WO1998008076A1 - Process for the assaying of a biological tissue with nichtionogen radiation - Google Patents

Process for the assaying of a biological tissue with nichtionogen radiation Download PDF

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Publication number
WO1998008076A1
WO1998008076A1 PCT/DE1997/001662 DE9701662W WO9808076A1 WO 1998008076 A1 WO1998008076 A1 WO 1998008076A1 DE 9701662 W DE9701662 W DE 9701662W WO 9808076 A1 WO9808076 A1 WO 9808076A1
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tissue
radiation
photons
doppler
scattering
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PCT/DE1997/001662
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German (de)
French (fr)
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Gerhard Mitic
Gerald SÖLKNER
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Siemens Aktiengesellschaft
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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/02—Detecting, measuring or recording pulse, heart rate, blood pressure or blood flow; Combined pulse/heart-rate/blood pressure determination; Evaluating a cardiovascular condition not otherwise provided for, e.g. using combinations of techniques provided for in this group with electrocardiography or electroauscultation; Heart catheters for measuring blood pressure
    • A61B5/026—Measuring blood flow
    • A61B5/0261—Measuring blood flow using optical means, e.g. infrared light

Definitions

  • macarcinoma today is mainly based on the imaging method of X-ray mammography.
  • parts of the public and the medical community are increasingly critical of this examination method, since damage to the irradiated tissue cannot be ruled out with certainty.
  • Clinical trials include light tomographic methods in which the tissue to be examined is illuminated with visible or infrared light and the reflected or transmitted radiation is detected. Since the measured intensities depend on the optical properties of the volume irradiated in each case, it is hoped that tissue types can be distinguished and physiological or pathological changes in the tissue can be determined and localized.
  • Possible applications of light tomography range from the detection of breast cancer to the registration of the oxygenation of the brain and extremities. Due to the multiple scattering of light in the tissue, the spatial resolution that can be achieved with these methods is usually only about 10-15 mm, while the established methods of medical diagnostics (X-ray computed tomography, nuclear magnetic resonance / NMR) still have structures as small as 1 mm depict. Improving the spatial resolution both in the lateral direction and in depth is therefore the primary goal of research and development [1]. 2. State of the art
  • the rotation and the translation speed of a body illuminated by a laser beam can be determined by analyzing the intensity fluctuations that occur in a speckle pattern.
  • these optical methods based on the speckle phenomenon have also been used in the field of medical diagnostics, for example to measure the average flow velocity of the blood in near-surface layers of tissue in vivo [2], [3].
  • FIG. 1 shows the arrangement of the arrangement normally used as a photon source or in a laser Doppler measuring device.
  • the lateral spatial resolution of light tomographic methods can be improved by using a gating technique [4-6].
  • the tissue is irradiated with short light pulses and only those photons are detected which reach the detector within a time window of typically 100-200 ps width that limits the photon transit time.
  • the mean width w of the tissue volume contributing to the measurement result decreases, see above that you can also map smaller structures.
  • the distance d between the transmitting and receiving fibers is reduced and the position of the time window is adjusted accordingly with respect to the trigger signal that triggers the short-term radiation.
  • the method known from [7] allows the localization of an object which absorbs IR radiation and is embedded in a strongly scattering medium.
  • the positional dependence of the phase shift between the injected and the injected optical signal is measured. It is a direct measure of the mean path length of the photons in the tissue and thus also a measure of their mean penetration depth.
  • the object of the invention is a method for the optical measurement of a characteristic (mean flow rate of the blood, degree of blood circulation, absorption capacity, etc.) of a biological tissue.
  • a characteristic mean flow rate of the blood, degree of blood circulation, absorption capacity, etc.
  • the method should make it possible to separate the photons originating from the depth range of interest from the photons scattered in higher or lower layers.
  • a method with the features specified in claim 1 has these properties.
  • the dependent claims relate to refinements and advantageous developments of the method according to the invention.
  • the degree of blood flow to the outer cerebral cortex can be optically determined without having to open the skull. Since essentially only the photons scattered in the deeper layers of the skull are evaluated 4 are taken into account, the blood flow in the scalp does not interfere with the measurement signal.
  • Photons which spread in a living and thus perfused tissue, are subject to both elastic and inelastic scattering processes.
  • the photon exchanges energy with the scattering object and thereby changes its wavelength or frequency.
  • This process known as the Doppler scattering of light, essentially takes place only in the areas of the tissue that are supplied with blood, the erythrocytes moving in the vessels with the blood stream acting in particular as scattering centers.
  • the mean number of Doppler scattering processes per photon increases with the mean length of the distance covered by the photons in the tissue and thus also with the mean penetration depth t.
  • v D the frequency change of the scattering particle
  • k f and ki the wave vectors of the incident and the scattered photon.
  • the Doppler scattering of the photons in the tissue results in a broadening of the frequency spectrum of the detected scattered light compared to the injected light, the extent of the broadening depending on the average number of Doppler scattering processes and therefore also depends on the average penetration depth of the photons.
  • S (v) of the detected scattered light higher frequencies are consequently to be attributed to those photons that penetrated deeper into the perfused tissue and were exposed to the conditions prevailing there (flow velocity of the blood, density and number of red blood cells, etc.) were.
  • Depth discrimination can therefore be achieved by subjecting the detected frequency spectrum S (v) to frequency filtering, in particular high-pass filtering ( ⁇ . The upper part of FIG. 2) or low-pass filtering. Then only those photons contribute to the measurement signal whose Doppler shift lies above or below the filter threshold, whose mean penetration depth is greater or less than a minimum value predetermined by the filter threshold. Band-pass filtering of the power spectrum S (v) ensures that only the photons scattered Doppler in a certain depth range of the tissue are evaluated.
