EP0656110A1 - Device for the qualitative and/or quantitative measurement of a sample to be analyzed - Google Patents

Device for the qualitative and/or quantitative measurement of a sample to be analyzed

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Publication number
EP0656110A1
EP0656110A1 EP93918900A EP93918900A EP0656110A1 EP 0656110 A1 EP0656110 A1 EP 0656110A1 EP 93918900 A EP93918900 A EP 93918900A EP 93918900 A EP93918900 A EP 93918900A EP 0656110 A1 EP0656110 A1 EP 0656110A1
Authority
EP
European Patent Office
Prior art keywords
sample
atr element
radiation
atr
angle
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP93918900A
Other languages
German (de)
French (fr)
Inventor
Yoon-Ok Kim
Ralf H. Pries
Dae-Jin Yoon
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
KIM Yoon-Ok
Original Assignee
Individual
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Individual filed Critical Individual
Publication of EP0656110A1 publication Critical patent/EP0656110A1/en
Withdrawn legal-status Critical Current

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Classifications

    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/17—Systems in which incident light is modified in accordance with the properties of the material investigated
    • G01N21/55—Specular reflectivity
    • G01N21/552—Attenuated total reflection
    • 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
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01D—MEASURING NOT SPECIALLY ADAPTED FOR A SPECIFIC VARIABLE; ARRANGEMENTS FOR MEASURING TWO OR MORE VARIABLES NOT COVERED IN A SINGLE OTHER SUBCLASS; TARIFF METERING APPARATUS; MEASURING OR TESTING NOT OTHERWISE PROVIDED FOR
    • G01D3/00—Indicating or recording apparatus with provision for the special purposes referred to in the subgroups
    • G01D3/028—Indicating or recording apparatus with provision for the special purposes referred to in the subgroups mitigating undesired influences, e.g. temperature, pressure
    • G01D3/036—Indicating or recording apparatus with provision for the special purposes referred to in the subgroups mitigating undesired influences, e.g. temperature, pressure on measuring arrangements themselves

Definitions

  • the invention relates to a device for the qualitative and quantitative in-vitro or in-vivo determination of a sample to be analyzed by means of attenuated total reflection using at least one radiation source, an ATR element and a detector unit.
  • ATR attenuated total reflection
  • n a light beam in a medium with a high refractive index n "strikes the interface obliquely to an optically thinner medium with n., Then the beam becomes the critical angle of total reflection when the angle of incidence ⁇ (angle between incident light beam and solder on the interface) exceeds, reflected back into the optically denser medium.
  • ⁇ angle between incident light beam and solder on the interface
  • ⁇ angle between incident light beam and solder on the interface
  • the ATR technology is now based on this. It requires a special optical device which is usually to be accommodated in the sample space of a spectrometer.
  • the ATR additive consists of a mirror system that directs the incident beam into a crystal, usually in the form of a trapezoidally cut prism with high reflectivity (e.g. KRS5, Ge, AgCl, etc.) that is in contact with the sample surface to be examined. In the original arrangement of Fahrenfort, total reflection occurs at the interface between the crystal and the sample.
  • a trapezoidally cut prism with high reflectivity e.g. KRS5, Ge, AgCl, etc.
  • This ATR type is therefore also referred to as a "multiple reflection unit", the method as FMIR (frustrated multiple internal reflection) or just MIR.
  • the invention is based on the object of specifying a device for determining the composition of a sample to be analyzed, with which both qualitative and quantitative determinations can be carried out with high accuracy not only in vitro but also in vivo.
  • the primary aim is to improve the accuracy of the analysis / measurement and to significantly increase the detection capability, which is an important criterion for assessing the quality of an analysis method.
  • the invention is based on the object of developing a measuring head in a miniaturized form which is smaller than the size of the conventional ATR additives.
  • a miniaturized measuring head opens up completely new application possibilities which go far beyond those of the current state of the art.
  • the invention is based, inter alia, on the surprising finding that this goal can be achieved, for example, by using an ATR element of the simplest geometric shape, namely semi-cylindrical or hemispherical. Contrary to the state of the art, no elaborately shaped crystals are required, which are usually not only expensive, but also very sensitive and sometimes even toxic (KRS5!), But instead simple commercial plano-convex microlenses made of glass or plastic are used, which are in the form of Own hemispheres.
  • single or multimode laser diodes with a different wavelength depending on the analysis task are used as the primary radiation source.
  • the device according to the invention requires, among other things. no monochromator.
  • Single-mode laser diodes for example, emit even strictly monochromatic radiation.
  • the device according to the invention eliminates the use of expensive diode arrays or photomultipliers.
  • a device which, on the one hand, receives the ATR element, but on the other hand also serves as a holder for one or more laser diodes and, moreover, provides support for one or more (depending on the number of laser diodes used) photodiodes.
