ES2639750T3 - Sistemas de espectroscopía de fluorescencia inducida por láser de resolución en el tiempo y sus usos - Google Patents

Sistemas de espectroscopía de fluorescencia inducida por láser de resolución en el tiempo y sus usos Download PDF

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ES2639750T3
ES2639750T3 ES14763125.3T ES14763125T ES2639750T3 ES 2639750 T3 ES2639750 T3 ES 2639750T3 ES 14763125 T ES14763125 T ES 14763125T ES 2639750 T3 ES2639750 T3 ES 2639750T3
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Pramod BUTTE
Paul LAPCHAK
David Scott KITTLE
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Cedars Sinai Medical Center
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    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
    • G01N21/63—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
    • G01N21/64—Fluorescence; Phosphorescence
    • G01N21/6486—Measuring fluorescence of biological material, e.g. DNA, RNA, cells
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    • G01J—MEASUREMENT OF INTENSITY, VELOCITY, SPECTRAL CONTENT, POLARISATION, PHASE OR PULSE CHARACTERISTICS OF INFRARED, VISIBLE OR ULTRAVIOLET LIGHT; COLORIMETRY; RADIATION PYROMETRY
    • G01J3/00—Spectrometry; Spectrophotometry; Monochromators; Measuring colours
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    • G01J3/0218—Optical elements not provided otherwise, e.g. optical manifolds, diffusers, windows using optical fibers
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    • G01J—MEASUREMENT OF INTENSITY, VELOCITY, SPECTRAL CONTENT, POLARISATION, PHASE OR PULSE CHARACTERISTICS OF INFRARED, VISIBLE OR ULTRAVIOLET LIGHT; COLORIMETRY; RADIATION PYROMETRY
    • G01J3/00—Spectrometry; Spectrophotometry; Monochromators; Measuring colours
    • G01J3/28—Investigating the spectrum
    • G01J3/2889—Rapid scan spectrometers; Time resolved spectrometry
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    • G01J3/00—Spectrometry; Spectrophotometry; Monochromators; Measuring colours
    • G01J3/28—Investigating the spectrum
    • G01J3/44—Raman spectrometry; Scattering spectrometry ; Fluorescence spectrometry
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    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
    • G01N21/63—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
    • G01N21/64—Fluorescence; Phosphorescence
    • G—PHYSICS
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    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
    • G01N21/63—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
    • G01N21/64—Fluorescence; Phosphorescence
    • G01N21/6402—Atomic fluorescence; Laser induced fluorescence
    • G—PHYSICS
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    • G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
    • G01N21/63—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
    • G01N21/64—Fluorescence; Phosphorescence
    • G01N21/6408—Fluorescence; Phosphorescence with measurement of decay time, time resolved fluorescence
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    • G01N21/63—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
    • G01N21/64—Fluorescence; Phosphorescence
    • G01N21/6428—Measuring fluorescence of fluorescent products of reactions or of fluorochrome labelled reactive substances, e.g. measuring quenching effects, using measuring "optrodes"
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    • G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
    • G01N21/63—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
    • G01N21/64—Fluorescence; Phosphorescence
    • G01N21/645—Specially adapted constructive features of fluorimeters
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    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/0059—Measuring for diagnostic purposes; Identification of persons using light, e.g. diagnosis by transillumination, diascopy, fluorescence
    • A61B5/0082—Measuring for diagnostic purposes; Identification of persons using light, e.g. diagnosis by transillumination, diascopy, fluorescence adapted for particular medical purposes
    • A61B5/0084—Measuring for diagnostic purposes; Identification of persons using light, e.g. diagnosis by transillumination, diascopy, fluorescence adapted for particular medical purposes for introduction into the body, e.g. by catheters
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    • 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
    • A61B5/14551—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 for measuring blood gases
    • A61B5/14556—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 for measuring blood gases by fluorescence
    • A—HUMAN NECESSITIES
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    • 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
    • A61B5/1459—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 invasive, e.g. introduced into the body by a catheter
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/48—Other medical applications
    • A61B5/4866—Evaluating metabolism
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    • G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
    • G01N21/63—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
    • G01N21/64—Fluorescence; Phosphorescence
    • G01N2021/6417—Spectrofluorimetric devices
    • G—PHYSICS
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    • G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
    • G01N21/63—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
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    • G01N2021/6417—Spectrofluorimetric devices
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Abstract

