CN101181152A - Method and device for fundus oculi affection early diagnosis using time discrimination autofluorescence lifetime imaging - Google Patents
Method and device for fundus oculi affection early diagnosis using time discrimination autofluorescence lifetime imaging Download PDFInfo
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Abstract
The invention relates to a novel measurement method and the device thereof, which combines the time-resolved self-fluorescence lifetime imaging technology and a laser scanning confocal ophthalmoscope and realizes the early diagnosis of the ocular fundus diseases by obtaining and analyzing the self-fluorescence intensity and the service life information of the ocular fundus. The light which is emitted by a pulse laser is sent to the scanning head of the laser scanning confocal ophthalmoscope to excite the ocular fundus inner-source flgorgen, and the fluorescence which is emitted from the ocular fundus is collected by a time-correlated single photon counter or a high-repetition-rate synchronous scanning camera, so as to realize the service life measurement and the imaging of the self-fluorescence. As the service life of the self-fluorescence of the ocular fundus is very sensitive to the micro-environment and the cell metabolism state of flgorgen molecule and is not affected by the difference of the intensity of the flgorgen of the ocular fundus, the measurement of the fluorescence service life provides a brand new route for the detection of ocular fundus diseases and the obtainment of the function information of ocular fundus. The invention can become the solution and the basis of the early diagnosis of various ocular fundus diseases, which plays an important role in pathogeny research, clinical diagnosis, staging and typing, prognosis judgement, real-time observation and the analysis of the development of ocular fundus diseases, therefore the invention can be widely applied in the field of medical research and clinical medical diagnosis.
Description
Technical field
The present invention is a kind of by measuring and analyze optical fundus using time discrimination autofluorescence lifetime situation of change, realizes the method and apparatus of fundus oculi disease early diagnosis.Contemporary ophthalmology confirms, the autofluorescence life-span is very responsive to the metabolization state of the kind of optical fundus fluorogen and retinal pigment epithelium, when the optical fundus produces abnormality, the change in autofluorescence life-span will be prior to the generation of pathological change form, so the measurement in autofluorescence life-span and imaging can be used as the important evidence that judges whether to produce fundus oculi disease.The present invention is intended to realize obtaining of optical fundus using time discrimination autofluorescence lifetime and space distribution information thereof, will detect and analysis provides important function information for ophthalmology medical science, and be worth having important use aspect medical research field and the clinical diagnose.
Background technology
People's optical fundus exists a large amount of endogenous fluorogens, and they can be produced autofluorescence by the optical excitation of certain wavelength.Some is directly relevant with the generation of retinal diseases in these fluorogens, and for example the generation of particulate accumulation of lipofuscin and age related macular degeneration is contacted directly in the layer of retina,pigment epithelium; Some then reflects the metabolism state of optical fundus cell by the emitted fluorescence information indirect.Therefore differentiate these fluorochromes groups and understand the situation of change of its microenvironment state of living in, significant to the diagnosis of fundus oculi disease.
Though the fluorescence spectrum technology is used widely in biomedical research and clinical diagnosis field, but do not possess higher spatial resolution by the method that selective exitation is composed or relatively the characteristics of emission spectra are carried out the endogenous fluorogen discriminating in optical fundus, and more weak fluorescence information is easy to be covered by stronger background.The relaxation time of processes such as autofluorescence life-span and cancellation, diffusion is similar, all has its different separately life-span characteristics when different electronics is in its excited state, and can not be subjected to the influence of the non-fluorescent material absorption spectrum in optical fundus.Therefore by the measurement of fluorescence lifetime, can as pH value and oxygen pressure etc., carry out the measurement of high-space resolution, realize the accurate discriminating of fluorogen component the metabolism physiological parameter of optical fundus cell microenvironment of living in.