  • the flat surface of the ATR The element lies in one plane (hereinafter referred to as "base area") with the said holding device and later serves to hold the sample substance, or can be pressed against the sample substance to be examined, for example.
  • the curved boundary surface of the ATR element projects into said receiving device and at the same time closes a cavity which serves as a light trap and can be designed differently.
  • the laser diode is arranged within the device in such a way that it is at an angle greater than the critical angle of total reflection for the corresponding medium onto the center point (or, in the case of semicylindrical ATR elements, the center line) of the .ATR element aims.
  • a photodiode corresponding to the laser diode is attached at the same angle, but on the side of the device opposite the laser diode. It should be noted here that the angle of radiation (on the laser diode side) and the angle of radiation (detector side) must be exactly the same.
  • the recording device allows the use of (almost) any number of laser diodes and the associated number of photodiodes. Depending on the shape of the ATR element used, these can be arranged parallel to or circularly around it. As you can easily see, many different constellations can be realized according to this principle, for example several laser diodes with the same wavelength but different angle of incidence, or several laser diodes with different wavelength but same angle of incidence, or combinations of both. of possibilities.
  • the wavelength of the radiation emitted by laser diodes is strongly temperature and current dependent. Usually, therefore, in addition to appropriate current or power stabilization, an attempt is also made to keep the temperature as constant as possible. According to the state of the art, this is usually achieved by cooling the laser diodes with fans, Peltier elements, using liquid nitrogen or the like. realized.
  • the present invention is further based on the surprising finding that suitable temperature control of the laser diode is also made possible by using thermistors.
  • PTC resistors PTC resistors
  • the PTC thermistors used can be used as control elements at the same time.
  • a (possibly also several) PTC resistor is brought into contact with the housing of the laser diode, preferably with the flange, according to the invention.
  • a device for the qualitative and / or quantitative in-vitro or in-vivo determination of the composition of a sample to be analyzed.
  • the device according to the invention has the combination of the following features: - At least one laser diode is provided which emits radiation at a certain angle
  • the device contains at least one PTC resistor for temperature control of the laser diode.
  • the device according to the invention is particularly characterized by its simplicity, which enables an extremely small size. This results in a wide range of possible applications, of which only the use for the analysis of human tissue, in particular for the in vivo examination of body fluids, and very specifically for the non-invasive determination of components of human blood (blood glucose, cholesterol, Alcohol, etc.) should be mentioned.

Abstract

A device for qualitatively and quantitatively measuring a sample to be analyzed in vitro or in vivo by means of attenuated total reflectance has at least one radiation source, an ATR element and a detector unit. The invention is characterised by the combination of the following characteristics: the radiation source generates a primary beam directed towards the ATR element and which hits the ATR element at an angle α which is larger than the limit angle of the total reflectance αT at the interface between the optically denser and the optically thinner medium; the sample to be analysed can be placed on at least one side of the ATR element and its surface-near layer interacts with the primary radiation; a detector unit which corresponds to the incidence angle of the primary radiation on the ATR element detects the radiation leaving the ATR element.

Description

Vorrichtung zur qualitativen und/oder quantitativen Bestimmung einer zu analysierenden ProbeDevice for the qualitative and / or quantitative determination of a sample to be analyzed
B e s c h r e i b u n gDescription
Technisches GebietTechnical field
Die Erfindung bezieht sich auf eine Vorrichtung zur qualitativen und quantitativen in-vitro oder in-vivo Bestimmung einer zu analysierenden Probe mittels abge¬ schwächter Total-reflexion unter Verwendung wenigstens einer Strahlungsquelle, eines ATR-Elementes sowie einer Detektoreinheit.The invention relates to a device for the qualitative and quantitative in-vitro or in-vivo determination of a sample to be analyzed by means of attenuated total reflection using at least one radiation source, an ATR element and a detector unit.
Stand der TechnikState of the art
Bekannt ist ein 1961 von Harrick und Fahrenfort erstmals beschriebenes Analyseverfahren für stark absorbierende Stoffe, die sogenannte "abgeschwächte Totalreflexion" (Attenuated Total Reflectance, ATR) . Es ist eine Re¬ flexionsmethode, die sich die physikalischen Erscheinungen an der Grenzfläche zweier optisch verschieden dichter Medien zunutze macht.Known is an analysis method for strongly absorbing substances which was first described in 1961 by Harrick and Fahrenfort, the so-called "attenuated total reflection" (ATR). It is a reflection method that takes advantage of the physical phenomena at the interface of two optically differently dense media.
