FR3089629A1 - Device for measuring the state of organization of collagen fibrils in corneal tissue and associated measurement method - Google Patents

Abstract

The invention relates to a device for measuring (1) a state of organization of collagen fibrils in a corneal tissue comprising- a light source (3) adapted to emit light towards a cornea (5) , - a spatial filtering system (9) arranged on the path of the light scattered by the cornea (5) and configured to select an observation zone (ZO) of the cornea (5), - a spectral detector (11) of the light scattered by the observation zone of the cornea and configured for detection at large angles of scattering, the light source (3) and the spectral detector (11) being configured so that the wavelength of observation is included in one of the following wavelength ranges: (390nm- 430nm), (470nm-490nm), (500nm-525nm), (540nm-590nm), - a processing unit (13) configured to correlate the measurement from the spectral light detector (11) with an organized state of collagen fibrils. Figure to be published with the abstract: Fig. 7

Description

Description

Title of the invention: Device for measuring the state of organization of collagen fibrils in corneal tissue and associated measurement method

The present invention relates to a device for measuring the state of organization of collagen fibrils in corneal tissue and an associated measurement method.

Figure 1 presents a photo according to a histological section of the human cornea with the epithelium Cl, the Bowman C2 membrane, the stroma C3, the Descemet D4 membrane and the endothelium D5.

The cornea of the eye of a living being is transparent to light in order to let outside light pass inside the eye to be detected by photoreceptor cells of the retina.

However, during life, this transparency can be altered, for example by the development of certain pathologies or by lesions. In particular, the formation of edema can lead to swelling and then clouding of the cornea, which tends to decrease or even destroy the visual acuity of a living being concerned.

Multiple studies have been conducted to understand this phenomenon of clouding and have found that clouding of the corneal tissue generally results from an increase in the scattering of light in the cornea. In fact, when the cornea is healthy, collagen fibrils in the stroma C3 have a very organized structure which, by destructive interference mechanisms, makes it possible to prevent light scattering phenomena and therefore form an essential element for ensuring the corneal transparency.

These collagen fibrils are housed in lamellae in the corneal stroma C3 which represents most of the thickness of the cornea. For the human eye, collagen fibers are about 36nm in diameter grouped in lamellae parallel to the surface of the cornea. The stroma C3 contains more than 200 lamellae 1 to 2pm thick each.

The arrangement of the fibers in a given strip is very ordered forming parallel columns and regularly spaced about 40nm for the human eye. It is this ordering that gives the cornea its clarity, solidity and shape.

These observations have already been noted in the article by Maurice D.M. (1957) "The structure and transparency of the cornea. "J. Physiol. 136,263-286, who presented initial calculations concluding that the cornea would not be transparent if the fibrils were arranged completely randomly. In his work, he concluded that the transparency of the cornea results from the ordered structure / organization of the fibrils creating destructive interference for light passing through the cornea in all directions except for light transmitted forward.

The article "Wavelenght dependencies of light scattering in normal and cold swollen rabbit corneas and their structural implications", Larrel, et al. J. Physiol. (1973), 233, pp. 589-612. describes light scattering studies on edematous corneas of rabbits. This article highlights that inhomogeneities in the structure of the lamellae cause an increase in diffusion and therefore a loss of transparency. This study highlights in particular measurements of light transmission through the cornea, measurements which can only be practiced on a cornea taken extracorporeally.

Although these articles show qualitatively and according to an overall observation a causal link between the disorganization of the fibrils in the cornea and the transparency of the cornea, no study has succeeded in precisely quantifying this dependence.

Indeed, the link between the diffusion and the disorganization as a function of the wavelength is not direct. In the aforementioned articles, simplifying hypotheses show a spectral variation of the diffusion in l / λ ³ or l / λ ² depending on whether the cornea is edematous or not. However, a study of the inventors of the present invention has shown that this variation is not as simple.

Furthermore, it would be advantageous to have a device making it possible to quantitatively measure a state of organization of collagen fibrils in a coma tissue, in particular in vivo. A better understanding of this state of organization would allow an ophthalmologist, for example, to make a more precise diagnosis on the pathology of his patient and to plan more suitable treatments.