The confocal ophthalmoscope of laser scanning is the technology that is used to measure fundus oculi disease that occurs over nearly 10 years, and it is with focussed laser beam pointwise high-velocity scanning optical fundus, and measures the light from the point of irradiation reflected back, thereby reconstructs the image on optical fundus.Owing to adopt point-to-point measurement, and utilize confocal pinhole to stop to fall scattered light, therefore have certain chromatography resolution capability.Whether this method can be checked out each tissue of ophthalmic, normal as each hyaline tissue of matter between optic nerve, retina, choroid and refraction of eye.But because limited to the amplification of fundus image, make that producing the trickle change at initial stage in disease can not observe very clearly, and at the initial stage of disease, the variation of fundus tissue form is not obvious often or be difficult to measure.Therefore, seek a kind of brand-new formation method that optical fundus details, especially function information can accurately be provided, become modern ophthalmology medical science and clinical problem demanding prompt solution in order to the early diagnosis of realizing fundus oculi disease.The present invention combines autofluorescence life-span imaging technique with confocal scanning laser ophthalmoscope, realize the measurement of optical fundus autofluorescence life-span imaging, for the early diagnosis of fundus oculi disease provides new method and foundation.
Summary of the invention
The present invention will be by the particular design of light path system, mechanical system and electronic system, with time correlation single photon counter or scanning camera and the coupling of laser scanning co-focusing ophthalmoscope, when utilizing ophthalmoscope that patient is carried out examination of ocular fundus, be obtained from the body fluorescence signal.Adopt the time domain approach measurements and calculations life-span, utilize computer processing system to obtain optical fundus time resolution autofluorescence image, and scan the fundus reflex image formation comparative information that ophthalmoscope produces with confocal laser.
The present invention utilizes illustrating as shown in Figure 1 of burnt Oph principle of time correlation single photon counter coupled laser scanning copolymerization and device.Device mainly is made up of high repetition frequency ultrashort pulse laser 101, doubler 102, photodiode control unit 105, laser scanning co-focusing ophthalmoscope 106, dichroic mirror 107, edge filter 108, microchannel plate photomultiplier tube 109, preamplifier 110, time correlation single photon counter 111, photomultiplier tube 112 and computer processing system 113 etc.
The present invention utilizes illustrating as shown in Figure 3 of burnt Oph principle of scanning camera coupled laser scanning copolymerization and device.Device mainly is made up of high repetition frequency ultrashort pulse laser 301, DISCHARGE PULSES EXTRACTION device 302, doubler 303, optical-electrical converter 306, delayer 307, laser scanning co-focusing ophthalmoscope 308, dichroic mirror 309, edge filter 310, picosecond streak camera 311, CCD camera read-out system 312, photomultiplier tube 313 and computer processing system 314 etc.
The present invention adopts high repetition laser, as titanium gem locked mode femto-second laser or other high repetition frequency femtosecond or picosecond laser or the laser diode laser instrument excitation source as optical fundus time resolution autofluorescence measuring system.Its spectral region is the also wavelengthtunable of fixed wave length both, and wavelength allows excursion 400-1000nm.According to selecting different wave length can carry out the detection (laser as the short wavelength is fit to observe retina top layer and vitreous body, and long wavelength's laser then is used to check retina deep layer and choroid) at optical fundus different depth and position.
The present invention has adopted the DISCHARGE PULSES EXTRACTION device in high repetition frequency ultrashort pulse laser such as femtosecond laser light path, the ultrashort pulse repetition rate of high repetition frequency ultrashort pulse laser such as ti sapphire laser output is reduced, and the fluorescence lifetime scope that can survey can be from picosecond to the microsecond level.
After the present invention adopted doubler that the light pulse of low-repetition-frequency is passed through, wavelength became original half, with autofluorescence at the bottom of the one-photon excitation mode exciting eye.
The present invention utilizes beam splitter that laser beam is divided into two, a branch of input autofluorescence lifetime measurement system, the Oph light source irradiation eyeball of another Shu Zuowei confocal laser scanning.
The present invention utilizes photodiode control unit to realize vitals in the time correlation single photon counter---the time width of cloth transducer triggering, triggering mode is the inversion pulse reference mode, this pattern can be guaranteed photon count rate efficiently.
The present invention utilizes a dichroic mirror that optical fundus autofluorescence signal is separated from the fundus reflex optical signal, achieves the contrast imaging of time resolution autofluorescence and fundus reflex light.
The present invention adopts the sniffer of highly sensitive microchannel plate photomultiplier tube as fluorescence signal, utilize the detection of characteristics such as its time response is fast, spatial resolving power is high, the single photon counting ability is strong to single photon, realization is to the high sensitivity detection of small-signal, and result of detection is input to the time correlation single photon counter, the triggering state of width of cloth transducer during end.
