Multimodal Retinal Imaging Platform

Abstract

The present invention relates to oblique transscleral illumination of the fundus by at least one physical point source around the eye, which enables dark-field imaging in combination with optical coherence tomography imaging.

Description

[Technical field]

[0001] The present invention relates to an ophthalmic illumination and imaging system with oblique transscleral illumination of the fundus with at least one physical point source around the eye, enabling imaging (e.g., darkfield) combined with optical coherence tomography imaging. [Background technology]

[0002] Retinal diseases are the leading cause of blindness in developed countries. For example, an estimated 196 million people will suffer from age-related macular degeneration in 2020. Although significant efforts have been made to develop novel therapeutic strategies to rescue retinal neurons and the retinal pigment epithelium (RPE), optimal means to evaluate the efficacy of such treatments are still lacking. The instruments used in ophthalmology clinics for routine fundus examinations do not allow for the observation of subtle changes in cell morphology present in the early stages of the disease degenerative process.

[0003] The retina is a complex, intricate tissue composed of many layers, and imaging of individual cells is extremely challenging for many reasons, including ocular aberrations that reduce lateral resolution, as well as eye movement artifacts and poor contrast of transparent cells.

[0004] Another limitation is that most of the light entering the pupil is absorbed or reflected at the interfaces of photoreceptor segments, overwhelming the weak signal backscattered from neurons or RPE cells. The photoreceptor signal is greatest when the illuminating light is incident on the center of the pupil and drops off sharply when it is incident on its edge. This angle-dependent reflection of the retina is commonly referred to as the optical Stiles-Crawford effect (SCE).

[0005] Light reflected by the photoreceptors allows their observation using adaptive optics (AO) to correct ocular aberrations in combination with flood illumination optical coherence tomography (OCT) or scanning laser ophthalmoscopy (SLO). Recent studies have proposed optical methods to observe the neural retina and RPE cells using AO-SLO with offset aperture, split detector, dark field, autofluorescence, or AO-OCT.

[0006] Despite the high quality results obtained, these methods suffer from very small field of view (FOV), lack of image clarity, safety concerns, or acquisition times that are too long for clinical use.

[0007] In WO / 2017 / 195163 A1 (ECOLE POLYTECHNIQUE FEDERALE DE LAUSANNE (EPFL) [CH]), the applicant describes a method for imaging ocular tissues, comprising: providing oblique illumination to the eye by a plurality of emitting regions of a light delivery device, the plurality of emitting regions being independently controllable and arranged to direct light to at least one of the retina and the iris of the eye; generating an output beam from light backscattered from the at least one of the retina and the iris by the oblique illumination, capturing the output beam with an imaging system to give a sequence of images of the fundus of the eye, and extracting phase and absorption contrast images from the sequence of images of the fundus, the sequence of images of the fundus of the imaging step being obtained by sequentially illuminating one or more of the plurality of emitting regions in the step of providing oblique illumination. In other words, the method of transscleral illumination enables dark field and phase gradient techniques by using the scattering properties of the fundus. Transscleral oblique flood illumination enhances the contrast of many of the biological structures that make up the retinal layers and, in combination with adaptive optics high-resolution imaging, allows the observation of cells that play key roles in disease-related degenerative processes. Obtaining high-resolution images at the cellular level provides new insights into the structure of the retina and, consequently, a better understanding of retinal degenerative disease processes.

[0008] In vivo observation of the human retina at the cellular level is important for detecting pathologies before irreversible vision loss occurs, tracking the time course of retinal diseases, and assessing and monitoring the early effects of treatments. Despite tremendous advances in optical coherence tomography (OCT) and adaptive optics systems, in vivo imaging of some retinal cells remains elusive.

[0009] Laforest T. et al. “Transcleral Optical Phase Imaging of the Human Retina-TOPI” https: / / arxiv.org / abs / 1905.06877 disclosed transcleral optical phase imaging (TOPI) that allows imaging of retinal cells with high contrast, high resolution and acquisition times suitable for clinical use. TOPI relies on combining high-angle oblique illumination of the retina with adaptive optics to enhance the phase contrast of transparent cells.

[0010] Transscleral Optical Phase Imaging (TOPI) provides label-free, high-contrast images with cellular resolution of retinal layers over a wide field of view without the drawbacks of long exposure times. The method is based on transscleral flood illumination of the retina, which significantly increases the signal-to-noise ratio (SNR) of many retinal structures compared to transpupillary illumination. Light transmitted through the sclera provides oblique illumination of the posterior retina, which is imaged with a transpupillary AO full-field camera system.