Indeed, in monitoring, an ophthalmologist could follow the degradation or not of the transparency of the cornea of his patient, this at an early stage which would allow him to prescribe a treatment before the lesions or pathology are no longer curable and thus avoid having to perform a transplant.

Furthermore, after a corneal injury or, for example, a surgical intervention, the ophthalmologist would have a possibility of more precisely monitoring the recovery of his patient and the healing progress of the cornea.

To this end, the invention aims to provide a device for measuring the state of organization of collagen fibrils in a coma tissue and an associated measurement method.

More specifically, the invention relates to a device for measuring a state of organization of collagen fibrils in a coma tissue comprising

- a light source suitable for emitting light towards a cornea,

- a spatial filtering system arranged on the path of the light scattered by the cornea and configured to select a corneal observation area,

- a spectral detector of the light scattered by the observation zone of the cornea and configured for detection at large angles of scattering, the light source and the spectral detector being configured so that the observation wavelength is within one of the following wavelength ranges: (390nm- 430nm), (470nm-490nm), (500nm-525nm), (540nm-590nm),

- a processing unit configured to correlate the measurement from the spectral light detector with an organized state of collagen fibrils.

Thanks to the device according to the invention, there is a fine gradation of the disorganization of the fibrils.

The invention may have one or more of the following aspects taken alone or in combination:

In one aspect, the observation wavelength is within one of the following wavelength ranges: (390nm- 415nm), (475nm-485nm), (505nm-515nm), (545nm-575nm) .

In another aspect, the observation wavelength is in the wavelength range of (545nm-575nm), in particular between 550 and 560nm, more specifically at 555nm.

The spatial filtering system is configured for observation of an observation zone of the cornea.

The light source comprises for example a laser, in particular a monochromatic laser.

The spectral detector comprises for example a photodetector as well as a monochromator element and is configured to select the light scattered at the scattering angles between 30 ° and 70 °.

The monochromator element can include a band pass interference filter or a spectrometer.

The processing unit is in particular configured to graduate the state of organization between 100% disorganized for a set of lamellas of fibrils arranged completely randomly and 0% for a set of lamellas of fibrils arranged perfectly organized.

In another aspect, the processing unit is calibrated on the basis of a digital light scattering model taking into account multilayer stacks of lamellae having a thickness of between 1.5 and 2.5 μm, in particular equal at 2pm thickness and presenting organizational states between 100% and 0%.

The invention also relates to a method for measuring the state of organization of collagen fibrils in a corneal tissue in which

- we illuminate an area of observation of a cornea,

- the light scattered at wide angles is detected by the observation zone of the cornea and at an observation wavelength within one of the following wavelength ranges: (390nm- 430nm), (470nm-490nm ), (500nm-525nm), (540nm-590nm,

- and the measurement of the scattered light is correlated with a state of organization of collagen fibrils.

In one aspect, the observation wavelength is within one of the following wavelength ranges: (390nm- 415nm), (475nm-485nm), (505nm-515nm), (545nm-575nm ).

In another aspect, the observation wavelength is in the wavelength range of (545nm-575nm), in particular between 550 and 560nm, and more specifically at 555nm.

We detect in particular the light scattered at wide angles on scattering angles in particular between 30 ° and 70 °.

According to yet another aspect, a degree of disorganization of the lamellae of fibrils is measured according to a gradation of the state of organization of between 100% disorganized for a set of lamellae of fibrils arranged completely randomly and 0% for a set of strips of fibrils arranged in a perfectly organized manner.

The graduation is for example calibrated on the basis of a digital light scattering model taking into account multilayer stacks of lamellae having a thickness between 1.5 and 2.5 pm, in particular equal to 2 pm thickness and having organizational states between 100% and 0%.

The invention will be described in detail with reference to the following appended figures showing one or more exemplary embodiments of the present invention:

[Fig.l] presents a photo according to a histological section of the human cornea,

[Fig-2] shows an example of a part of a coverslip containing completely organized fibrils constructed from MET images,

[Fig-3] shows an example of a part of a coverslip containing completely disorganized fibrils constructed from MET images,

[Fig-4] shows an example of a stack of disorganized stroma 20% lamellae,

[Fig.5] represents on a graph the diffusion at large angles of diffusion as a function of the wavelength of various models of comean tissue having different states of organization,

[Fig.6] represents on a graph the scattering at large scattering angles as a function of the state of disorganization of a comean tissue model at a wavelength of 555nm,

[Fig.7] shows according to a block diagram an exemplary embodiment of a measuring device according to the invention,

[Fig.8] shows a flow diagram of an exemplary embodiment of a measurement method according to the invention.