The present invention adopts preamplifier that the fluorescence signal of input microchannel plate photomultiplier tube is amplified in advance, not only can effectively amplify and the high speed output signal, and can reduce noise and pile up, and provide input protection to prevent overload.
The present invention adopts the scan converter and the ramp voltage scanning circuit of particular design, can under the repetition rate of≤1MHz, work, and can under identical repetition rate, send ramp voltage pulse, thereby can provide different temporal resolutions and different time-quantum methods with Different Slope.
The present invention realizes the high sensitivity detection to small-signal by image enhancement technique, efficiency light coupling technique and synchronous scanning mode of operation.
The present invention adopts the optical system of particular design or light cone to realize that the efficiency light between synchronous scanning image converter tube fluorescent screen and the CCD read-out system is coupled.Can monitor and write down data messages such as the fluorescence spectrum of sample and time-resolved fluorescence intensity in real time by the real-time read-out system of CCD camera.
The present invention utilizes Multiple-Index Model to fit the fluorescence information of each pixel in the optical fundus time resolution autofluorescence image, utilizes the different life-span distribution situation of pseudo-colours mark.
The present invention utilizes optical fundus autofluorescence and reflected light imaging method simultaneously, and retinal vessel net distribution in the reflected image is corresponding with optical fundus autofluorescence life diagram picture, in order to proofread and correct the error that causes owing to the eyeball fine motion in the examination of ocular fundus process.
Description of drawings
The measuring method and the device sketch map thereof of the burnt ophthalmoscope one-photon excitation of Fig. 1 time correlation single photon counter coupled laser scanning copolymerization fluorescence lifetime.
The measuring method in Fig. 2 time correlation single photon counter coupled laser scanning burnt ophthalmoscope two-photon fluorescence excitation life-span of copolymerization and device sketch map thereof.
Burnt ophthalmoscope one-photon excitation fluorescence lifetime measurement method of Fig. 3 scanning camera coupled laser scanning copolymerization and device sketch map thereof.
Burnt ophthalmoscope two-photon fluorescence excitation lifetime measurement method of Fig. 4 scanning camera coupled laser scanning copolymerization and device sketch map thereof.
The specific embodiment
Be described in further detail below in conjunction with the enforcement of accompanying drawing technical scheme.
Among Fig. 1, by high repetition frequency ultrashort pulse laser such as titanium gem locked mode femto-second laser 101, the near-infrared ultrashort pulse of output is through behind the doubler 102, by being divided into two bundles behind the beam splitter 104, wherein the energy of a branch of light is lower, after photodiode 105 detections, the single photon counter 111 of being correlated with input time.This bundle synchronizing signal triggers the time width of cloth transducer of 111 inside with the inversion pulse reference mode, produces a high level and as the beginning of timing.A branch of in addition light is main beam, and the probe with the confocal ophthalmoscope 106 of optical fiber 103 input laser scannings is focused to the scanning that any is used to finish each position, optical fundus on the optical fundus, realizes the autofluorescence measurement of one-photon excitation optical fundus.Light pulse arrives the maximum radiant energy of cornea less than the maximum exposure amount that allows.Optical signal from the confocal ophthalmoscope output of laser scanning after dichroic mirror 107 beam split, separates the autofluorescence signal with reflected light signal.Each part light is all imported different detectors respectively by optical fiber.Reflected light signal is collected by photomultiplier tube 112 and is used for subsequently reflected light imaging 114; After the autofluorescence signal then amplifies in advance via edge filter 108,109 detections of microchannel plate photomultiplier tube, preamplifier 110, the single photon counter 111 of being correlated with input time.The microchannel plate photomultiplier tube can only be surveyed a photon at every turn, and the triggering state of width of cloth transducer when being finished by this photon signal, promptly becomes low level by high level.Be subjected to the time that pulsed light excites back fluorescent photon arrival 109 by a large amount of measurements optical fundus, thereby obtaining the attenuation law of fluorescence intensity.The imaging deviation that causes for the fine motion when the illumination of compensation eyeball, the imaging simultaneously of time resolution autofluorescence and fundus reflex light, and be that standard is corresponding with optical fundus life-span image result with retinal vessel net distribution in the reflected image, promptly when the imaging of record reflected light, the displacement vector that eyeball moves is calculated and is used for the calibration of fluorescence lifetime imaging process by computer 113.With such method, the time mutually in each time channel of light single photon counter the record of photon will proofread and correct and be the initial condition of eyeball before being moved.Based on the number of photon in each passage, will obtain the autofluorescence life-span of each position, optical fundus as 115.