  • FIG. 3 shows the schematic structure of a laser double measuring device, which is particularly suitable for determining the degree of blood circulation in deeper layers of a biological tissue 3.
  • the intensity of the primary radiation on the tissue surface is typically around 120 mW.
  • the diameter of their respective end faces is comparatively small at 2r ⁇ 10-20 ⁇ m (the diameter dspeckie «• * ⁇ / NA one
  • the scattered light which is frequency-shifted due to the Doppler effect, is coherently superimposed with the light not Doppler-scattered (heterodyne overlay).
  • Doppler-scattered light is also mixed with Doppler-scattered light (coherent ho odyne superimposition), the beat produced in both cases containing the Doppler frequencies which are approximately proportional to the blood flow.
  • the intensity of the scattered light emerging at the tissue surface and detected by the detector-side monomode glass fibers 10/11 drops considerably.
  • the source-side glass fiber 8 consequently emits about 10 15 photons per second into the tissue 3.
  • This value lies in the range of the maximum count rates still to be processed by single photon detectors, so that the coherent reception of the scattered light does not represent a major restriction with regard to the signal intensity and the measuring time.
  • Photo ultipliers and so-called “avalanche” photodiodes are used in particular as photon detectors 12/13.
  • the detector 12 (avalanche photodiode) of the first evaluation electronics is a digital correlator 14 (Brookhaven Instruments, BI 9000) AT), which determines the temporal photon autocorrelation function ⁇ I ( ⁇ ) -I (t + ⁇ )> / ⁇ I> 2.
  • a computer 15 converts the temporal autocorrelation function by a
  • a spectrum analyzer 16 Hewlett Packard, HP 35665 A
  • the detector 13 avalanche photodiode
  • the size R is the blood flow, i.e. H. the product of
  • the range of functions of the average speed of the red blood cells is approximately proportional.
  • Results of a Monte Carlo simulation confirm the assumption that the frequency shift of the scattered versus the incident light caused by Doppler scattering depends on the mean penetration depth of the photons in a homogeneously perfused tissue.
  • Figure 4 shows the results of the simulation calculation.
  • the curves are very noisy due to the small number (10 6 ) of simulated photons (in the experiment, tissue 3 is irradiated with about 10 le photons / second). Below approximately 10 kHz, the mean penetration depth t increases approximately linearly with the Doppler shift.
  • differential absorption measurements can also be carried out, for example to determine the blood volume or the local degree of oxygenation of the blood.
  • the tissue is illuminated with at least two radiation probes, the wavelengths of which are matched to the absorption maxima of oxyhemoglobin or deoxyhemoglobin.
  • Each of the stray light components is then subjected to the evaluation process described above.
  • a component with the modulation frequency (typically 70-200 MHz) is also observed in the power spectrum of the detected scattered light (see the upper part of FIG. 5).
  • the Doppler shifts occur as sidebands around the signal component at the modulation frequency and can be determined and evaluated by overlay reception.

Abstract

On the basis of multiple scattering of photons in tissues, the local resolution that can be obtained through an phototomographical process is currently only 10-15mm. By way of comparison, established medical diagnostic processes can provide images of up to 1mm.The Doppler scattering of photons in areas of tissue supplied with blood leads to enlargement of the frequency spectrum of the light detected in relation to incident light, wherein the amount of enlargement depends on the average number of Doppler scattering processes per photon and consequently on the average penetration depth of the photons. Discrimination of depth can thereby be achieved by subjecting the power spectrum of the detected scattering to a high-pass filtering. Only photons whose Doppler displacement is located above the filter threshold or whose average penetration depth is above a minimal value which is predetermined by the filter threshold, contribute to the measuring signal.Optical tompography, transcranial measurement of brain function, measurement of the degree of the blood flow in deep layers of tissue.

Description

Beschreibungdescription
Verfahren zur Untersuchung eines biologischen Gewebes mit nich ionisierender StrahlungMethod for examining a biological tissue with non-ionizing radiation
1. Einleitung1 Introduction
Die Diagnose des Ma makarzinoms stützt sich heute vorwiegend auf das bildgebende Verfahren der Röntgenmam ographie . Teile der Öffentlichkeit und der Ärzteschaft stehen dieser Untersuchungsmethode allerdings zunehmend kritisch gegenüber, da man eine Schädigung des durchstrahlten Gewebes nicht mit Sicherheit ausschließen kann.The diagnosis of macarcinoma today is mainly based on the imaging method of X-ray mammography. However, parts of the public and the medical community are increasingly critical of this examination method, since damage to the irradiated tissue cannot be ruled out with certainty.