[0011] TOPI was demonstrated in healthy volunteers without pupil dilation to provide images of RPE cells and other retinal structures and allow for cellular quantification. The feasibility of the technique was also demonstrated on ex vivo samples using a laboratory phase microscope with similar parameters to the in vivo device. Label-free phase images of cells in thick retinal samples were shown to match the quality of confocal fluorescence microscopy.

[0012] The method described in WO / 2018 / 197288 A1 (IMAGINE EYES [FR]) is a multiscale device with several illumination modules combined with a scanning system. The scanning system is made either by SLO or OCT with adaptive optics. The multiscale allows the localization of high-resolution images on the fundus, but the transpupillary illumination module does not allow the observation of retinal pigment epithelial cells, which play an important role in degenerative retinal diseases.

[0013] Fundus camera systems using transscleral or transpalpebral illumination have been developed. WO / 2017 / 151921 Al (BIOLIGHT ENG LLC [US]) describes a wide-field transscleral or transpalpebral system using different devices for light projection systems and shapes as well as scleral / skin tissue. WO / 2004 / 091362 A2 (MEDIBELL MEDICAL VISION TECHNOLOGIES LTD. [IL]) discloses a fundus imaging system with projection of a beam onto the sclera. Another device using transscleral illumination to image the choroid is disclosed in US2015 / 055094 A1 (ANNIDIS HEALTH SYSTEMS CORP [CA]).

[0014] Finally, in 2017, Lingenfelder et al. presented a transscleral illumination system using LEDs, called the Transscleral LED illumination pen', Biomed. Eng. Lett. 7, 2017. All of these methods aim to capture fundus images with a wide field of view and show large structures such as blood vessels, but they do not aim to see inside tissues at a microscopic scale or at the cellular level.

[0015] None of these methods use adaptive optics to correct for ocular aberrations and reach the diffraction limit of resolution, and therefore none of these methods can provide a view of the individual cells that make up the retinal tissue. Summary of the Invention

[0016] None of the prior art systems are believed to provide a system that uses oblique transscleral / transpalpebral illumination to simultaneously provide en-face, high resolution cellular level images of the retina, and an optical coherence tomography (OCT) system to visualize in-depth cross-sectional areas of the imaged retina.

[0017] A drawback of high resolution imaging at the cellular level is the difficulty in selecting and locating the depth of the imaging zone in the multi-layered retinal tissue. OCT is a method specifically developed to observe the structure of the tissue in detail. Combining an OCT system with the high resolution cellular image produced by oblique flood illumination allows for precise localization of the high resolution cellular image, allowing the physician to select which layer of cells to image. As well as the addition of a wide field fundus visualisation, having also a cross-sectional depth map of the retina allows for an understanding of which part of the fundus tissue is imaged on the high resolution cellular image. The horizontal or lateral position is provided by the wide field and the vertical or depth position is provided by the OCT. Depending on the speed of its accompanying scanning system, an OCT system can be used simultaneously for both wide field and cross-sectional images.

[0018] Advantageously, according to the present invention, the optical coherence tomography depth-related signal provides depth information of the en-face image, in other words the en-face image, in the fundus tissue. The depth-related signal contains information about the detailed anatomy of the fundus tissue. Although the en-face image shows a frontal imaging plane in the same tissue, the exact depth of this imaging plane is not easy to determine alone. The optical imaging system that generates the en-face image has a focusing system that can vary the depth of the imaging plane. For example, with a known calibration of the OCT system and the en-face imaging focusing system, the depth of the en-face imaging plane can be inferred from the OCT depth-related signal.

[0019] According to the invention, the depth-related signals are processed to provide direct feedback for adjusting the imaging depth of the frontal image.

[0020] For example, the present invention may further comprise a calibration step to match the depth scale of the depth-related signal with the depth scale of the transscleral signal.

[0021] According to the present invention, the depth-related signal from the OCT system is used as direct feedback regarding the imaging depth of the imaging system.

[0022] This feedback is used to perform depth control of imaging depth, which can be performed as an automatic-closed loop depth control of imaging depth or as an open loop user control of imaging depth.

[0023] Thus, the control of the imaging depth of the optical imaging system is directly linked to the feedback signal of the OCT system. - Acquire an "en face" oblique illumination image at a given depth of interest, which is particularly useful for pathological retinas where there is damage to the laminar structures. - Acquire a stack of "en face" images that directly correlate with the precise depth of the OCT system. - Accurately position and correlate the morphology of different retinal layers and the "en face" images obtained with the OCT system. - Accurately identify the types of cells or tissue structures present in "en face" images. From the OCT system, it is possible to generate better quality "en face" images by knowing the correct optical defocus in the imaging system that links to the specific retinal layer one wants to image.