Trifft ein Lichtstrahl in einem Medium mit hohem Brechungsindex n„ schräg auf die Grenzfläche zu einem optisch dünneren Medium mit n. , so wird der Strahl, wenn der Einfallswinkel α (Winkel zwischen einfallendem Licht¬ strahl und Lot auf der Grenzfläche) den Grenzwinkel der Totalreflexion übersteigt, in das optisch dichtere Medium zurückreflektiert. Ein Teil der elektromagnetischen Ener¬ gie dringt aber trotzdem einige Lichtwellenlängen tief in das optisch dünnere Medium ein (Oberflächenwellen) . Kehrt die Energie dieses Anteils wieder völlig in das Medium mit höherem Brechungsindex zurück, dann spricht man von Totalreflexion. Wird aber die ins optisch dünnere Medium eingedrungene elektromagnetische Strahlung absor¬ biert, dann fehlen die entsprechenden Wellenlängen bzw. Energieanteile im reflektierten Strahl.If a light beam in a medium with a high refractive index n "strikes the interface obliquely to an optically thinner medium with n., Then the beam becomes the critical angle of total reflection when the angle of incidence α (angle between incident light beam and solder on the interface) exceeds, reflected back into the optically denser medium. However, some of the electromagnetic energy penetrates a few light wavelengths deep into the optically thinner medium (surface waves). If the energy of this portion returns completely to the medium with a higher refractive index, then one speaks of total reflection. However, if the electromagnetic radiation that has penetrated into the optically thinner medium is absorbed, then the corresponding wavelengths or energy components are missing in the reflected beam.
Auf dieser Grundlage beruht nun die ATR-Technik. Sie er¬ fordert eine spezielle optische Einrichtung, die üblicher¬ weise im Probenraum eines Spektrometers unterzubringen ist. Der ATR-Zusatz besteht aus einem Spiegelsystem, das den einfallenden Strahl in einen Kristall meist in der Form eines trapezförmig geschnittenen Prismas von hohem Reflexionsvermögen (z.B. KRS5, Ge, AgCl, o.a.) lenkt, der mit der zu untersuchenden Probenoberfläche in Kontakt steht. In der ursprünglichen Anordnung von Fahrenfort kommt es an der Grenzfläche zwischen Kristall und Probe einmal zur Totalreflexion. Heute verwendet man meistens flache Kristallplatten, an die die Probe von beiden Seiten angedrückt wird. Die Strahlung tritt durch das abgeschräg¬ te schmale Ende in den Kristall ein, wird zwischen den Oberflächen (bis zu 50 mal) hin und her reflektiert und verläßt denselben durch das andere schmale Kristallende. Dieser ATR-Typ wird deshalb auch als "Vielfachreflexions- einheit", die Methode als FMIR (frustrated multiple internal reflection) oder auch nur MIR bezeich¬ net.The ATR technology is now based on this. It requires a special optical device which is usually to be accommodated in the sample space of a spectrometer. The ATR additive consists of a mirror system that directs the incident beam into a crystal, usually in the form of a trapezoidally cut prism with high reflectivity (e.g. KRS5, Ge, AgCl, etc.) that is in contact with the sample surface to be examined. In the original arrangement of Fahrenfort, total reflection occurs at the interface between the crystal and the sample. Today, flat crystal plates are mostly used, to which the sample is pressed from both sides. The radiation enters the crystal through the beveled narrow end, is reflected back and forth between the surfaces (up to 50 times) and leaves the same through the other narrow crystal end. This ATR type is therefore also referred to as a "multiple reflection unit", the method as FMIR (frustrated multiple internal reflection) or just MIR.
Aus den bereits erwähnten physikalischen Grundlagen folgen nun die Bedingungen und die Möglichkeiten der ATR-Technik. Für das Zustandekommen eines ATR-Spektrums sind folgende Punkte maßgebend: - Der Unterschied der Brechungsindizes von Re¬ flexionselement und Probe bei einer gewählten Wellenlänge,The conditions and possibilities of ATR technology now follow from the physical principles already mentioned. The following points are decisive for the formation of an ATR spectrum: The difference in the refractive indices of the reflection element and the sample at a selected wavelength,
- der Einfallswinkel α,- the angle of incidence α,
- die Absorption der Probe,- the absorption of the sample,
- der optische Kontakt zwischen ATR-Kristall und Probe,- the optical contact between the ATR crystal and the sample,
- die Anzahl n der Reflexionen innerhalb des Kristalls,the number n of reflections within the crystal,
- die ausgeleuchtete Fläche des Kristalls,- the illuminated area of the crystal,
- die Eindringtiefe der Oberflächenwelle in die Probe.- The depth of penetration of the surface wave into the sample.
Quantitative Messungen waren mit der ATR-Technik bisher in der Regel nicht möglich, da der Kontakt zwischen Probe und Reflexionselement vom Anpreßdruck bzw. von der Oberflächenbeschaffenheit der Probe abhängt.Until now, quantitative measurements were generally not possible with the ATR technology, since the contact between the sample and the reflection element depends on the contact pressure or the surface properties of the sample.