In der klinischen Erprobung befinden sich lichttomographische Verfahren, bei denen man das zu untersuchende Gewebe mit sichtbarem bzw. Infrarotlicht beleuchtet und die reflektierte oder transmittierte Strahlung nachweist. Da die gemessenen Intensitäten von den optischen Eigenschaften des jeweils durchstrahlten Volumens abhängen, hofft man, Gewebearten unterscheiden und physiologische bzw. pathologische Veränderungen im Gewebe feststellen und lokalisieren zu können. Mögliche Anwendungen der Lichttomographie reichen von der Detek- tion des Mammakarzinoms bis hin zur Registrierung der Oxyge- nerierung des Gehirns und der Extremitäten. Aufgrund der Vielfachstreuung des Lichtes im Gewebe liegt die mit diesen Verfahren erreichbare Ortsauflösung in der Regel bei nur etwa 10-15 mm, während die etablierten Verfahren der medizinischen Diagnostik (Röntgen-Computer-Tomographie, Kernspinresonanz /NMR) noch bis zu 1 mm kleine Strukturen abbilden. Die Verbesserung der Ortsauflösung sowohl in lateraler Richtung als auch in der Tiefe ist daher vorrangiges Ziel der Forschung und Entwicklung [1] . 2. Stand der TechnikClinical trials include light tomographic methods in which the tissue to be examined is illuminated with visible or infrared light and the reflected or transmitted radiation is detected. Since the measured intensities depend on the optical properties of the volume irradiated in each case, it is hoped that tissue types can be distinguished and physiological or pathological changes in the tissue can be determined and localized. Possible applications of light tomography range from the detection of breast cancer to the registration of the oxygenation of the brain and extremities. Due to the multiple scattering of light in the tissue, the spatial resolution that can be achieved with these methods is usually only about 10-15 mm, while the established methods of medical diagnostics (X-ray computed tomography, nuclear magnetic resonance / NMR) still have structures as small as 1 mm depict. Improving the spatial resolution both in the lateral direction and in depth is therefore the primary goal of research and development [1]. 2. State of the art
Durch Analyse der in einem Speckle-Muster auftretenden Inten- sitätsfluktuationen kann man die Rotation und die Translationsgeschwindigkeit eines von einem Laserstrahl beleuchteten Körpers bestimmen. Seit einigen Jahren finden diese auf dem Speckle-Phänomen basierenden optischen Verfahren auch im Bereich der medizinischen Diagnostik Anwendung, um beispiels- weise die mittlere Fließgeschwindigkeit des Blutes in oberflächennahen Schichten eines Gewebes in vivo zu messen [2], [3] .The rotation and the translation speed of a body illuminated by a laser beam can be determined by analyzing the intensity fluctuations that occur in a speckle pattern. For some years now, these optical methods based on the speckle phenomenon have also been used in the field of medical diagnostics, for example to measure the average flow velocity of the blood in near-surface layers of tissue in vivo [2], [3].
Die Figur 1 zeigt die in einem Laser-Doppler-Meßgerät übli- cherweise gewählte Anordnung der als Photonenquelle bzw.FIG. 1 shows the arrangement of the arrangement normally used as a photon source or in a laser Doppler measuring device.
Strahlungsempfänger dienenden Lichtleiter 1/2 auf der Oberfläche des Gewebes 3 (Messung in Reflexion) . Ihr Abstand d beträgt maximal etwa 2-5 mm, wobei der detektorseitige Lichtleiter 2 im stationären Fall (Einstrahlung von cw-Licht) nur solche Photonen erfaßt, deren Streuweg innerhalb des dunkel dargestellten Volumens 4 verläuft. Mit dem Abstand d der Lichtleiter 1/2 wächst die mittlere Breite w des für die Messung relevanten Volumens 4 stark an. Zudem dringen die Photonen tiefer in das Gewebe 3 ein, wobei sich die mittlere Eindringtiefe näherungsweise zu t = c • {d}1 2 berechnet. Die Messung der Eigenschaften eines biologischen Gewebes in tieferliegenden Schichten (großes d) geht daher immer mit einer schlechteren lateralen Ortsauflösung (größeres w) einher.Radiation receiver serving light guide 1/2 on the surface of the tissue 3 (measurement in reflection). Their distance d is at most about 2-5 mm, the detector-side light guide 2 in the stationary case (irradiation of cw light) only detecting those photons whose scattering path runs within the volume 4 shown in the dark. With the distance d between the light guides 1/2, the mean width w of the volume 4 relevant for the measurement increases strongly. In addition, the photons penetrate deeper into tissue 3, the mean depth of penetration being approximately calculated as t = c • {d} 1 2 . The measurement of the properties of a biological tissue in deeper layers (large d) is therefore always accompanied by a poorer lateral spatial resolution (larger w).
Durch Anwendung einer Gating-Technik [4-6] läßt sich die laterale Ortsauflösung lichttomographischer Verfahren verbessern. Hierbei bestrahlt man das Gewebe mit kurzen Lichti - pulsen und weist nur solche Photonen nach, welche den Detektor innerhalb eines die Photonenlaufzeit begrenzenden Zeit- fensters von typischerweise 100-200 ps Breite erreichen. Als Folge der LaufZeitbegrenzung verringert sich die mittlere Breite w des zum Meßergebnis beitragenden Gewebevolumens, so daß man auch kleinere Strukturen noch abbilden kann. Um auch tieferliegende Strukturen zu analysieren, wird der Abstand d zwischen Sende- und Empfangsfaser verkleinert und die Lage des Zeitfensters bezüglich des die kurzzeitige Bestrahlung auslösenden Triggersignals entsprechend angepaßt.The lateral spatial resolution of light tomographic methods can be improved by using a gating technique [4-6]. Here, the tissue is irradiated with short light pulses and only those photons are detected which reach the detector within a time window of typically 100-200 ps width that limits the photon transit time. As a result of the running time limitation, the mean width w of the tissue volume contributing to the measurement result decreases, see above that you can also map smaller structures. In order to also analyze deeper structures, the distance d between the transmitting and receiving fibers is reduced and the position of the time window is adjusted accordingly with respect to the trigger signal that triggers the short-term radiation.