[0024] It is therefore one object of the present invention to provide an ophthalmic illumination system and method for transscleral illumination in combination with an optical coherence tomography system for probing the fundus through the pupil.

[0025] In particular, the present invention relates to the combination of: - a transscleral light delivery system having one or more light sources that emit light toward the sclera or surrounding skin of the eye to be measured, providing oblique transscleral illumination of the fundus (1); and - An ophthalmic illumination system is provided that includes a combination of an OCT light source and an optical coherence tomography (OCT) system directed at the pupil of a subject eye, the OCT light source having a reference arm, a sample arm and a detection arm.

[0026] Another object of the invention is an ophthalmic illumination and imaging system, preferably including a combination of: - an oblique light delivery system having one or more light sources that provide oblique illumination to the fundus and direct transscleral or transpalpebral illumination light toward the sclera or surrounding skin of the eye to be measured, respectively; and - an ophthalmic illumination and imaging system comprising a combination of an OCT light source, an optical coherence tomography system directed at a pupil of an eye to be measured, the optical coherence tomography system comprising a reference arm, a sample arm and a detection arm, the system further comprising an optical imaging system that collects oblique illumination light scattered by the fundus and produces one or more en face images of the fundus; The optical imaging system is characterized by further comprising a focusing system configured to adjust the depth of an imaging plane of the imaging optical system in response to a depth-related signal provided by the OCT system.

[0027] Another object of the present invention is to provide an ophthalmic illumination and imaging device, in which a transscleral light delivery system is combined with an OCT system, said ophthalmic illumination and imaging device comprising: - a scanning system for scanning a fundus with said OCT system; an aberration correction system including a probing light source, a wavefront sensor, and a wavefront corrector; - a high-resolution transscleral anatomical or angiographic imaging system using a high-resolution camera; - a wide-field transscleral anatomical or angiographic imaging system using a wide-field camera; and - a system for transpupillary anatomical or angiographic imaging, the system including a transpupillary flood illumination source and a high resolution camera; The present invention is characterized by comprising:

[0028] The advantage of the present invention is that it provides high resolution imaging of fundus tissue at the cellular level using active or passive correction of transscleral scattered light and optical aberrations of the eye, and localizes the imaging depth with an OCT system. Passive aberration correction is, but is not limited to, custom lenses or mirrors. Active aberration correction is, but is not limited to, deformable mirrors, adjustable lenses, or liquid crystal phase modulators.

[0029] Another object or advantage of the present invention is to provide direct feedback on the imaging depth of a transscleral high-resolution imaging system using a signal from an optical coherence tomography system. This feedback is preferably used to perform automatic, closed-loop, depth control of the imaging depth or to perform open-loop user control of the imaging depth. Thus, the control of the high-resolution imaging depth is directly tied to the feedback signal of the OCT system.

[0030] Other objects and advantages of the present invention will become apparent to those skilled in the art from a consideration of the following detailed description which follows, taken in conjunction with the following illustrative drawings and the appended claims.

[0031] Further particular advantages and features of the present invention will become more apparent from the following non-limiting description of at least one embodiment thereof, which refers to the accompanying drawings. [Brief description of the drawings]

[0032] [Figure 1] FIG. 1 illustrates a combination of an OCT system and transscleral illumination of the eye with a light delivery system. [Diagram 2] FIG. 1 is a diagram illustrating the principle of transscleral illumination of the fundus. [Diagram 3] FIG. 1 is a diagram illustrating the principle of transpalpebral illumination of the fundus. [Figure 4] FIG. 2 shows the system of FIG. 1 implemented in a front-facing optical imaging system that provides front-facing images of the fundus by two different photodetectors (cameras). [Diagram 5]FIG. 1 illustrates the principle of extracting vascular information from a series of anatomical images to generate angiographic images. [Figure 6] FIG. 1 is a schematic diagram of an adaptive optics principle consisting of a transpupillary probing light source, a wavefront sensor and a wavefront corrector. [Figure 7] FIG. 1 illustrates an apparatus for an ophthalmic illumination system capable of producing multi-wavelength transscleral illumination. [Figure 8] FIG. 2 shows a device of a system implementing the imaging mode described in FIG. 1, in which a wide-field retinal image is generated by a scanning (point-by-point) imaging system. [Figure 9] FIG. 3 illustrates an arrangement of a system implementing the imaging mode described in FIG. 2, in which a transpupillary flood illumination modality is added to the primary transscleral illumination. [Figure 10] FIG. 1 is a block diagram of a multimodal imaging system including transscleral high resolution and wide field, angiographic anatomy, transpupillary high resolution, and transpupillary OCT. [Figure 11] FIG. 11 shows an ophthalmic illumination and imaging device embodying the principles described in FIGS. 1 to 10. [Figure 12] FIG. 1 illustrates a closed-loop depth control based on depth-related signals obtained from an OCT system. [Figure 13] FIG. 1 illustrates an ophthalmic illumination and imaging device embodying a combination of many of the systems described in this invention. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0033] Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. The publications and applications discussed herein are provided solely for their disclosure prior to the filing date of this application. Nothing herein should be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention. Additionally, the materials, methods, and examples are illustrative only and are not intended to be limiting.