Darstellung der ErfindungPresentation of the invention
Der Erfindung liegt insoweit die Aufgabe zugrunde, eine Vorrichtung zur Bestimmung der Zusammensetzung einer zu analysierenden Probe anzugeben, mit der sich sowohl qualitative als auch quantitative Bestimmungen mit hoher Genauigkeit nicht nur in vitro sondern auch in vivo durchführen lassen. Gegenüber den bekannten Vor¬ richtungen sollen dabei in erster Linie die Analyse- /Meßgenauigkeit verbessert sowie das Nachweisvermögen, welches ein wichtiges Kriterium für die Beurteilung der Güte eines Analyseverfahrens ist, erheblich erhöht werden. Weiterhin liegt der Erfindung die Aufgabe zu¬ grunde, einen Meßkopf in miniaturisierter Form zu ent¬ wickeln, der die Baugröße der herkömmlichen ATR-Zusätze um Größenordnungen unterschreitet.In this respect, the invention is based on the object of specifying a device for determining the composition of a sample to be analyzed, with which both qualitative and quantitative determinations can be carried out with high accuracy not only in vitro but also in vivo. Compared to the known devices, the primary aim is to improve the accuracy of the analysis / measurement and to significantly increase the detection capability, which is an important criterion for assessing the quality of an analysis method. Furthermore, the invention is based on the object of developing a measuring head in a miniaturized form which is smaller than the size of the conventional ATR additives.
Ein erfindungsgemäßer miniaturisierter Meßkopf eröffnet völlig neue Anwendungsmöglichkeiten, die weit über jene des heutigen Standes der Technik hinausgehen. Der Erfindung liegt u.a. die Überraschende Erkenntnis zugrunde, das dieses Ziel z.B. durch die Verwendung eines ATR-Elementes einfachster geometrischer Form, nämlich halbzylindrisch oder halbkugelförmig, erreicht werden kann. Entgegen dem Stand der Technik werden also keine aufwendig geformten Kristalle, die üblicherweise nicht nur teuer, sondern auch sehr empfindlich und bisweilen sogar giftig (KRS5!) sind benötigt, sondern es gelangen z.B. einfache handelsübliche plankonvexe Mikrolinsen aus Glas oder Kunststoff, welche die Form von Halbkugeln besitzen, zum Einsatz.A miniaturized measuring head according to the invention opens up completely new application possibilities which go far beyond those of the current state of the art. The invention is based, inter alia, on the surprising finding that this goal can be achieved, for example, by using an ATR element of the simplest geometric shape, namely semi-cylindrical or hemispherical. Contrary to the state of the art, no elaborately shaped crystals are required, which are usually not only expensive, but also very sensitive and sometimes even toxic (KRS5!), But instead simple commercial plano-convex microlenses made of glass or plastic are used, which are in the form of Own hemispheres.
Als Primärstrahlungsquelle werden, entgegen :dem Stand der ATR-Technik, Single- oder multimodige Laserdioden (Fabry-Perot-Typ) mit je nach Analysenaufgabe unter¬ schiedlicher Wellenlänge benutzt. Die erfindungsgemäße Vorrichtung benötigt u.a. keinen Monochromator. Singlemodige Laserdioden senden beispielsweise selbst streng monochromatische Strahlung aus.Contrary to the state of the art in ATR, single or multimode laser diodes (Fabry-Perot type) with a different wavelength depending on the analysis task are used as the primary radiation source. The device according to the invention requires, among other things. no monochromator. Single-mode laser diodes, for example, emit even strictly monochromatic radiation.
Als Strahlungsdetektoren werden, abhängig von den emittierten Wellenlängenbereichen der als Primärstrahlungsquelle(n) eingesetzten Laserdiode(n) einfache (üblicherweise ungekühlte) Photodioden (z.B. Ge-Detektoren) verwendet. Die erfindungsgemäße Vorrich¬ tung erübrigt den Einsatz teurer Diodenarrays oder Photomultiplier.Depending on the emitted wavelength ranges of the laser diode (s) used as the primary radiation source (s), simple (usually uncooled) photodiodes (e.g. Ge detectors) are used as radiation detectors. The device according to the invention eliminates the use of expensive diode arrays or photomultipliers.