Das aus [7] bekannte Verfahren erlaubt die Lokalisierung eines in einem stark streuenden Medium eingebetteten, IR-Strah- lung absorbierenden Objektes. Die Bestrahlung des zu untersu- chenden Körpers erfolgt mit intensitätsmoduliertem Licht der Wellenlänge λ = 800 nm, wobei die Modulationsfrequenz im Bereich von f = 10-300 MHz liegt. Gemessen wird die Ortsabhängigkeit der Phasenverschiebung zwischen dem eingekoppelten und dem ausgekoppeltem optischen Signal. Sie ist ein direktes Maß für die mittlere Weglänge der Photonen im Gewebe und damit auch ein Maß für deren mittlere Eindringtiefe.The method known from [7] allows the localization of an object which absorbs IR radiation and is embedded in a strongly scattering medium. The body to be examined is irradiated with intensity-modulated light of wavelength λ = 800 nm, the modulation frequency being in the range of f = 10-300 MHz. The positional dependence of the phase shift between the injected and the injected optical signal is measured. It is a direct measure of the mean path length of the photons in the tissue and thus also a measure of their mean penetration depth.
3. Gegenstand, Ziele und Vorteile der Erfindung3. Object, aims and advantages of the invention
Die Erfindung hat ein Verfahren zur optischen Messung eines Merkmals (mittlere Fließgeschwindigkeit des Blutes, Grad der Durchblutung, Absorptionsvermögen usw. ) eines biologischen Gewebes zum Gegenstand. Insbesondere bei der Untersuchung geschichtet aufgebauter Strukturen soll es das Verfahren ermög- liehen, die aus dem interessierenden Tiefenbereich stammenden Photonen von den in höher- oder tieferliegenden Schichten gestreuten Photonen zu separieren. Ein Verfahren mit den in Patentanspruch 1 angegebenen Merkmalen besitzt diese Eigenschaften. Die abhängigen Ansprüche betreffen Ausgestaltungen und vorteilhafte Weiterbildungen des erfindungsgemäßen Verfahrens .The object of the invention is a method for the optical measurement of a characteristic (mean flow rate of the blood, degree of blood circulation, absorption capacity, etc.) of a biological tissue. In particular when examining layered structures, the method should make it possible to separate the photons originating from the depth range of interest from the photons scattered in higher or lower layers. A method with the features specified in claim 1 has these properties. The dependent claims relate to refinements and advantageous developments of the method according to the invention.
Mit Hilfe des im folgenden beschriebenen Verfahrens, läßt sich beispielsweise der Grad der Durchblutung der äußeren Großhirnrinde optisch bestimmen, ohne den Schädelknochen öffnen zu müssen. Da im wesentlichen nur die in tieferliegenden Schichten des Schädels gestreuten Photonen bei der Auswertung 4 berücksichtigt werden, wirkt sich der Blutfluß in der Kopfhaut nicht störend auf das Meßsignal aus.With the help of the method described below, the degree of blood flow to the outer cerebral cortex, for example, can be optically determined without having to open the skull. Since essentially only the photons scattered in the deeper layers of the skull are evaluated 4 are taken into account, the blood flow in the scalp does not interfere with the measurement signal.
4. Beschreibung eines Ausführungsbeispiels4. Description of an embodiment
Photonen, welche sich in einem lebenden und damit durchbluteten Gewebe ausbreiten, sind sowohl elastischen als auch unelastischen Streuprozessen unterworfen. Während eines als unelastisch bezeichneten Streuvorgangs tauscht das Photon Ener- gie mit dem streuenden Objekt aus und ändert dadurch seine Wellenlänge bzw. Frequenz. Dieser als Dopplerstreuung des Lichtes bezeichnete Vorgang findet im wesentlichen nur in den durchbluteten Bereichen des Gewebes statt, wobei insbesondere die sich in den Gefäßen mit dem Blutstrom bewegenden Erythro- zyten als Streuzentren wirken. Unter der Annahme einer homogenen Durchblutung des Gewebes nimmt die mittlere Anzahl der Dopplerstreuprozesse pro Photon mit der mittleren Länge der von den Photonen im Gewebe zurückgelegten Wegstrecke und damit auch mit der mittleren Eindringtiefe t zu. In Figur 2 sind die entsprechenden Verhältnisse für zwei von einem Sender 5 in das homogen durchblutete Gewebe 3 eingekoppelte und auf verschiedenen Pfaden zum Empfänger 6 gelangende Photonen schematisch dargestellt. Das auf dem längeren Pfad 2 laufende Photon dringt tiefer in das Gewebe 3 ein (t2 > ti) und wird, erkennbar an den vielen Richtungswechseln, häufiger gestreut. Jeder Dopplerstreuprozeß geht einher mit einer durchPhotons, which spread in a living and thus perfused tissue, are subject to both elastic and inelastic scattering processes. During a scattering process known as inelastic, the photon exchanges energy with the scattering object and thereby changes its wavelength or frequency. This process, known as the Doppler scattering of light, essentially takes place only in the areas of the tissue that are supplied with blood, the erythrocytes moving in the vessels with the blood stream acting in particular as scattering centers. Assuming a homogeneous blood flow to the tissue, the mean number of Doppler scattering processes per photon increases with the mean length of the distance covered by the photons in the tissue and thus also with the mean penetration depth t. FIG. 2 schematically shows the corresponding relationships for two photons coupled into the homogeneously perfused tissue 3 by a transmitter 5 and arriving at the receiver 6 on different paths. The photon running on the longer path 2 penetrates deeper into the tissue 3 (t 2 > ti) and, as can be seen from the many changes in direction, is scattered more frequently. Every Doppler scattering process goes along with one
vD = (l/2π)-(kf - -vv D = (l / 2π) - (k f - -v