[0034] In case of conflict, the present specification, including definitions, will control.

[0035] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the subject matter of this specification belongs. As used herein, the following definitions are provided to facilitate the understanding of the present invention.

[0036] The term "comprise" is generally used in the sense of including, i.e. allowing for the presence of one or more features or components.

[0037] As used in this specification and claims, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise.

[0038] As used herein, the terms "subject" or "patient" are well-recognized in the art and are used interchangeably herein to refer to a mammal, most preferably a human. In some embodiments, a subject may be a normal subject. The term does not denote a particular age or sex. Thus, adult and neonatal subjects, whether male or female, are intended to be encompassed.

[0039] Optical coherence tomography (OCT) is an imaging technique that uses low-coherence light to capture one-, two-, and three-dimensional images with micrometer resolution from within light-scattering media (e.g., biological tissue). It is used in medical imaging and industrial non-destructive testing (NDT). Optical coherence tomography is based on low-coherence interferometry, typically with near-infrared light. The use of relatively long wavelengths of light allows it to penetrate into scattering media. Another optical technique, confocal microscopy, typically does not penetrate as deeply into the sample, but with higher resolution.

[0040] Scattering is the process by which electromagnetic radiation (eg, light) or particles are deflected or scattered as a result of interaction with matter.

[0041] Backward scattering (or backscattering) is the reflection of electromagnetic radiation, particles, or signals back in the direction from which they came. This is usually a diffuse reflection due to scattering, as opposed to specular reflection from a mirror, although specular backscattering can occur at normal incidence with a surface.

[0042] The "sclera", also known as the white of the eye, is an opaque, fibrous, protective outer layer of the human eye, containing mainly collagen and some elastic fibers. The sclera is a connective tissue composed mainly of white collagen fibers. It lies posteriorly beneath (outside) the choroid and anteriorly, transparent above the iris and pupil, called the cornea.

[0043] The "eye fundus" or fundus of the eye is the inner surface of the eye opposite the lens and includes the retina, optic disc, macula, fovea, and posterior pole. The fundus can be examined by ophthalmoscopy and / or fundus imaging.

[0044] The term "transcleral" means across the sclera of the eye, i.e., the white of the eye.

[0045] The term "transpalpebral" means through the eyelid or skin surrounding the eye and then through the sclera.

[0046] A first object of the present invention is to provide an ophthalmic illumination system, the system comprising: - a transscleral light delivery system (2) having one or more light sources that emit light toward the sclera (4) of the eye to be measured or the skin (5) surrounding the eye, providing transscleral oblique illumination of the fundus (1); - a combination of an OCT light source (9), a reference arm (10), a sample arm (11), an optical beam splitter (12) and an optical detection arm (14) directed towards the pupil (8) of the eye (6) to be measured.

[0047] Preferably, the light delivery system (2) does not come into contact with the skin or sclera surrounding the eye to be measured.

[0048] Advantageously, the optical coherence tomography system generates depth-related signals (15) of the fundus tissue anatomy and creates one-dimensional (16), two-dimensional (17) or three-dimensional (18) OCT images of said fundus (1).

[0049] Preferably, the invention further comprises an optical imaging system (19) that collects transscleral oblique illumination light scattered by the fundus (1) and creates one or more en-face images (51) of the fundus (1) on one or more light-sensitive detectors or cameras (35, 36).

[0050] According to one embodiment, a series of frontal images (51) are analyzed and processed to extract time-correlated information and enhance the contrast of time-varying biological features such as blood vessels (52).

[0051] According to the invention, the optical coherence tomography system depth related signal (15) provides depth information of the en face image (51) within the fundus tissue.

[0052] According to one embodiment, the optical coherence tomography system depth-related signal (15) is processed to provide real-time closed-loop feedback (56) to control the imaging depth of the front-facing image (51).

