the preceding claims, wherein the substance is glucose and the optical radiation, a first radiation component with the wavelength of an absorption maximum in the optical spectrum of glucose in the medium and a second radiation component with the wavelength of an absorption minimum in the optical spectrum of glucose in the Contains medium.

6. Device according to one of the preceding claims, wherein the optical source includes a laser, preferably a semiconductor laser, preferably a quantum cascade laser for emitting the optical radiation.

7. Device according to one of the preceding claims, wherein the photoacoustic cell (2) contains a cavity (21), preferably a Helmholtz resonator, which has the acoustic resonance frequency in the ultrasonic range.

8. Device according to one of the preceding claims, wherein the acoustic resonance spectrum of the photoacoustic cell (2) main maxima at a first and a second resonant frequency in the ultrasonic range and the control circuit (3) is arranged, the optical source for simultaneous delivery of a first optical radiation component in To control pulses whose repetition frequency corresponds to the first resonant frequency, and a second optical radiation component in pulses whose repetition frequency corresponds to the second resonant frequency, wherein the first and the second optical radiation component is preferably the first and second optical radiation components mentioned in claim 5.

9. Device according to one of the preceding claims, wherein the photoacoustic cell (2) has a cavity (21) which is provided on opposite sides with a first and a second windowless opening (25, 26) which are arranged so that the optical radiation from the source (1) enters the cavity (21) through the first opening (25) and through the cavity to the second opening (26) and a skin area of a patient placed thereon.

10. Device for measuring a substance in a medium by means of photoacoustic spectroscopy, comprising:

a photoacoustic cell (2) for detecting an acoustic wave occurring upon irradiation of the medium with the optical radiation, and with an acoustic transducer ^') 24) for converting the acoustic wave into an electrical measuring signal (7), and a control circuit (3) for controlling the optical source and for receiving the measurement signal,

characterized in that

the photoacoustic cell (2) has a cavity (21) provided on opposite sides with first and second windowless apertures (25, 26) arranged to transmit the optical radiation from the source (1) the first opening (25) enters the cavity (21) and passes through the cavity to the second opening (26) and a skin area of a patient placed thereon.

11. The apparatus of claim 9 or 10, wherein the cavity (21) has a main space (22), at its opposite ends, the two windowless openings (25, 26) are arranged, of which the first (25) has approximately the same cross-sectional area as the main space (22) and the second (26) has a hundredth to a quarter of the cross-sectional area of the main space (22).