Throughout the description, the same elements are indicated by the same reference numbers.

The following embodiments are examples. Although the description refers to one or more embodiments, this does not necessarily mean that each reference relates to the same embodiment, or that the characteristics apply only to a single embodiment. Simple features of different embodiments can also be combined or interchanged to provide other embodiments.

The work leading to the present invention started from the observation that overall, the diffusion of a corneal tissue having disorganized fibrils is greater than that of a corneal tissue with perfectly organized fibrils as shown by prior art studies cited above.

Starting from this observation, the inventors took as a starting point a model of light scattering by the cornea exposed in the thesis of Olivier Casadessus defended on December 7, 2012 at the University of Aix-Marseille and cited by reference. During this thesis, studies were carried out to characterize the development of edema in human corneal grafts, in particular by angularly analyzing the intensity of the light scattered by the grafts. More specifically, experiments have been able to show a link between the increase in light scattering on the one hand and that in the thickness of a corneal graft on the other hand.

In chapter 4, this thesis describes an electromagnetic modeling of the interaction mechanisms between light and the cornea. This modeling is based on an approach where to calculate the scattering by a medium having different layers, we calculate the scattering obtained in the case where a single layer is inhomogeneous, in terms of refractive index and we then sum the electromagnetic field obtained for each layer separately. In this thesis, we do not take into account for the modeling of a state of organization or disorganization of fibrils. Experiments have been carried out which have demonstrated that the electromagnetic modeling used makes it possible to describe the scattering of light. In particular, the scattered light intensity calculated using the simulation is in agreement with the angularly resolved intensities actually measured during experiments. The variation in light scattering has been attributed in particular to the formation of lakes in the stroma and the heterogeneities induced by them in the stroma which have been observed by coherence tomography and the systematic presence of which has been observed for thicknesses. stroma exceeding 800pm. However, this work could not quantitatively link the state of disorganization of the fibril strips to the scattered light.

For reasons of simplification and in agreement with experimental and theoretical observations of Casadessus, we limit ourselves in the present invention to looking only at the scattering at large scattering angles, that is to say the light scattered between 30 ° and 70 ° and only the contribution of the stroma, the thickness of which is most important for a cornea, is taken into account. Thus, the surface contributions could have been neglected and only the volume scattering ("bulk scattering" in English) is taken into account. In the modeling, a maximum refractive index n max = l-41 which corresponds to the refractive index of collagen fibrils, and a minimum refractive index n _min = 1.36 which corresponds to the refractive index of the matrix housing the fibrils, were used.

For a realistic modeling of the corneal tissue, the results use MET images available in the literature ("Meek 2003," Tranparency, swelling and scarring in the corneal stroma. EYE, 17,927-936). In addition, these images being representative of a very small area of the tissue, the modeling was chosen to combine different images to obtain models of lamellae of fibrils perfectly organized on the one hand and perfectly disorganized on the other hand with a thickness of 2 pm are the basis of the results.

FIG. 2 shows an example of a part of a coverslip containing completely organized fibrils constructed from MET images (Transmission electron microscopy or “TEM” for Transmission Electron Microscopy in English) and FIG. 3 shows an example of a part of a coverslip containing completely disorganized fibrils constructed from TEM images.

Then, from these individual lamellae, stacks of 25 lamellae of fibrils were created so that a stack has a thickness of about 50 μm. This corresponds to about 10% of the thickness of the stroma and is representative enough to characterize the light scattered by the entire stroma.

The stacking of the lamellae was carried out randomly to avoid problems of periodicity in the calculations. 25 different stacks were created. For stacking with perfectly organized fibrils (organized tissue or 0% disorganized) only the lamellae with perfectly organized fibrils were used. For a stack with perfectly disorganized fibrils (100% disorganized), only the strips with perfectly disorganized fibrils were used.