Among Fig. 2, as excitation source, directly enter measuring system and then can realize the autofluorescence life-span imaging of one-photon excitation optical fundus by the near-infrared ultrashort pulse of picosecond pulse laser device 201 output.
Among Fig. 3, behind the near-infrared ultrashort pulse process DISCHARGE PULSES EXTRACTION device 302 by high repetition frequency ultrashort pulse laser such as 301 outputs of titanium gem locked mode femto-second laser, repetition rate drops to≤1MHz from 76MHz.The light pulse of low-repetition-frequency is by behind the doubler 303, wavelength becomes original half, be divided into two-beam by fiber-optic transfer and by beam splitter 305, wherein the energy of a branch of light is lower, be used to trigger quick photodetector 306, behind delayer 307, be input to the scanning circuit of scanning camera 311 in order to the driver sweep camera; A branch of in addition light is main beam, directly imports the probe of the confocal ophthalmoscope 308 of laser scanning, realizes the one-photon excitation of optical fundus autofluorescence.Optical signal from the confocal ophthalmoscope output of laser scanning after dichroic mirror 309 beam split, separates the autofluorescence signal with reflected light signal.Reflected light signal is collected by photomultiplier tube 313 and is used for subsequently reflected light imaging 315; The one-dimensional space information of autofluorescence focuses on the slit of scanning camera, when scanning camera works in the dynamic scan pattern, just can obtain the scanogram of the optical fundus one-dimensional space on fluorescent screen.Scan the optical fundus successively, just can obtain the fluorescence decay curve of two-dimensional space and form fluorescence lifetime image 316.By the optical system of particular design or the coupling of light cone realization synchronous scanning image converter tube fluorescent screen and CCD camera 312.By this real-time read-out system and computer processing system 314, can proofread and correct the error that causes owing to the eyeball fine motion in the examination of ocular fundus process in real time.
In the system shown in Figure 4, behind the near-infrared ultrashort pulse process DISCHARGE PULSES EXTRACTION device 402 of high repetition frequency ultrashort pulse laser 401 outputs,, directly enter measuring system and then can realize the autofluorescence life-span imaging of two-photon excitation optical fundus without doubler.
In sum, the present invention is system coupled with advanced time-domain fluorescent lifetime measurement with traditional laser scanning co-focusing ophthalmoscope, obtain optical fundus autofluorescence intensity and life-span image information, be various fundus disease such as age-related macular degeneration at present, the special property sent out macular hole, central serous chorioretinopathy, the early diagnosis problem of multiple heritability retinopathy etc. has proposed solution and foundation, to comprising etiological study, clinical diagnosis, typing by stages, prognosis is judged, observe and analyze the optical fundus PD at body in real time and all play an important role, can be widely used in medical research field and clinical diagnose aspect.
Claims (21)
1. method and apparatus that using time discrimination autofluorescence lifetime imaging is used for fundus oculi affection early diagnosis.It is characterized in that time-domain fluorescent lifetime measurement and the confocal ophthalmoscope coupling of laser scanning, the new device that is used to observe optical fundus information and realizes the fundus oculi disease early diagnosis.This system separates the fundus reflex light that measures simultaneously with autofluorescence, be sent to respectively in video monitor and the fluorescence lifetime imaging system after being collected by different detectors, and utilize computer processing system that the autofluorescence life diagram is looked like to proofread and correct.
2. method according to claim 1, it is characterized in that the time-domain fluorescent lifetime measurement system that is adopted is made up of ultrashort pulse femto-second laser, DISCHARGE PULSES EXTRACTION device, doubler and high repetition frequency psec synchronous scanning camera system etc., the optical fundus fluorogen is adopted one-photon excitation.