Un sistema para caracterizar una muestra (101) biológica analizando la emisión de luz fluorescente de la muestra biológica (101) tras la excitación, que comprende: (i) una fuente de láser (100) conectada a una muestra biológica (101) a través de fibras de excitación (ExF), en la que el láser (100 está configurado para irradiar la muestra biológica (101) con un pulso de láser a una longitud de onda predeterminada para causar que la muestra biológica (101) produzca una señal correspondiente de fluorescencia; (ii) fibras colectoras (CF), donde las fibras colectoras (CF) recogen la señal de fluorescencia de la muestra biológica (101), y retransmiten la señal de fluorescencia a un desmultiplexador (104); (iii) un desmultiplexador (104) que está configurado para dividir la señal de fluorescencia de las fibras colectoras (CF) a longitudes de onda predeterminadas; y (iv) un dispositivo de retardo óptico (105); caracterizado porque el desmultiplexador (104) está configurado para dividir la señal de fluorescencia de las fibras colectoras (CF) a longitudes de onda predeterminadas para obtener bandas espectrales de <365 nm, 365-410 nm, 410- 450 nm, 450-495nm, 500-560 nm, 560-600 nm y >600 nm, donde el desmultiplexador (104) comprende un primer dispositivo de división de longitud de onda a aproximadamente >495 nm, un segundo dispositivo de división de longitud de onda a aproximadamente 560 nm, un tercer dispositivo de división de longitud de onda a aproximadamente 600 nm, un cuarto dispositivo de división de longitud de onda a aproximadamente 410 nm, un quinto dispositivo de división de longitud de onda a aproximadamente 450 nm, y un sexto dispositivo de división de longitud de onda a aproximadamente 365 nm, donde la señal de fluorescencia de las fibras colectoras (CF) es dividida por el primer dispositivo divisor de longitud de onda en una señal <495 nm y una señal >495 nm, la señal >495 nm es dividida por el segundo dispositivo divisor de longitud de onda en una señal de 500-560 nm y una señal >560 nm, la señal >560 nm es dividida por el tercer dispositivo divisor de longitud de onda en una señal de 560-600 nm y una señal >600 nm, la señal <495 nm es dividida por el cuarto dispositivo divisor de longitud de onda en una señal <410 nm y una señal de 410-480 nm, la señal de 410- 480 nm es dividida por el quinto dispositivo divisor de longitud de onda en una señal de 410-450 nm y una señal de 450- 495 nm, y la señal <410 nm es dividida por el sexto dispositivo divisor de longitud de onda en una señal <365 nm y una señal de 365-410 nm.