For intermediate stacks, a perfectly organized fibril lamella was gradually replaced by a perfectly disorganized fibril lamella starting from the posterior part towards the anterior part to mimic the growth of real edema.

Thus, a “4% disorganized” stack comprises 24 strips with perfectly organized fibrils and a single strip with perfectly disorganized fibrils. A 20% disorganized stack comprises 20 strips with perfectly organized fibrils and 5 strips with perfectly disorganized fibrils.

Figure 4 shows an example of a 20% disorganized stack. In this figure L _X ^A represents a lamella where A = O for "Organized", that is to say a lamella with perfectly organized fibrils as in FIG. 2 or A = DO for "Disorganized", that is ie a coverslip with perfectly disorganized fibrils as in Figure 3 and x = 1,2,3 corresponds to one of the three coverslips created from MET images. For this figure 4, only 13 out of the 25 LX ^A lamellae have been represented, all the lamellae not shown are Lx ° lamellae.

Starting from this model, the inventors calculated for different wavelengths the total integrated intensity (TIS for “Total integrated scattering” in English) for scattering angles between, for example, 30 ° and 70 °. Of course, a wider or more restricted range of diffusion angles could have been chosen (for example 25 ° to 75 ° or 45 ° -65 °, or 40 ° to 50 °) without departing from the scope of the present invention. In choosing this range, it is only important that the scattering of surface light can be neglected.

The result of this calculation is shown in FIG. 5 which represents on a graph the scattering at large angles as a function of the wavelength of various models of comean tissue having different states of organization.

The values plotted in FIG. 5 are shown in the following tables:

[Tables 1]

tough TJSpour TiS for TJS.p-Oüf. ' BS for BS for BS for Fabric fear BS for BS for • d ^! 'wave TiïSU fabric 4% fabric S% fabric 12% fabric 15% fabric 20% 24% tïssu2S% fabric 32% (nm) G.F “5n.S.5é disorganized disorganized desGfjgsRésés desGfgsnïse disorganized disorganized disorganized disorganized ¢ 32.3 0.0755 0.0823 C $ 0803 0.0824 0.0773 C $ GSO4 5.0733 9.GSÎ3 9.0738 5-83 ¢ 1 0.0955 0.0938 0.037 0.0351 3.0354 0.093 0.192 0.1 555 0.0646 0.0668 0.0676 0.0747 0.0355 0.0905 0.0934 oaoz 0.10 = .532 a, 0599 G .. 105 S, 106 3.11 0.114 0.117 ¢ 113 C $ 117 ¢ 118 5il 0.164 0.265 0.163 0.151. 0.163 0.153 ¢ 157 9.158 47S 0.107 0.4G7 0.11 water 0.113 0.114 0.117 0.117 445 9,176 0.188 0.187 0.19 0.185 0.135 0.182 0.185 0.184 33S 0.217 3.22.7 _ G, 253 0.249 _ ¢ 263 g; 278 g; 294

[Tables!]

wavelength (nm) τ-s for 36% disorganized tissue TiS for tissue 40% disorganized TiS for disorganized tsssu44% TiS for 43% disorganized tissue TSS for 52% disorganized tissue TiS for woven. 56% disorganized TiS for disorganized 6’3% tissue TiS for disorganized dssu64%: TiS for woven 68% disorganized 532.8 0.0793 0..0SS9 0.0796 0.0007 0.0S 0.0854 ¢ 0082 0.0835 0.0852 .583 0.101 9,106 0.104 0.109 0.11 ¢ 115 0.115 0.114 0.119 555 0.0974 ¢ 102 0.103 O.WB 0.114 0.1.24 0.128 0.132 0.137 532 0.112 0.1.13 0.114. 0.116 0.115 0.117 0.12 0.118 ¢ 119 511 0.151 ¢ 153 3.154 0.157 G, 149 0.151 0.153 0.145 0.147 478 0.12 0.121 0.121 G, 122 0.125 0.126 3.128 0.129 0.13 445 0.181 0.184 ¢ 183 0.185 ¢ 103 at 286 ^: 0.187 0.182 0.185 130 0.291 ¢ 298 0.303 0.31 ¢ 317 0.324 > 3.34 0.386 0.343