gegebenen Frequenzänderung vD , wobei v den Geschwindigkeits- vektor des streuenden Teilchens, kf und ki die Wellenvektoren des einfallenden bzw. des gestreuten Photons bezeichnen. Die Dopplerstreuung der Photonen im Gewebe hat eine Verbreiterung des Frequenzspektrums des detektierten Streulichts gegenüber dem eingekoppelten Licht zur Folge, wobei das Ausmaß der Verbreiterung von der mittleren Anzahl der Dopplerstreuprozesse und damit auch von der mittleren Eindringtiefe der Photonen abhängt. Im Frequenz- oder Leistungsspektrum S(v) des nachgewiesenen Streulichts sind höhere Frequenzen demzufolge auf solche Photonen zurückzuführen, welche tiefer in das durch- blutete Gewebe eingedrungen und den dort herrschenden Bedingungen (Fließgeschwindigkeit des Blutes, Dichte und Anzahl der roten Blutkörperchen usw.) ausgesetzt waren. Eine Tiefendiskriminierung läßt sich also dadurch erreichen, daß man das detektierte Frequenzspektrum S(v) einer Frequenzfilterung, insbesondere einer Hochpaßfilterung (ε. den oberen Teil der Figur 2) oder Tiefpaßfilterung unterwirft. Zum Meßsignal tragen dann nur solche Photonen bei, deren Dopplerverschiebung oberhalb bzw. unterhalb der Filterschwelle liegt, deren mittlere Eindringtiefe größer bzw. kleiner ist als ein durch die Filterschwelle vorgegebener Mindestwert. Eine Bandpaßfilterung des Leistungsspektru s S(v) gewährleistet, daß nur die in einem bestimmten Tiefenbereich des Gewebes dopplergestreu- ten Photonen ausgewertet werden.given frequency change v D , where v denotes the velocity vector of the scattering particle, k f and ki the wave vectors of the incident and the scattered photon. The Doppler scattering of the photons in the tissue results in a broadening of the frequency spectrum of the detected scattered light compared to the injected light, the extent of the broadening depending on the average number of Doppler scattering processes and therefore also depends on the average penetration depth of the photons. In the frequency or power spectrum S (v) of the detected scattered light, higher frequencies are consequently to be attributed to those photons that penetrated deeper into the perfused tissue and were exposed to the conditions prevailing there (flow velocity of the blood, density and number of red blood cells, etc.) were. Depth discrimination can therefore be achieved by subjecting the detected frequency spectrum S (v) to frequency filtering, in particular high-pass filtering (ε. The upper part of FIG. 2) or low-pass filtering. Then only those photons contribute to the measurement signal whose Doppler shift lies above or below the filter threshold, whose mean penetration depth is greater or less than a minimum value predetermined by the filter threshold. Band-pass filtering of the power spectrum S (v) ensures that only the photons scattered Doppler in a certain depth range of the tissue are evaluated.
Die Figur 3 zeigt den schematischen Aufbau eines Laser-Dopp- ler-Meßgeräts, das sich insbesondere zur Bestimmung des Grades der Durchblutung in tieferen Schichten eines biologischen Gewebes 3 eignet. Als Photonenquelle dient eine cw-Laserdiode 7 (Spectra Diode Labs., SDL 5421), deren Strahlung (λ = 820 nm) man mit Hilfe einer Glasfaser 8 in das Gewebe 3 einkoppelt. Die Intensität der Primärstrahlung an der Gewebeoberfläche beträgt typischerweise etwa 120 mW. Eine Halterung 9 ermöglicht es, den Abstand d zwischen der quellenseitigen Glasfaser 8 und den beiden detektorseitigen Glasfasern 10/11 zwischen d = 5 mm und d = 60 mm zu variieren. Um sicherzustellen, daß die detektorseitigen Glasfasern 10/11 nur die aus einzelnen oder wenigen Kohärenzzonen (sogenannte Speckies) stammende Streustrahlung erfassen, ist der Durchmesser ihrer jeweiligen Endflächen mit 2r ≤ 10 - 20 um vergleichs- weise klein bemessen (der Durchmesser dspeckie «•* λ/N.A. einerFIG. 3 shows the schematic structure of a laser double measuring device, which is particularly suitable for determining the degree of blood circulation in deeper layers of a biological tissue 3. A cw laser diode 7 (Spectra Diode Labs., SDL 5421) serves as the photon source, the radiation (λ = 820 nm) of which is coupled into the tissue 3 with the aid of a glass fiber 8. The intensity of the primary radiation on the tissue surface is typically around 120 mW. A bracket 9 makes it possible to vary the distance d between the source-side glass fiber 8 and the two detector-side glass fibers 10/11 between d = 5 mm and d = 60 mm. In order to ensure that the glass fibers 10/11 on the detector side only detect the scattered radiation originating from individual or a few coherence zones (so-called speckies), the diameter of their respective end faces is comparatively small at 2r ≤ 10-20 µm (the diameter dspeckie «• * λ / NA one
Kohärenzzone hängt von der Apertur N.A. des jeweiligen Detektors und der Wellenlänge λ ab; für λ= 0.82μm und N.A.= 0,12 =-> dspeckie = 6,8 μm) . An den gewebeseitigen Endflächen der Glasfasern 10/11 überlagert sich das durch den Dopplereffekt frequenzverschobene Streu-licht mit dem nicht dopplergestreu- ten Licht kohärent (heterodyne Überlagerung) . Zudem wird auch dopplergestreutes Licht mit dopplergestreutem Licht gemischt (kohärente ho odyne Überlagerung) , wobei die in beiden Fällen entstehende Schwebung die dem Blutfluß näherungsweise proportionalen Dopplerfrequenzen enthält.Coherence zone depends on the aperture NA of the respective detector and the wavelength λ; for λ = 0.82μm and NA = 0.12 = -> dspeckie = 6.8 μm). On the fabric-side end faces of the glass fibers 10/11, the scattered light, which is frequency-shifted due to the Doppler effect, is coherently superimposed with the light not Doppler-scattered (heterodyne overlay). In addition, Doppler-scattered light is also mixed with Doppler-scattered light (coherent ho odyne superimposition), the beat produced in both cases containing the Doppler frequencies which are approximately proportional to the blood flow.