[0053] According to another embodiment, the optical coherence tomography system depth related signal (15) is processed to provide a depth open loop control of the acquisition of front-facing images (51).

[0054] Advantageously, the ophthalmic illumination system of the present invention further comprises correction of ocular optical aberrations for at least one front-facing image (51).

[0055] According to one embodiment, the correction of optical aberrations is performed by static optical elements or by computational means.

[0056] According to another embodiment, the correction of optical aberrations is performed in real time using an adaptive optics closed loop comprising a pupil-probing light source (30), a wavefront sensor (31) and a wavefront corrector (32) capable of spatially shaping the wavefront of the light forming the front-facing image (51).

[0057] Preferably, the transpupillary probing light source (30) is the same as the OCT light source (9).

[0058] According to yet another embodiment, the ophthalmic illumination system of the present invention further comprises a transpupillary flood illumination source (44) and an imaging system for generating a front image (51) of the fundus (1) from backscattered light (23) derived from the transpupillary flood illumination source (44).

[0059] Preferably, the light delivery system (2) providing transscleral oblique illumination of the fundus (1) has different wavelengths, advantageously providing functional information selected from the list comprising blood flow oxygenation and retinal pigment epithelial cell activity.

[0060] Another object of the present invention is to provide an ophthalmic illumination and imaging device in which a transscleral light delivery system (2) is combined with the above-mentioned OCT system (7), - a scanning system (45) for scanning the fundus (1) with said OCT system (7), an aberration correction system including a probing light source (30), a wavefront sensor (31) and a wavefront corrector (32); - a system for high-resolution transscleral anatomical or angiographic imaging (28, 29) using a high-resolution camera (36), - a system for wide-field transscleral anatomical or angiographic imaging (26, 27) using a wide-field camera (35), and a system (24) for transpupillary anatomical or angiographic imaging, comprising a transpupillary flood illumination source (21) and a high-resolution camera (36); Equipped with.

[0061] The present invention is further described with respect to various specific embodiments below.

[0062] The transscleral light delivery system (2) (see FIG. 1) comprises at least one light source (3) that emits a light beam (59) towards the eye (6). The light beam reaches the surface of the sclera (4) or the skin (5) around the eye and diffuses in the tissue. A portion of the light penetrates the sclera (4) and eye envelope (58), propagates through the vitreous body (57) and provides oblique illumination of the fundus (1). This illumination is called transscleral oblique illumination of the fundus.

[0063] Illumination is provided by a single or combination of multiple light sources in the wavelength range of 400 nm to 1200 nm, including, but not limited to, light emitting diodes, superluminescent diodes, quantum dot sources, lamps, blackbody radiation sources, and laser sources.

[0064] Light is delivered by placing a light source in direct contact with the tissue (sclera or skin), or guided from the light source to the tissue using a guide material such as, but not limited to, water, polymer, or glass, or propagating through air from the light source to the illumination surface (cornea, sclera, or skin). The light beam can be converging, diverging, or collimated, depending on the illumination technique selected. The light can be, but is not limited to, linearly polarized, circularly polarized, unpolarized (meaning it does not exhibit any known selective polarization), and a mixture of different polarizations.

[0065] In the Fourier domain, oblique illumination with a plane wave corresponds to a shift to higher spatial frequencies. In addition, directing light at a higher angle to the fundus also produces more oblique back illumination, resulting in higher contrast.

[0066] Advantageously, the optical coherence tomography system (7) generates a depth-related signal (15) of the fundus tissue anatomy and generates a one-dimensional, two-dimensional or three-dimensional depth-related signal of the fundus (1). The OCT light source 9 emits light that is split into a reference arm (10) and a sample arm (11). The light beam of the sample arm (11) propagates to the fundus (1) tissue and is partially reflected back to the OCT system detection arm (14). The light beam of the reference arm (10) is reflected by a mirror surface (33) and returns to the detection arm (14). The two light beams reflected from the sample arm (11) and the reference arm (10) interfere in the detection arm (14) and the intensity of this interference is measured by a photodetector (13) at the end of the detection arm. The detector (13) can be, but is not limited to, a spectrometer (38) with a diffraction grating (37) and a line array detector (38) in the case of spectral domain OCT, or a photodiode for swept-source OCT. The electrical signal coming from the detector is a depth-related signal (15) of the fundus anatomy. Depending on the configuration of the scanning system (45), the depth-related signal (15) is further used by the computer to generate a one-, two- or three-dimensional OCT image of the fundus. No scanning system allows the calculation of a one-dimensional (16) depth-related signal that indicates a depth line in the fundus tissue. A single-axis scanning system allows the calculation of a two-dimensional (17) depth-related signal of the fundus that indicates a cross-section in the fundus tissue. A two-axis scanning system or two single-axis scanning systems allows the calculation of a three-dimensional (18) depth-related signal of the fundus that indicates a volume in the fundus tissue. The scanning system is successively tilted to direct the light beam of the sample arm (11) to different points within the fundus in order to record depth-related signals (15) over a region or volume of tissue.