Erfindungsgemäß wird deshalb eine Vorrichtung geschaf¬ fen, die einerseits das ATR-Element aufnimmt, anderer¬ seits aber auch als Halterung für eine oder mehrere Laserdioden dient und darüberhinaus einer oder mehreren (je nach Anzahl der eingesetzten Laserdioden) Photodioden Halt bietet. Die plane Fläche des ATR- Elementes liegt in einer Ebene (im weiteren Text "Grundfläche" genannt) mit der besagten Aufnahmevor- richtung und dient später zur Aufnahme der Probens¬ ubstanz, bzw. kann z.B. gegen die zu untersuchende Probensubstanz gepresst werden. Die gekrümmte Grenzflächedes ATR-Elementes ragt in die besagte Auf¬ nahmevorrichtung hinein und verschließt dabei gleich¬ zeitig einen Hohlraum der als Lichtfalle dient und unterschiedlich gestaltet sein kann.According to the invention, therefore, a device is created which, on the one hand, receives the ATR element, but on the other hand also serves as a holder for one or more laser diodes and, moreover, provides support for one or more (depending on the number of laser diodes used) photodiodes. The flat surface of the ATR The element lies in one plane (hereinafter referred to as "base area") with the said holding device and later serves to hold the sample substance, or can be pressed against the sample substance to be examined, for example. The curved boundary surface of the ATR element projects into said receiving device and at the same time closes a cavity which serves as a light trap and can be designed differently.
Die Laserdiode wird innerhalb der besagten Vorrichtung so angeordnet, daß sie unter einem Winkel größer als der Grenzwinkel der Totalreflexion für das entsprechen¬ de Medium auf den Mittelpunkt (bzw. bei halbzylinder- förmigen ATR-Elementen die Mittellinie) des .ATR-Elemen¬ tes zielt. Eine zu der Laserdiode korrespondierende Photodiode wird unter dem selben Winkel, jedoch auf der der Laserdiode gegenüberliegenden Seite der Vorrichtung befestigt. Zu beachten ist hierbei, daß Einstrahlungs¬ winkel (Laserdiodenseitig) und Ausstrahlungswinkel (Detektorseitig) genau gleich sein müssen.The laser diode is arranged within the device in such a way that it is at an angle greater than the critical angle of total reflection for the corresponding medium onto the center point (or, in the case of semicylindrical ATR elements, the center line) of the .ATR element aims. A photodiode corresponding to the laser diode is attached at the same angle, but on the side of the device opposite the laser diode. It should be noted here that the angle of radiation (on the laser diode side) and the angle of radiation (detector side) must be exactly the same.
Entsprechendes gilt natürlich bei der Verwendung mehre¬ rer Laserdioden: Die Aufnahmevorrichtung erlaubt den Einsatz (nahezu) beliebig vieler Laserdioden und der dazugehörigen Anzahl von Photodioden. Diese können je nach Form des verwendeten ATR-Elementes parallel zu bzw. kreisförmig um dieses herum angeordnet sein. Wie man leicht sieht können nach diesem Prinzip viele un¬ terschiedliche Konstellationen realisiert werden, z.B. mehrere Laserdioden mit der selben Wellenlänge aber unterschiedlichem Einstrahlwinkel, oder aber mehrere Laserdioden mit unterschiedlicher Wellenlänge aber gleichem Einstrahlwinkel, oder auch Kombinationen bei- der Möglichkeiten.The same applies, of course, when using several laser diodes: the recording device allows the use of (almost) any number of laser diodes and the associated number of photodiodes. Depending on the shape of the ATR element used, these can be arranged parallel to or circularly around it. As you can easily see, many different constellations can be realized according to this principle, for example several laser diodes with the same wavelength but different angle of incidence, or several laser diodes with different wavelength but same angle of incidence, or combinations of both. of possibilities.
Die Wellenlänge der von Laserdioden emittierten Strah¬ lung ist stark temperatur- und stromabhängig. Üblicher¬ weise wird daher versucht neben einer entsprechenden Strom- oder Leistungsstabilisierung auch die Temperatur möglichst konstant zu halten. Entsprechend dem Stand der Technik wird dies meist durch Kühlung der Laser¬ dioden durch Ventilatoren, Peltierelemente, Verwendung von flüssigem Stichstoff o.a. realisiert.The wavelength of the radiation emitted by laser diodes is strongly temperature and current dependent. Usually, therefore, in addition to appropriate current or power stabilization, an attempt is also made to keep the temperature as constant as possible. According to the state of the art, this is usually achieved by cooling the laser diodes with fans, Peltier elements, using liquid nitrogen or the like. realized.
Der vorliegenden Erfindung liegt weiterhin die überra¬ schende Erkenntnis zugrunde, daß eine geeignete Tempe¬ raturregelung der Laserdiode auch durch Verwendung von Thermistoren ermöglicht wird. Insbesondere geschieht das durch Verwendung von Kaltleitern (PTC-Widerständen) welche als Heizelemente eingesetzt werden um die Tempe¬ ratur der Laserdiode auf einen Wert oberhalb der Umge¬ bungstemperatur, welcher durch den Laserstrom allein nicht erreicht wird, hochzuheizen. Aufgrund ihrer spe¬ ziellen Kennlinie können die verwendeten Kaltleiter gleichzeitig als Regelelemente eingesetzt werden. Ein (ggf. auch mehrere) PTC-Widerstand wird dabei erfin¬ dungsgemäß mit dem Gehäuse der Laserdiode, vorzugsweise mit dem Flansch, in Kontakt gebracht.The present invention is further based on the surprising finding that suitable temperature control of the laser diode is also made possible by using thermistors. In particular, this is done by using PTC resistors (PTC resistors) which are used as heating elements in order to heat up the temperature of the laser diode to a value above the ambient temperature, which is not reached by the laser current alone. Because of their special characteristic, the PTC thermistors used can be used as control elements at the same time. A (possibly also several) PTC resistor is brought into contact with the housing of the laser diode, preferably with the flange, according to the invention.