Description

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en relación con el sujeto de control (normal). En algunas realizaciones, una alteración en la señal de fluorescencia de biomoléculas es una disminución en la señal de fluorescencia de biomoléculas en el sujeto en relación con el sujeto de control (normal). En una realización, una alteración en el estado redox de NADH es indicativa de la viabilidad del tejido. En una realización, un aumento en la fluorescencia de NADH en un sujeto es indicativo de la acumulación de NADH y de la mala viabilidad tisular.
La invención también proporciona métodos para monitorear el metabolismo celular en un sujeto que lo necesite, utilizando el sistema descrito en la presente memoria. El método incluye el uso del sistema TR-LIFS aquí descrito para medir la fluorescencia emitida por biomoléculas (por ejemplo, estado redox de NADH) en el que una alteración en la señal de fluorescencia es indicativa del metabolismo celular. En algunas realizaciones, una alteración en la señal de fluorescencia de biomoléculas es un aumento en la señal de fluorescencia de biomoléculas en el sujeto en relación con el sujeto de control (normal). En algunas realizaciones, una alteración en la señal de fluorescencia de biomoléculas es una disminución en la señal de fluorescencia de biomoléculas en el sujeto en relación con el sujeto de control (normal). En una realización, la fluorescencia de NADH puede usarse para monitorear el metabolismo celular. El metabolismo celular puede monitorearse continuamente o periódicamente. En diversas realizaciones, el monitoreo continuo del metabolismo celular permite, por ejemplo, la evaluación de la viabilidad y vulnerabilidad de las células en condición isquémica, los efectos de los fármacos (por ejemplo, durante el desarrollo del fármaco o para optimizar ventanas terapéuticas) sobre el metabolismo celular y/o monitoreo simultáneo del pH y de los niveles de oxígeno para determinar el estado metabólico de la célula.
Como se describe en la presente memoria, la invención también proporciona métodos para detecciones de tumores utilizando sistemas TR-LIFS descritos en la presente memoria.
Ejemplos
Ejemplo 1
Monitoreo continuo del metabolismo celular
Los sistemas descritos en el presente documento permiten el monitoreo continuo de los cambios en el nivel de NADH a escalas muy minuciosas para determinar cambios en el estado metabólico en respuesta al agotamiento de oxígeno, efecto de fármacos neuroprotectores, etc. (Figuras 1 y 5).
La nicotinamida adenina dinucleótido (NADH) está implicada en la reacción redox para la producción de ATP en la respiración aeróbica. NADH se produce en las mitocondrias durante el ciclo de glicólisis y ácido cítrico (TCA). NADH se oxida a NAD+ en la membrana mitocondrial que produce ATP en el proceso. Este proceso se interrumpe en condiciones que incluyen, pero no se limitan a la isquemia debida a accidente cerebrovascular. En una condición de oxígeno bajo, NADH se acumula en la célula, y el agotamiento persistente de oxígeno puede resultar en la muerte celular, llevando a la ruptura completa de NADH. Estas variaciones en el nivel de NADH permiten evaluar la viabilidad y la vulnerabilidad de las células en condiciones isquémicas. Las fluctuaciones en los niveles de NADH pueden evaluarse midiendo la emisión de fluorescencia de NADH. NAD+ y NADH ambos tienen una fuerte absorción en el espectro UV, pero difieren en sus características de fluorescencia. NADH demuestra una fuerte fluorescencia en la banda violeta/azul alrededor de 440/460 nm de longitud de onda dependiendo de su estado enlazado (al citocromo) frente al estado libre. Medir esta fluorescencia en tiempo real permite monitorear los cambios en el nivel de NADH, evaluando el estado metabólico de NADH, monitoreando así el metabolismo celular.
Con el fin de excitar el tejido, se utilizó un láser Nd:YaG de conmutación Q que emite a una longitud de onda de 350 nm, funcionando a 1 KHz con un ancho de pulso (FWHM) de 400 ps (Teem Photonics PNVM02510). La energía total por pulso no excedió 5 μJ lo que impidió el fotoblanqueo de NADH. La luz de excitación se suministró al tejido usando una sonda óptica trifurcada hecha a medida. La sonda constaba de una fibra central de 600 micras para suministrar la luz de excitación rodeada por doce fibras de 200 micras para recoger la fluorescencia (Figura 3). Cada una de las otras fibras de las doce fibras colectoras se agruparon formando dos canales. Un canal/haz de recolección conectado a un espectrómetro (Ocean Optics, Maya), que mide el espectro de fluorescencia cada 100 ms y el otro canal/haz conectado a un divisor de haz (desmultiplexador). El divisor de haz a 452 nm de longitud de onda separó la fluorescencia significativa libre y ligada, que se registró mediante MCP-PMT y un espectrómetro.
El cerebro de conejo se retiró después de sacrificar el animal en el OR y se transportó en una solución fría de Kreb-Ringer rica en oxígeno al laboratorio. La corteza se separó y se colocó en solución de Kreb-Ringer con burbujeo continuo de la mezcla de 95% de O2 y 5% de CO2 para mantener vivo el tejido. La sonda se ajustó en el tejido con el fin de registrar la fluorescencia como se muestra en la Figura 5. Se registró un NADH basal (unido y libre) hasta que la fluorescencia del tejido se equilibró y estabilizó. Después de aproximadamente 30 minutos, se añadió una dosis medida de rotenona 50 nM, que bloquea la unión de NADH al citocromo en la mitocondria. Se añadieron concentraciones adicionales de rotenona cada 10 min.
Se registró el efecto de varias concentraciones de rotenona en el tejido cerebral de conejo (Figura 6). Los resultados mostraron que las concentraciones de ambos NADH, libre y ligado se puede asignar en tiempo real (cada 100 ms) y se registró la respuesta a los estímulos externos. La Figura 6 muestra un gráfico continuo del nivel de fluorescencia de NADH durante un periodo de más de 2 horas. Al añadir la concentración de 50 nM de rotenona a la solución, se observó
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Claims (1)

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US9095414B2 (en) * 2011-06-24 2015-08-04 The Regents Of The University Of California Nonlinear optical photodynamic therapy (NLO-PDT) of the cornea
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