[0067] Preferably, the present invention further comprises an optical imaging system (19) as shown in Fig. 4, which collects the transscleral oblique illumination light scattered by the fundus (1) and creates one or more en-face images (51) of the fundus on one or more light-sensitive detectors (cameras) (35, 36). The optical imaging system (19) comprises optical lenses and mirrors to conjugate the fundus plane with the detector plane of the camera. Thus, the camera can capture the light scattered by the fundus and generate an image of the fundus. By reproducing the focal length of the optical lenses, images of different magnifications of the fundus can be generated by different cameras.

[0068] In one embodiment, per Figure 4, a long focal length imaging lens (47) produces a high resolution front image on camera (36). In the same embodiment, a shorter focal length imaging lens (46) produces a wide field of view front image on camera (35).

[0069] According to one embodiment, as shown in FIG. 5, a series of frontal images (51) are analyzed and processed to extract time-correlated information and enhance contrast of time-varying anatomy such as blood vessels.

[0070] 6, a series of en face images 51 of the fundus statically includes retinal vessels (52) and other tissue structures (53) over time. Since blood signals change over time, only blood vessel images (angiograms) are extracted from the series of images (image sequence) when calculating the time-correlated image (41).

[0071] Preferably, the light source illuminating the sclera (4) has different wavelengths with two LEDs (40 and 41) (FIG. 7) that provide functional information. The different wavelengths are used for en face images and the images are processed to extract functional information of the retina such as, but not limited to, blood flow oxygenation or the health of the retinal pigment epithelium (RPE) cells.

[0072] The LEDs (40 and 41) have peak wavelengths of 810 nm and 890 nm, allowing differentiation of vascular oxygenation due to the different absorption curves of oxygenated versus non-oxygenated hemoglobin.

[0073] An implementation is shown according to Figure 7 in which two LEDs (40 and 41) with different peak wavelengths A1 and A2 are used to provide two light sources of transscleral illumination. These are combined by a dichroic mirror (39) and illuminate the sclera of the eye (6) by a transscleral light delivery system (2).

[0074] According to a particular embodiment of the invention, the optical coherence tomography depth-related signal (15) provides depth information of the en face image in the fundus tissue. As mentioned above, the depth-related signal contains information about the detailed anatomy of the fundus tissue. The en face image shows a frontal imaging plane inside the same tissue, but the exact depth of this imaging plane is not easy to determine alone. The optical imaging system (19) generating the en face images (26, 27, 28, 29) has a focusing system that allows to vary the depth of the imaging plane. With a known calibration of the OCT system (7) and the en face imaging focusing system, the depth of the en face imaging plane can be inferred from the OCT depth-related signal (15).

[0075] According to another embodiment, the invention further comprises a correction of the optical aberrations of the eye for at least one front image. The lateral resolution of imaging in the eye is limited by its pupil size and the optical aberrations of the eye. The lateral resolution of imaging is directly linked to the smallest elements observable in the fundus tissue. The higher the lateral resolution, the smaller the elements can be observed and the more details can be seen inside the tissue. A way to increase this lateral resolution and maximize the details seen in the tissue is to correct the aberrations of the eye by computational means or optical elements. When the aberrations are completely corrected, a so-called diffraction-limited imaging performance is reached inside the eye (i.e. limited only by the diffraction of light by the finite aperture size of the pupil of the eye).

[0076] Advantageously, the correction of aberrations is performed by static optical elements, such as, but not limited to, mirrors, custom lenses that correct defocus, astigmatism, and the badal system.

[0077] Alternatively, the correction of aberrations is performed computationally on the recorded images using image processing techniques, which may consist of, but are not limited to, using measurements of the aberrations of the eye and the optical imaging system and digitally modifying the images to account for and correct said aberrations.