Beschrieben wird eine Vorrichtung (Meßkopf, Sensorkopf) zur qualitativen und/oder quantitativen in-vitro oder in-vivo Bestimmung der Zusammensetzung einer zu analy¬ sierenden Probe.A device (measuring head, sensor head) is described for the qualitative and / or quantitative in-vitro or in-vivo determination of the composition of a sample to be analyzed.
Die erfindungsgemäße Vorrichtung weist die Kombination folgender Merkmale auf: - es ist mindestens eine Laserdiode vorgesehen, welche unter einem bestimmten Winkel Strahlung aussendet inThe device according to the invention has the combination of the following features: - At least one laser diode is provided which emits radiation at a certain angle
- ein geometrisch einfachst gestaltetes ATR-Element auf dessen planer Grundfläche die zu untersuchende Probens¬ ubstanz positioniert werden kanna geometrically simplest ATR element on whose flat base the sample substance to be examined can be positioned
- sowie mindestens ein zur Laserdiode korrespondieren¬ der Strahlungsdetektor,- and at least one radiation detector corresponding to the laser diode,
- ferner enthält die Vorrichtung mindestens einen PTC- Widerstand zur Temperaturregelung der Laserdiode.- Furthermore, the device contains at least one PTC resistor for temperature control of the laser diode.
Die erfindungsgemäße Vorrichtung zeichnet sich insbe¬ sondere durch ihre Einfachheit aus, welche eine äußerst geringe Baugröße ermöglicht. Daraus resultiert ein weites Feld von Anwendungsmöglichkeiten, von denen abschließend nur noch einmal der Einsatz zur Analyse menschlichen Gewebes, insbesondere zur in vivo Untersu¬ chung von Körperflüssigkeiten sowie ganz speziell zur non-invasiven Bestimmung von Bestandteilen des mensch¬ lichen Blutes (Blutglucose, Cholesterin, Alkohol, etc.) erwähnt werden soll. The device according to the invention is particularly characterized by its simplicity, which enables an extremely small size. This results in a wide range of possible applications, of which only the use for the analysis of human tissue, in particular for the in vivo examination of body fluids, and very specifically for the non-invasive determination of components of human blood (blood glucose, cholesterol, Alcohol, etc.) should be mentioned.

Claims

P a t e n t a n s p r ü c h e Patent claims
1. Vorrichtung zur qualitativen und quantitativen in- vitro oder in-vivo Bestimmung einer zu analysierenden Probe mittels abgeschwächter Total-reflexion unter Verwendung wenigstens einer Strahlungsquelle, eines ATR-Elementes sowie einer Detektoreinheit, gekennzeichnet durch die Kombination folgender Merkmale:1. Device for the qualitative and quantitative in vitro or in vivo determination of a sample to be analyzed by means of attenuated total reflection using at least one radiation source, an ATR element and a detector unit, characterized by the combination of the following features:
- die Strahlungsquelle erzeugt einen auf das ATR-Ele¬ ment gerichteten Primärstrahl, der das ATR-Element unter dem Winkel α, der größer als der Grenzwinkel der Totalreflexion α- am Übergang vom optisch dichteren zum dünneren Medium ist, trifft,the radiation source generates a primary beam directed at the ATR element, which strikes the ATR element at an angle α which is greater than the critical angle of total reflection α at the transition from the optically denser to the thinner medium,
- an wenigstens einer Seite des ATR-Elementes ist die zu analysierende Probe anbringbar, deren obeflächennahe Schicht in Wechselwirkung mit der PrimärStrahlung tritt,the sample to be analyzed can be attached to at least one side of the ATR element, the layer close to the surface of which interacts with the primary radiation,
- eine zum Einfallswinkel der Primärstrahlung in das ATR-Element korrespondierende Detektoreinheit dete- ktiert die aus dem ATR-Element austretende Strahlung.- A detector unit corresponding to the angle of incidence of the primary radiation into the ATR element detects the radiation emerging from the ATR element.
2. Vorrichtung nach Anspruch 1, dadurch gekennzeichnet, daß zur Bestimmung der Proben- substanz ein Meßstrahl erdorderlich ist, der in selbstkalibrierender Weise am Detektor ein in Abhängig¬ keit von der Meßprobe stehendes Meßsignal erzeugt.2. Apparatus according to claim 1, characterized in that a measuring beam is required to determine the sample substance, which generates a measuring signal which is dependent on the measuring sample in a self-calibrating manner on the detector.