Aufgrund der optischen Dämpfung durch das zwischen dem Sender 8 und dem Empfänger liegende Gewebe sowie der angestrebten Auswertung einzelner bzw. weniger Speckies, sinkt die Intensität des an der Gewebeoberfläche austretenden und von den detektorseitigen Monomode Glasfasern 10/11 erfaßte Streulicht erheblich ab. So gelangen nur noch etwa 105-106 Photonen pro Sekunde zu den Detektoren 12/13, falls die Laserdiode 7 eine Leistung von 1 mW abgibt, die quellenseitige Glasfaser 8 demzufolge etwa 1015 Photonen pro Sekunde in das Gewebe 3 einstrahlt. Dieser Wert liegt im Bereich der von Einzelpho- tonen-Detektoren noch zu verarbeitenden maximalen Zählraten, so daß der kohärente Empfang des Streulichtes keine große Einschränkung hinsichtlich der Signalintensität und der Meßzeit darstellt. Als Photonendetektoren 12/13 finden insbesondere Photo ultiplier und sogenannte „Avalanche" -Photodioden (EG&G, SPCM-AQ-131) Verwendung. Dem Detektor 12 (Avalanche- Photodiode) der ersten Auswerteelektronik ist hierbei ein digitaler Korrelator 14 (Brookhaven Instruments, BI 9000 AT) nachgeschaltet, welcher die zeitliche Photonen-Autokorrelationsfunktion <I (τ)-I (t+τ)>/< I >2 bestimmt. Ein Rechner 15 wandelt die zeitliche Autokorrelationsfunktion durch eineDue to the optical attenuation by the tissue lying between the transmitter 8 and the receiver and the desired evaluation of individual or fewer speckles, the intensity of the scattered light emerging at the tissue surface and detected by the detector-side monomode glass fibers 10/11 drops considerably. Thus, only about 10 5 -10 6 photons per second reach the detectors 12/13 if the laser diode 7 emits a power of 1 mW, the source-side glass fiber 8 consequently emits about 10 15 photons per second into the tissue 3. This value lies in the range of the maximum count rates still to be processed by single photon detectors, so that the coherent reception of the scattered light does not represent a major restriction with regard to the signal intensity and the measuring time. Photo ultipliers and so-called "avalanche" photodiodes (EG&G, SPCM-AQ-131) are used in particular as photon detectors 12/13. The detector 12 (avalanche photodiode) of the first evaluation electronics is a digital correlator 14 (Brookhaven Instruments, BI 9000) AT), which determines the temporal photon autocorrelation function <I (τ) -I (t + τ)> / <I> 2. A computer 15 converts the temporal autocorrelation function by a
Fourier-Transformation in das gesuchte Dopplerfrequenz-Leistungsspektrum (Powerspectrum) S(v) um und unterwirft dieses der oben beschriebenen Hochpaßfilterung. In der zweiten Auswerteelektronik erzeugt ein mit dem Ausgangssignal des Detek- tors 13 (Avalanche-Photodiode) beaufschlagter Spektrumsanaly- sator 16 (Hewlett Packard, HP 35665 A) das Dopplerfrequenz- Leiεtungsspektrum S(v), wobei die Hochpaßfilterung wieder mit Hilfe des Rechners 15 durchgeführt wird.Fourier transform into the searched Doppler frequency power spectrum (Powerspectrum) S (v) and subjects this to the high-pass filtering described above. In the second evaluation electronics, a spectrum analyzer 16 (Hewlett Packard, HP 35665 A), which is supplied with the output signal of the detector 13 (avalanche photodiode), generates the Doppler frequency Power spectrum S (v), the high-pass filtering being carried out again using the computer 15.
Um aus dem gemessenen und hochpaßgefilterten Leistungsspektrum S(v) ein Maß für den Blutfluß bzw. die mittlere Fließgeschwindigkeit des Blutes in der durch die Grenzfrequenz der Dopplerverschiebung definierten Tiefe abzuleiten, kann man insbesondere das durchIn order to derive a measure for the blood flow or the average flow velocity of the blood in the depth defined by the limit frequency of the Doppler shift from the measured and high-pass filtered power spectrum S (v), one can in particular do this by
R:= konst ..1l v-S(v)dvR: = const ..1l v-S (v) dv
gegebene erste Moment R des Leistungsspektrums S(v) berechnen [8] . Die Größe R ist dem Blutfluß, d. h. dem Produkt dercalculate the given first moment R of the power spectrum S (v) [8]. The size R is the blood flow, i.e. H. the product of
Konzentration der roten Blutkörperchen und deren mittlerer Geschwindigkeit, das gewichtete Moment Rε Concentration of the red blood cells and their average speed, the weighted moment R ε
Rs:= R t J S(v)dv ] -R s : = R t JS (v) dv] -
des Leistungsspektrums der mittleren Geschwindigkeit der roten Blutkörperchen näherungsweise proportional.the range of functions of the average speed of the red blood cells is approximately proportional.