[Tables3]

waveguide TiS poür assü 72% disorganized TiS for 76% disorganized tissue TIS for 88% disorganized tissue TJS for disorganized S4% tissue US for disorganized S8% tissue TÎS for 92% disorganized tissue TÎS for 95% disorganized tissue T! S for 105% disorganized fabric 632.3 0..GS35 0.6855 0.6848 0.6823 ' Û.O798 8.0823 539 6.117 6.12 0.123 0.121 '0.128 0.127 '0.127 6.132 555 G..13S 0.145 0.148 0.157 0.158 0 162 0.167 6.171 532 6.12 0.125 0.121 0.126 0.126 0 12 ^ : 0.126 6.12.8 521 6.148 0.152 0.143 0.147 G 147 0.1.39 0.241 6.143 478 6.131. 0.134 0.135 Ü.12S 0.138 .133 0.141 6.142 445 6.182 0.183 0.186 0.188 0.182 0, -83 0.186 330 6.349 6.364 0.362 Ü..377 .0.386 0.382 0.39?

It can be seen in this FIG. 5 that for a stack of lamellae with perfectly organized fibrils, the integrated diffusion over the large diffusion angles (TIS) has oscillations as a function of the wavelength. These oscillations decrease as the number of disorganized fibril lamellae increases. In addition, we note that the impact of the state of disorganization of the fibrils is greater for certain wavelengths.

Indeed, for certain wavelength ranges, such as for example one of the following wavelength ranges: (390nm- 430nm), (470nm-490nm), (500nm-525nm), (540nm-590nm ), more specifically the wavelength ranges (390nm- 415nm), (475nm-485nm), (505nm-515nm), (545nm-575nm), and more particularly the wavelength range of (545nm-575nm ), especially between 550 and 560nm, more specifically at 555nm, it can be seen that the scattering of light at large angles, in particular between 30 ° and 70 ° has a significant dependence on the state of disorganization of the fibrils.

It is this important dependence and updated by the inventors by their specific work on the state of organization of the fibrils which can be used to measure in a quantified manner the state of organization of the fibrils in the cornea, this thanks to a judicious choice of wavelength ranges deduced from the results of the work presented in FIG. 5.

FIG. 6 for example shows in detail the TIS ("total integrated scattering") normalized diffusion compared to the TIS diffusion of a perfectly organized corneal tissue.

As a first approximation, for a wavelength of 555nm, we see that the diffusion increases in a quasi-linear way (see the straight line DL in dotted lines in FIG. 6) between a state of organization "0%" ( perfectly organized fibrils) and "100%" (perfectly disorganized fibrils) by a factor of 2.6.

This relationship, for a given wavelength, either in the form of the exact curve or in the form of a simplified linear relationship (straight line DL) therefore makes it possible to quantitatively measure the state of disorganization of the fibrils in the cornea, that is to say, according to an example of an assembly of a measuring device which will be detailed later, by measuring the diffusion at large angles, determine the state of organization of the fibrils in cornea. Such a measurement is non-intrusive and can be carried out in vivo. From the measurement and a quantified state of organization of the fibrils in the patient's cornea, the doctor, in particular the ophthalmologist, is able to more easily make a diagnosis on the cornea of his eye. patient and consider, if necessary, a treatment that is necessary to improve the patient's vision.

According to another application, the doctor can select from several corneal grafts the one which presents for example the best state of organization of the fibrils to give the most success possible during a corneal transplant.

Figure 7 shows an example of a device 1 for measuring the state of organization of collagen fibrils in a coma tissue.

This device comprises a light source 3 adapted to emit light towards a cornea 5, for example of an eye 7 of a patient shown diagrammatically in FIG. 7.

The light source 3 can for example be a laser or a polychromatic source with a broad spectrum of light emission, for example a halogen lamp.

On the path of the scattered light is placed a spatial filtering system 9, for example a diaphragm, for example in the form of a slot configured to select an observation zone ZO of the cornea 5.

Then the measuring device 1 comprises a spectral detector 11 of the light scattered by the observation zone ZO of the cornea 5, this detector is configured to select the light at large angles of scattering, that is to say say for example between 0 i = 30 ° and 0 ₂ = 70 °.