[0078] Alternatively, the correction of the aberrations is performed in real time by measuring the aberrations according to Fig. 6, with a transpupillary probing light source (30) and a wavefront sensor (31) and a wavefront corrector (32) capable of spatially shaping the collected light wavefront. This principle of correction of ocular aberrations is usually called an adaptive optical loop and consists of: The transpupillary probing light source (30) is focused on the fundus of the eye. A part of the collected light is backscattered and illuminates a wavefront sensor (31) placed in a conjugate pupil plane (42). The wavefront sensor is preferably implemented as a Shack-Hartmann sensor. The wavefront sensor is placed in a plane conjugate to the pupil plane of the eye. The image recorded on the wavefront sensor allows the measurement of the optical wavefront aberrations related to the ocular aberrations. A control for the wavefront corrector (32) is calculated and applied. The wavefront corrector can be, but is not limited to, a deformable mirror, a tunable lens, a liquid crystal modulator. The wavefront corrector is placed at the conjugate pupil plane between the pupil 8 and the wavefront sensor 31. Changes in the shape of the wavefront corrector 32 attempt to counteract the aberrations of the eye.

[0079] According to yet another embodiment, as shown in FIG. 9, the present invention further comprises a transpupillary flood illumination source (44) and an imaging system for producing a frontal image of the fundus (1) through backscattered light from said illumination source.

[0080] According to the invention, the depth-related signal (15) is processed to provide direct feedback for adjusting the imaging depth of the front-facing image.

[0081] Preferably, the transpupillary probing light source (30) for aberration measurements is the same as the OCT light source (9).

[0082] The invention further comprises a calibration step to match the depth scale of the depth-related signal (15) to the depth scale of the transscleral signal.

[0083] The image acquisition process differs depending on the imaging modality required, dark field or phase / absorption. In the case of dark field, imaging can be performed with only one illumination point without image processing. Images acquired for different imaging regions can be stitched together to obtain a larger field of view.

[0084] Transscleral illumination has two interesting properties that increase the low retinal contrast observed with transpupillary flood illumination. First, SCE allows very little of the high-angle transscleral illumination light to be coupled to the photoreceptors, allowing most of the light to reach the RPE layer. Second, direct backscattered illumination light is not collected by the imaging system, as there is no overlap with the collection path through the pupil. Thus, only light that is multiply scattered by different retinal layers enters the optical system and reaches the camera, providing dark-field imaging conditions. The illumination angle is much larger than that obtained via illumination through the pupil, creating a non-uniform excitation of retinal spatial frequencies that enhances the contrast of transparent objects.

[0085] As mentioned above, the present invention relates to an ophthalmic illumination system and imaging device for transscleral illumination, en face high resolution imaging at the cellular level, wide field imaging, and detailed visualization of the fundus. High resolution imaging is provided by transscleral illumination combined with correction of the optical aberrations of the eye, and detailed visualization is provided by optical coherence tomography.

[0086] In a first embodiment, according to FIG. 1 , the system is composed of, but is not limited to, a transscleral light delivery system (2) having one or more emitting regions (3) intended to non-contact illuminate the sclera (4) and then obliquely illuminate the fundus (1), in combination with an OCT system (7) comprising an OCT light source (9), an optical beam splitter (12), a reference arm (10), a sample arm (11) and an optical detection arm (14) and providing a depth-related signal (15).

[0087] In another embodiment, according to FIG. 4, the system comprises a primary retinal high resolution camera (36) that images the retina at high resolution, with digital sampling of, but not limited to, less than 2 μm / pixel, and a second wide field retinal camera (35) that images the retina over a wider field of view (typically greater than 30°) with digital sampling of 20 pm / pixel.

[0088] In addition, the main retina camera optical path includes an adaptive optical loop to correct the aberrations of the eye. The adaptive optical loop includes, but is not limited to, a wavefront detection light source directed at the pupil of the eye, a Shack-Hartmann wavefront sensor (31) that measures the backscattered light coming from the fundus, and a deformable mirror (33). The wavefront sensor (31) measures the optical aberrations of the eye in real time and sends control feedback to the deformable mirror. The wavefront detection light source is, but is not limited to, a laser light source, a superluminescent diode (17) or a light emitting diode (LED). The transpupillary probing light source (30) is split into two arms for performing interference: a sample arm (11) and a reference arm (10). The signal backscattered from the retina is separated into two parts, one part is used for wavefront measurement (5) and the other part is used to measure the interference with the reference arm (10).

[0089] In another embodiment, the wide-field front-view image is generated by an OCT system (7) or other eye scanning system such as a scanning laser ophthalmoscope (SLO), according to Fig. 4. A two-axis rotating mirror (31), or a pair of single-axis rotating mirrors, allows the OCT or scanning system (45) to image the fundus tissue across three dimensions (18) and depth-related signals (15).