3. Vorrichtung nach Anspruch 1 oder 2, dadurch gekennzeichnet, daß die Strahlungsquelle eine Laserdiode ist, deren Wellenlängenstabilität u.a. durch Temperaturkonstantregelung gewährbar ist. 3. Apparatus according to claim 1 or 2, characterized in that the radiation source is a laser diode whose wavelength stability can be ensured, inter alia, by constant temperature control.
4. Vorrichtung nach einem der Ansprüche 1 bis 3, dadurch gekennzeichnet, daß die Temperaturregelung mit einem Kaltleiter (PTC-Widerstand) derart vornehmbar ist, daß eine konstante Temperatur oberhalb der Umge¬ bungstemperatur einstellbar ist.4. Device according to one of claims 1 to 3, characterized in that the temperature control with a PTC thermistor (PTC resistor) can be carried out such that a constant temperature above the ambient temperature is adjustable.
5. Vorrichtung nach einem der Ansprüche 1 bis 4, dadurch gekennzeichnet, daß die Temperaturregelung mit einem Peltierelement derart vornehmbar ist, daß eine gewünschte Temperatur einstellbar ist.5. Device according to one of claims 1 to 4, characterized in that the temperature control can be carried out with a Peltier element such that a desired temperature can be set.
6. Vorrichtung nach einem der Ansprüche 1 bis 5, dadurch gekennzeichnet, daß das ATR-Element eine halb¬ zylindrische, halbkugelige oder irreguläre Form auf¬ weist.6. Device according to one of claims 1 to 5, characterized in that the ATR element has a semi-cylindrical, hemispherical or irregular shape.
7. Vorrichtung nach einem der Ansprüche 1 bis 6, dadurch gekennzeichnet, daß das ATR-Element eine plankonvexe Mikrolinse aus Glas oder Kunststoff ist.7. Device according to one of claims 1 to 6, characterized in that the ATR element is a plano-convex microlens made of glass or plastic.
8. Vorrichtung nach einem der Ansprüche 1 bis 7, dadurch gekennzeichnet, daß die Laserdiode bevorzugter¬ weise im Multi-Mode, gegebenenf lls auch im Single- Mode betreibbar ist.8. Device according to one of claims 1 to 7, characterized in that the laser diode is preferably operable in multi-mode, possibly also in single mode.
9. Vorrichtung nach einem der Ansprüche 1 bis 8, dadurch gekennzeichnet, daß die Detekoreinheit aus einer ungekühlten Photodiode besteht.9. Device according to one of claims 1 to 8, characterized in that the detector unit consists of an uncooled photodiode.
10. Vorrichtung nach einem der Ansprüche 1 bis 9, dadurch gekennzeichnet, daß ein Fassungsteil vorgesehen ist, das eine kompakte Zusammensetzung des ATR-Elemtes mit wenigstens einer Strahlungsquelle, die mit einem PTC-Widerstand kombinierbar ist, und Detektoreinheiten entsprechender Anzahl ermöglicht.10. Device according to one of claims 1 to 9, characterized in that a mounting part is provided which has a compact composition of the ATR element with at least one radiation source, which can be combined with a PTC resistor, and detector units appropriate number allows.
11. Vorrichtung nach Anspruch 10, dadurch gekennzeichnet, daß das ATR-Element derart in die Fassung einbringbar ist, daß es mit seiner ge¬ wölbten Oberseite in das Innere einer vorgesehenen Ausparung in der Fassung einbringbar ist und dadurch einen inneren Hohlraum einschließt, der als Lichtfalle dient.11. The device according to claim 10, characterized in that the ATR element can be inserted into the socket in such a way that it can be inserted with its curved top into the interior of a recess provided in the socket and thereby includes an inner cavity which as Light trap serves.
12. Vorrichtung nach Anspruch 11, dadurch gekennzeichnet, daß sich im Inneren der Aus¬ sparung ein weiterer Detektor in Kombination zu einem Körper mit lichtsammelnden Eigenschaften befindet, der zur Messung der Reflektanzstrahlung dient.12. The apparatus according to claim 11, characterized in that there is another detector in the interior of the recess in combination with a body with light-collecting properties, which is used to measure the reflectance radiation.
13. Vorrichtung nach einem der Ansprüche 1 bis 12, dadurch gekennzeichnet, daß Lichtquelle und zugehörige Detektoreinheit gemäß Einfalls- und Ausfallswinkel angeordnet sind.13. Device according to one of claims 1 to 12, characterized in that the light source and associated detector unit are arranged according to the angle of incidence and angle of incidence.