Ergebnisse einer Monte-Carlo-Simulation bestätigen die Annahme, wonach die durch Dopplerstreuung hervorgerufene Frequenzverschiebung des gestreuten gegenüber dem eingestrahlten Licht von der mittleren Eindringtiefe der Photonen in einem homogen durchbluteten Gewebe abhängt. Figur 4 zeigt die Ergebnisse der Simulationsrechnung. Dargestellt ist jeweils die mittlere Eindringtiefe t der Photonen in Abhängigkeit von der detektierten Dopplerfrequenz für zwei zu d= 5 mm und d= 10 mm vorgegebenen Glasfaserabstände. Bei höheren Frequenzverschie- bungen sind die Kurven aufgrund der nur kleinen Anzahl (106) simulierten Photonen stark verrauscht (im Experiment bestrahlt man das Gewebe 3 mit etwa 10le Photonen/Sekunde) . Unterhalb von etwa 10 kHz nimmt die mittlere Eindringtiefe t annähernd linear mit der Dopplerverschiebung zu. Weiterhin fällt auf, daß die elastisch gestreuten Photonen (v=0) bei einer Vergrößerung des Photonenabstandes von d = 5 mm auf d = 10 mm deutlich tiefer in das Gewebe eindringen. Zudem wächst die mittlere Eindringtiefe bei größerem Abstand d langsamer mit der Dopplerfrequenz an.Results of a Monte Carlo simulation confirm the assumption that the frequency shift of the scattered versus the incident light caused by Doppler scattering depends on the mean penetration depth of the photons in a homogeneously perfused tissue. Figure 4 shows the results of the simulation calculation. The mean penetration depth t of the photons is shown as a function of the detected Doppler frequency for two glass fiber spacings predefined at d = 5 mm and d = 10 mm. At higher frequency shifts, the curves are very noisy due to the small number (10 6 ) of simulated photons (in the experiment, tissue 3 is irradiated with about 10 le photons / second). Below approximately 10 kHz, the mean penetration depth t increases approximately linearly with the Doppler shift. It is also striking that the elastically scattered photons (v = 0) penetrate deeper into the tissue when the photon spacing is increased from d = 5 mm to d = 10 mm. In addition, the average depth of penetration increases more slowly with the Doppler frequency at a greater distance d.
5. Ausgestaltungen und Weiterbildungen des Verfahrens5. Refinements and developments of the process
Mit Hilfe des erfindungsgemäßen Verfahrens lassen sich auch differentielle Absorptionsmessungen durchführen, um beispielsweise das Blutvolumen oder den lokalen Oxygenierungs- grad des Blutes zu bestimmen. Hierbei beleuchtet man das Ge- webe mit mindestens zwei Strahlungssonden, deren Wellenlängen auf das Absorptionsmaxima des Oxyhämoglobins bzw. des Deoxy- hämoglobins abgestimmt sind. Jeder der Streulichtanteile wird dann wieder dem oben beschriebenen Auswerteprozeß unterworfen .With the aid of the method according to the invention, differential absorption measurements can also be carried out, for example to determine the blood volume or the local degree of oxygenation of the blood. Here, the tissue is illuminated with at least two radiation probes, the wavelengths of which are matched to the absorption maxima of oxyhemoglobin or deoxyhemoglobin. Each of the stray light components is then subjected to the evaluation process described above.
Wird das Gewebe mit intensitätsmoduliertem Licht bestrahlt, beobachtet man auch im Leistungsspektrum des detektierten Streulichtes eine die Modulationsfrequenz (typischerweise 70-200 Mhz) aufweisende Komponente (s. den oberen Teil der Figur 5) . Die Dopplerverschiebungen treten als Seitenbänder um den Signalanteil bei der Modulationsfrequenz auf und können durch Überlagerungsempfang bestimmt und ausgewertet werden.If the tissue is irradiated with intensity-modulated light, a component with the modulation frequency (typically 70-200 MHz) is also observed in the power spectrum of the detected scattered light (see the upper part of FIG. 5). The Doppler shifts occur as sidebands around the signal component at the modulation frequency and can be determined and evaluated by overlay reception.