3. method according to claim 1 is characterized in that the time-domain fluorescent lifetime measurement system that is adopted is made up of ultrashort pulse femto-second laser, DISCHARGE PULSES EXTRACTION device and high repetition frequency picosecond streak camera system etc., and the optical fundus fluorogen is adopted two-photon excitation.
4. method according to claim 1 is characterized in that the time-domain fluorescent lifetime measurement system that is adopted is made up of high repetition laser and time correlation single photon counter etc.
5. method according to claim 4 is characterized in that used high repetition laser, can be femto-second laser both, is used for the two-photon excitation of optical fundus fluorogen, can be the picosecond pulse laser device also, is used for the one-photon excitation of optical fundus fluorogen.
6. according to claim 2 and 3 described methods, it is characterized in that both also wavelengthtunables of fixed wave length of laser optical spectral limit, wavelength allows excursion 400-1000nm, according to selecting different wave length can carry out the detection at optical fundus different depth and position.
7. according to claim 2 and 3 described methods, it is characterized in that adopting the DISCHARGE PULSES EXTRACTION device in the high repetition laser light path, the ultrashort pulse repetition rate that high repetition laser is exported drops to 50kHz-1MHz from 50MHz-500MHz.
8. method according to claim 1 is characterized in that adopting time correlation single photon counter, gate image intensifier, gate CCD camera or picosecond streak camera to carry out the time domain measurement of fluorescence lifetime.
9. method according to claim 4 is characterized in that adopting highly sensitive microchannel plate photomultiplier tube to survey the single photon signal of autofluorescence, realizes the high sensitivity detection to small-signal.
10. method according to claim 4; it is characterized in that amplifying in advance, not only can effectively amplify output signal, improve output speed with the fluorescence signal of a preamplifier to input microchannel plate photomultiplier tube; reduce noise and pile up, and can provide input protection to prevent overload.
11. according to claim 2 and 3 described methods, it is characterized in that the ultrashort pulse that utilizes beam splitter that light source is sent is divided into two different bundles of energy, be respectively applied for scanning camera synchronously and the exciting of optical fundus fluorogen.
12. method according to claim 4 is characterized in that the ultrashort pulse that utilizes beam splitter that light source is sent is divided into two different bundles of energy, is respectively applied for the triggering of time correlation single photon counter.
13., it is characterized in that the lower a branch of light pulse of energy is by the relevant single photon counter of entry time behind the photodiode control unit, as the start trigger pulse of time correlation single photon counter according to right 12 described methods.
14. according to claim 4,13 described methods, it is characterized in that single photon signal that the microchannel plate photomultiplier tube is detected termination trigger impulse as the time correlation single photon counter, in conjunction with claim 12 described formation inversion pulse reference modes, guarantee photon count rate efficiently
15. method according to claim 1, the light pulse that it is characterized in that entering the confocal ophthalmoscope probe of laser scanning focuses on the back through pointing instrumentation and is imported by 10 micron fiber.
16., it is characterized in that utilizing dichroic mirror that the optical fundus autofluorescence is separated with reflected light according to claim 2,3 and 4 described methods.
17., it is characterized in that the synchronous scanning image converter tube has the long-pending photocathode of large working area according to claim 2 and 3 described methods, have the electron-optical focusing system of good picture element and little time distortion, have the deflection system that satisfies the requirement of broad beam picture element.
18., it is characterized in that adopting the real-time read-out system of CCD, and the optical coupling between read-out system and the synchronous scanning image converter tube in real time or realize by optical lens or by light cone according to claim 2 and 3 described methods.
19., it is characterized in that isolated autofluorescence signal is by input microchannel plate photomultiplier tube behind the edge filter according to claim 1 and 16 described methods.
20. according to claim 1,2,3 and 4 described methods, it is characterized in that the reflected light and the imaging respectively of time resolution autofluorescence of optical fundus same position, when the imaging of record reflected light, the displacement vector that eyeball moves is noted down and is used for the calibration of fluorescence lifetime imaging process by computer data processing system.
21. method according to claim 1 is characterized in that the fluorescence information of each pixel in the optical fundus time resolution autofluorescence image utilizes Multiple-Index Model to fit.
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