14. Vorrichtung nach einem der Ansprüche 1 bis 13, dadurch gekennzeichnet, daß die Energieversorgung der Lichtquelle sowie die zugehörige Temperaturregelung selbstkalibrierend ist.14. Device according to one of claims 1 to 13, characterized in that the energy supply of the light source and the associated temperature control is self-calibrating.
15. Vorrichtung nach einem der Ansprüche 1 bis 14, dadurch gekennzeichnet, daß die Änderung der physikali¬ schen Parameter Temperatur, Leistung, Stromstärke sowie weitere physikalische Parameter je nach Auflagendruck der Probe zur Bestimmung der Probensubstanz heranzieh¬ bar ist.15. The device according to one of claims 1 to 14, characterized in that the change in the physical parameters temperature, power, current and other physical parameters depending on the pressure of the sample for determining the sample substance can be used.
16. Vorrichtung nach einem der Ansprüche 1 bis 15, dadurch gekennzeichnet, daß die Änderungen der physika¬ lischen Änderungen der Luft, z.B. der Temperatur zur Bestimmung der Probensubstanz heranziehbar ist.16. The device according to one of claims 1 to 15, characterized in that the changes in the physical changes in the air, for example the temperature, can be used to determine the sample substance.
17. Vorrichtung nach einem der Ansprüche 1 bis 16, dadurch gekennzeichnet, daß die Kompensation der von der Probe und der Luft verursachten Änderungen der physikalischen Parameter durch geeignete mathematische Auswertealgorithmen, bspw. durch multilineare Regressi¬ on, erfolgt.17. Device according to one of claims 1 to 16, characterized in that the compensation of the changes in the physical parameters caused by the sample and the air is carried out by suitable mathematical evaluation algorithms, for example by multilinear regression.
18. Vorrichtung nach einem der Ansprüche 1 bis 17, dadurch gekennzeichnet, daß durch ortsabhängige Dotierung des Laserchips der Primärstrahlungsquelle bzw. durch Änderung der Stromstärke dessen innere Struktur derart änderbar ist, daß eine unterschiedliche Elektronendichte erzielbar ist, die eine Orts¬ abhängigkeit des Brechungsindex bewirkt, so daß eine Aussendung von mehreren Strahlungsbündeln gleicher und/oder unterschiedlicher Wellenlänge erfolgt.18. Device according to one of claims 1 to 17, characterized in that its internal structure can be changed by location-dependent doping of the laser chip of the primary radiation source or by changing the current intensity such that a different electron density can be achieved, which causes a location-dependent index of refraction , so that multiple radiation beams of the same and / or different wavelengths are emitted.
19. Vorrichtung nach einem der Ansprüche 1 bis 18, dadurch gekennzeichnet, daß von einer19. Device according to one of claims 1 to 18, characterized in that one
Primärstrahlungsquelle mehr als ein Strahlungsbündel in das ATR-Element einstrahlbar ist, das unterschied¬ lichen Wechselwirkungen mit der Probe in unterschied¬ licher Eindringtiefe unterliegt.Primary radiation source more than one radiation beam can be irradiated into the ATR element, which is subject to different interactions with the sample at different penetration depths.
20. Verfahren unter Anwendung der Vorrichtung gemäß Ansprüche 1 bis 19, dadurch gekennzeichnet, daß die detektierte Strahlung je nach Bedarf vor und/oder nach jeder Probenanalyse durch einer Referenzmessung an Luft gemessen wird. 20. The method using the device according to claims 1 to 19, characterized in that the detected radiation is measured as required before and / or after each sample analysis by a reference measurement in air.
21. Verfahren nach Anspruch 20 zur non-invasiven Be¬ stimmung von Blutbestandteilen, bspw. Blutglucose, Cholesterin, Alkohol etc. dadurch gekennzeichnet, daß eine blutdurchströmte Hautstelle, vorzugsweise im Bereich eines Fingerab¬ drucks, derart auf die Meßoberfläche des ATR-Elements auflegbar ist, daß der Meßerfolg vollständig bzw. weitgestgehend unabhängig vom Auflagedruck der Haut¬ stelle ist. 21. The method according to claim 20 for the non-invasive determination of blood constituents, for example blood glucose, cholesterol, alcohol, etc., characterized in that a skin area through which blood flows, preferably in the region of a fingerprint, can be placed in this way on the measuring surface of the ATR element is that the measurement success is completely or largely independent of the contact pressure of the skin.
EP93918900A 1992-08-21 1993-08-19 Device for the qualitative and/or quantitative measurement of a sample to be analyzed Withdrawn EP0656110A1 (en)

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DE4227813A DE4227813A1 (en) 1992-08-21 1992-08-21 Device for the qualitative and / or quantitative determination of a sample to be analyzed
PCT/DE1993/000757 WO1994004909A1 (en) 1992-08-21 1993-08-19 Device for the qualitative and/or quantitative measurement of a sample to be analyzed

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