6. Literatur6. Literature
[1] Diagnostic Imaging; Jan. 1994, S. 69-76[1] Diagnostic Imaging; Jan. 1994, pp. 69-76
[2] Optics Letters; 10(1985), S. 104-106[2] Optics Letters; 10 (1985), pp. 104-106
[3] Phys. Rehab. Kur Med; 4(1994), S. 105-109 [4] Applied Optics; 30(1991), S. 788-794[3] Phys. Rehab. Cure med; 4 (1994), pp. 105-109 [4] Applied Optics; 30 (1991), pp. 788-794
[5] Applied Optics; 32(1993), S. 574-579[5] Applied Optics; 32 (1993), pp. 574-579
[6] Laser u. Optoelektronik; 27(1995), S. 43-47 [7] Psychophysiology; 31(1994), S. 211-215 [8] Applied Optics; 20(1981), S. 2097-2107 [6] Laser and. Optoelectronics; 27 (1995), pp. 43-47 [7] Psychophysiology; 31 (1994), pp. 211-215 [8] Applied Optics; 20 (1981), pp. 2097-2107

Claims

Patentansprüche claims
1. Verfahren zur Untersuchung eines biologischen Gewebes mit nichtionisierender Strahlung durch Ausführen der folgenden Schritte: a) Bestrahlen eines ersten Bereiches der Gewebeoberfläche oder der Oberfläche eines das Gewebe enthaltenden Körpers mit nichtionisierender, kohärenter elektromagnetischer Strahlung; b) Nachweis der von einem zweiten Bereich der Gewebeoberfläche oder der Oberfläche des Körpers emittierten Streustrahlung und c) Bestimmung des Leistungsspektrums der Streustrahlung, dadurch gekennzeichnet, d) daß nur solche Intensitätswertes S(v) des Leistungsspektrums bei der Bestimmung eines Merkmals des Gewebes berücksichtigt werden, deren zugeordnete Frequenz v höher oder niedriger ist als eine vorgegebene Grenzfrequenz vF, wobei die Grenzfrequenz vF als Maß für die mittlere Eindringtiefe der Photonen dient.1. A method for examining a biological tissue with non-ionizing radiation by performing the following steps: a) irradiating a first region of the tissue surface or the surface of a body containing the tissue with non-ionizing, coherent electromagnetic radiation; b) detection of the scattered radiation emitted by a second area of the tissue surface or the surface of the body, and c) determination of the power spectrum of the scattered radiation, characterized in that d) that only those intensity values S (v) of the power spectrum are taken into account when determining a characteristic of the tissue , whose assigned frequency v is higher or lower than a predetermined cut-off frequency v F , the cut-off frequency v F serving as a measure of the mean penetration depth of the photons.
2 . Verfahren nach Anspruch 1 , d a d u r c h g e k e n n z e i c h n e t , daß die durch den Dopplereffekt hervorgerufene Verschiebung der Frequenz der das Gewebe beleuchtenden Strahlung gemessen wird und daß das Doppler-Leistungsspektrum ermittelt und einer Hochpaß-, Tiefpaß- oder Bandpaßfilterung unterworfen wird.2nd Method according to Claim 1, that the shift in the frequency of the radiation illuminating the tissue caused by the Doppler effect is measured and that the Doppler power spectrum is determined and subjected to high-pass, low-pass or band-pass filtering.
3. Verfahren nach Anspruch 1 oder 2, dadurch gekennzeichnet, daß das Gewebe mit monochromatischer Strahlung der Wellenlänge 500 nm ≤ λ < 1100 ran durchstrahlt wird.3. The method according to claim 1 or 2, characterized in that the tissue is irradiated with monochromatic radiation of wavelength 500 nm ≤ λ <1100 ran.
4. Verfahren nach einem der Ansprüche 1 bis 3, dadurch gekennzeichnet, daß die Streustrahlung mittels eines ersten Lichtleiters (10, 11) erfaßt und einem Photonendetektor (12, 13) zugeführt wird, wobei die wirksame Querschnittsfläche des Lichtleiters (10, 11) annähernd der Größe einer Kohärenzzone der aus der Oberfläche des Gewebes (3) oder des Körpers austretenden Streustrahlung entspricht.4. The method according to any one of claims 1 to 3, characterized in that the scattered radiation is detected by means of a first light guide (10, 11) and fed to a photon detector (12, 13), the effective cross-sectional area of the light guide (10, 11) being approximately the size of a coherence zone from the surface of the fabric (3) or scattered radiation emitted by the body.
5. Verfahren nach Anspruch 4, dadurch gekennzeichnet, daß die mittlere Eindringtiefe der elektromagnetischen5. The method according to claim 4, characterized in that the average depth of penetration of the electromagnetic
Strahlung durch eine Änderung des Abstandes (d) zwischen dem ersten und dem zweiten Bereich variiert wird.Radiation is varied by changing the distance (d) between the first and the second region.
6. Verfahren nach einem der Ansprüche 1 bis 5, dadurch gekennzeichnet, daß ein Moment des Leistungsspektrums berechnet und als Maß für den Grad der Durchblutung des Gewebes herangezogen wird.6. The method according to any one of claims 1 to 5, characterized in that a moment of the power spectrum is calculated and used as a measure of the degree of blood flow to the tissue.
7. Verfahren nach einem der Ansprüche 1 bis 4, dadurch gekennzeichnet, daß das Gewebe (3) mit elektromagnetischer Strahlung unterschiedlicher Wellenlänge beleuchtet wird und daß für jede der resultierenden Streustrahlungen die Verfahrensschritte b)-d) ausgeführt werden .7. The method according to any one of claims 1 to 4, characterized in that the fabric (3) is illuminated with electromagnetic radiation of different wavelengths and that the process steps b) -d) are carried out for each of the resulting scattered radiation.
8 . Verfahren nach einem der Ansprüche 1 bis 6 , d a d u r c h g e k e n n z e i c h n e t , daß die Insität der kohärenten elektromagnetischen Strahlung moduliert wird. 8th . Method according to one of claims 1 to 6, d a d u r c h g e k e n n z e i c h n e t, that the entity of the coherent electromagnetic radiation is modulated.
PCT/DE1997/001662 1996-08-23 1997-08-06 Process for the assaying of a biological tissue with nichtionogen radiation WO1998008076A1 (en)

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