The light source 3 and the spectral detector 11 are configured so that the observation wavelength is within one of the following wavelength ranges: (390nm- 430nm), (470nm-490nm) , (500nm-525nm), (540nm-590nm), more specifically the wavelength ranges (390nm- 415nm), (475nm-485nm), (505nm-515nm), (545nm-575nm), and more particularly the wavelength range of (545nm-575nm), especially between 550 and 560nm, more specifically at 555nm.

Among these wavelength ranges, those of (540nm-590nm) and more particularly (545nm-575nm), in particular between 550 and 560nm, more specifically at 555nm are preferred, since they lie in the length range wave between about 500nm and 590nm where the human eye has its greatest sensitivity.

When we say that the light source 3 and the spectral detector 11 are configured so that the observation wavelength is within a certain range of wavelengths, we must take into account the spectrum of emission of the light source and of the configuration of the spectral detector 11 with a photodetector and a monochromator element so that several cases can arise.

According to a first example, the light source 3 is a monochromatic laser. In this case, for example the spectral detector 11 includes an optic with a filter as a monochromator element, for example an interference bandpass filter centered on the wavelength of the laser to eliminate the contribution of ambient light. The laser can be a modulated laser which, with a synchronous detection assembly ("Lock-in-amplifier" in English), allows to further eliminate the contribution of ambient light. This arrangement also works, with pulsed or continuous light with a continuous spectrum lamp, for example a halogen lamp.

Instead of the filter, it is also possible to carry out the wavelength selectivity of the detector by a Bragg grating spectrometer as a monochromator element for example.

For detection, the spectral detector 11 is for example equipped with a photodetector such as a photomultiplier or even a CCD or CMOS camera or equivalent.

Finally, a processing unit 15 is connected to the light source 3 and to the spectral detector 11.

This processing unit 15 comprises for example a processor and memories and is configured to control the light source 3 as well as to acquire and process the measurement signals coming from the spectral detector 11.

The processing unit 15 is further configured to correlate the measurement from the spectral light detector 11 with a state of organization of collagen fibrils.

Using the calculations presented above, for example with regard to FIG. 6, the processing unit 15 is configured to graduate the state of organization between 100% disorganized for a set of lamellae of fibrils completely randomly arranged and 0% for a set of lamellae of fibrils arranged in a perfectly organized manner.

This graduation is for example carried out for a wavelength of 555nm on the basis of FIG. 6 either by using the exact curve as presented, or by using as a first approximation a linear curve DL which, for this specific case presents a linear increase of a factor 2.6 between a state of organization 0%, that is to say perfectly organized and 100%, that is to say perfectly disorganized.

Of course, the same correlations can be made for other wavelengths as long as these lie within the wavelength ranges mentioned above.

Thus, it can be provided that the processing unit 15 is calibrated on the basis of a digital light scattering model taking into account multilayer multilayer stacks of lamellae having a thickness of between 1.5 and 2.5 μm , notably equal to 2pm thick and having organizational states between 100% and 0%.

The measuring device 1 operates for example according to the method for measuring an organized state of collagen fibrils in a corneal tissue illustrated in FIG. 8.

According to a step 102, an observation zone ZO of a cornea 5 is illuminated.

Then in a step 104, the light scattered at wide angles (for example the scattering angles between 30 ° and 70 °) is detected by the observation zone of the cornea and at a wavelength of observation included in one of the following wavelength ranges: (390nm- 430nm), (470nm-490nm), (500nm-525nm), (540nm-590nm), more specifically the wavelength ranges (390nm- 415nm ), (475nm-485nm), (505nm-515nm), (545nm-575nm), and more particularly the wavelength range of (545nm-575nm), in particular between 550 and 560nm, more specifically at 555nm.

Finally, according to a step 106, the measurement of the scattered light is correlated with a state of organization of collagen fibrils as explained above.

More specifically, step 106 makes it possible to measure a degree of disorganization of the lamellae of fibrils according to a gradation of the state of organization of between 100% disorganized for a set of lamellae of fibrils arranged completely randomly and 0 % for a set of lamellae of fibrils arranged in a perfectly organized manner.

This graduation is calibrated on the basis of a digital light scattering model taking into account multilayer stacks of lamellae having a thickness between 1.5 and 2.5 pm, in particular equal to 2 pm thickness and having states d 'organization between 100% and 0%, as explained above.

It is therefore understood that with a fairly simple and inexpensive apparatus and based on the work of the inventors of the present invention, one can determine a state of organization of the fibrils in the cornea which is interesting information for an ophthalmologist to make a diagnosis and, if necessary, to provide suitable treatment for the pathology diagnosed.

Claims (1)

Claims [Claim 1] Device for measuring (1) an organizational state of collagen fibrils in a coma tissue comprising - a light source (3) adapted to emit light towards a cornea (5), - a spatial filtering system (9) arranged on the path of the light scattered by the cornea (5) and configured to select an observation zone (ZO) of the cornea (5), - a spectral detector (11) of the light scattered by the observation zone of the cornea and configured for detection at large angles of scattering, the light source (3) and the spectral detector (11) being configured so that the observation wavelength is within one of the following wavelength ranges: 390nm430nm, 470nm-490nm, 500nm-525nm, 540nm-590nm, - a processing unit (15) configured to correlate the measurement from the spectral light detector (11) with an organized state of collagen fibrils. [Claim 2] Measuring device according to claim 1, characterized in that the observation wavelength is within one of the following wavelength ranges: 390nm- 415nm, 475nm-485nm, 505nm-515nm, 545nm-575nm. [Claim 3] Measuring device according to claim 1, characterized in that the observation wavelength is in the wavelength range of 545nm-575nm, in particular between 550 and 560nm, more specifically at 555nm. [Claim 4] Device according to any one of claims 1 to 3, characterized in that the spatial filtering system (9) is configured for observation of an area ZO of the cornea. [Claim 5] Device according to any one of Claims 1 to 4, characterized in that the light source (3) comprises a laser, in particular a monochromatic laser. [Claim 6] Device according to any one of Claims 1 to 5, characterized in that the spectral detector (11) comprises a photodetector as well as a monochromator element and is configured to select the light scattered at scattering angles between 30 ° and 70 ° . [Claim 7] Device according to claim 6, characterized in that the monochromator element comprises a band pass interference filter. [Claim 8] Device according to claim 6, characterized in that the monochromator element comprises a spectrometer. [Claim 9] Device according to any one of Claims 1 to 8, characterized in that the processing unit (15) is configured to grade the state of organization between 100% disorganized for a set of lamellae of fibrils arranged completely randomly and 0% for a set of lamellae of fibrils arranged in a perfectly organized manner. [Claim 10] Device according to claim 9, characterized in that the processing unit (15) is calibrated on the basis of a digital light scattering model taking into account multilayer stacks of lamellae having a thickness of between 1.5 and 2 , 5pm, in particular equal to 2pm thickness and having organizational states between 100% and 0%. [Claim 11] Method for measuring the state of organization of collagen fibrils in a corneal tissue in which - we illuminate an observation area of a cornea (5), - the light scattered at wide angles is detected by the observation zone (ZO) of the cornea and at an observation wavelength within one of the following wavelength ranges: 390nm430nm, 470nm-490nm, 500nm -525nm, 540nm-590nm - and the measurement of the scattered light is correlated with a state of organization of collagen fibrils. [Claim 12] Measuring method according to claim 11, characterized in that the observation wavelength is within one of the following wavelength ranges: 390nm- 415nm, 475nm-485nm, 505nm-515nm, 545nm-575nm. [Claim 13] Measuring method according to claim 10, characterized in that the observation wavelength is in the wavelength range of 545nm-575nm, in particular between 550 and 560nm, and more specifically at 555nm. [Claim 14] Method according to any one of Claims 11 to 13, characterized in that the light scattered at wide angles is detected over scattering angles between 30 ° and 70 °. [Claim 15] Measuring method according to any one of claims 11 to 14, characterized in that a degree of disorganization of the lamellae of fibrils is measured according to a graduation of the state of organization of between 100% disorganized for a set of lamellae of fibrils arranged completely randomly and 0% for a set of lamellas of fibrils arranged in a perfectly organized manner. [Claim 16] Method according to claim 15, characterized in that the graduation is calibrated on the basis of a digital light scattering model taking into account multilayer stacks of lamellae having a thickness between 1.5 and 2.5pm , notably equal to 2pm thickness and having organizational states between 100% and 0%.