[0090] In another embodiment, according to Fig. 9, the system includes a transpupillary floodlight source (44) to provide transpupillary floodlighting of the fundus (1) over a large area (34). The transpupillary light source (30) is, but is not limited to, an LED. Light emitted from this light source and backscattered at the fundus (1) is used to generate a high resolution image on the photoreceptors on the primary retinal camera (25). Photoreceptors are directional cells that reflect a portion of the light that enters the pupil (8) and are therefore better observable using transpupillary illumination compared to transscleral illumination.

[0091] According to FIG. 10, a light beam is directed towards the sclera (4) or towards the pupil (8) of the eye (6). Backscattered light (23) from the transpupillary illumination is collected to produce: - Transpupillary retinal anatomy or angiography (24) - Optical Coherence Tomography Retinal Anatomy Images (25)

[0092] Multiply scattered light from the transscleral illumination (22) is collected to produce: - Transscleral wide-field retinal anatomy images (26) - Transscleral wide-field retinal angiography images (27) - Transscleral high-resolution retinal anatomy images (28) - Transscleral high-resolution retinal angiogram (29).

[0093] According to FIG. 11, after illuminating the eye (6), the multiply scattered light is collected by an ophthalmic illumination system. A light source (9) for OCT or a light source (30) for wavefront transpupillary probing illuminates the eye (6) through the pupil (8). A transpupillary probing light source (30) for wavefront detection is recorded in a wavefront sensor (31) and gives feedback to a wavefront corrector (32) to correct ocular aberrations. The same transpupillary probing light source (30) for wavefront detection can be the same as the OCT light source (9). The OCT system (7) is in the reference arm (10) for its reference mirror (33). A fiber beam splitter (12) transmits or collects light to or from the eye (6). The beam splitter (12) also transmits and receives light to and from the OCT light source (17). A transscleral light source (16) illuminates the eye (6) and multiply scattered light (22) from the transscleral illumination is collected. The retina (14) is imaged onto a wide field camera (35) and a high resolution camera (36). The camera sensors are at conjugate retinal planes (43).

[0094] The following schemes are presented as embodiments. - The transscleral illumination system is coupled to an optical coherence tomography system (7).

[0095] 1 and 4, the OCT system (7) consists of a light beam directed towards the pupil (8), an OCT light source (9), a reference mirror (33), a fiber beam splitter (12), a diffraction grating (37) and a multi-pixel light-sensitive detector (27). After illuminating the retina, the backscattered light (23) from the transpupillary illumination is collected by the beam splitter (12) and sent to the OCT system (7) where it is recorded in a spectrometer (38) consisting of the diffraction grating (37) and the photodetector (13).

[0096] A high resolution imaging system collects the transcleral illumination light exiting the pupil (8) and uses adaptive optics to correct for optical aberrations in the eye.

[0097] 1 and 2, the beam directed to the sclera (transcleral light delivery system) (2) illuminates the fundus (1) after penetrating and diffusing inside the eye envelope tissue, and the multiply scattered light (22) from the transcleral illumination is collected by the imaging system, and the retina is imaged onto a high-resolution camera (36) and a wide-field camera (35). Optical aberrations are corrected by a wavefront sensor (31) and a wavefront corrector (32).

[0098] The adaptive optics system consists of a probing light source that is directed at the pupil and reflects on the fundus (1), a wavefront sensor (31) that measures ocular aberrations by analyzing the probing light source reflection, and a wavefront corrector (32) that corrects the ocular aberrations based on the measurements of the wavefront sensor (31).

[0099] According to FIG. 2, a probing light source (18) is focused on the retina and a wavefront sensor (31) measures the ocular aberrations.

[0100] A wavefront-probing light source is used to measure the wavefront on one portion and generate interference on the other portion.

[0101] According to Fig. 2, the probing light source (18) is also used as the OCT light source (9). Splitting can be done either by, but not limited to, a beam splitter (12), intensity by a dichroic mirror (39), or wavelength.

[0102] The optical coherence tomography signal (7) is processed to deliver feedback to the adaptive optics system to focus the high-resolution imaging system to the selected depth.

[0103] A calibration step is required to match the optical depth obtained by the OCT system 7 with the optical depth of the other imaging modality in order to calculate the feedback based on the depth-related signal (15). The calibration includes the positioning of the reference mirror (33) and the knowledge of the relationship between the OCT depth and the other imaging modality depth, which depends on both wavelengths, and the adjusted imaging depth for the null defocus term applied to the wavefront corrector.

[0104] According to FIG. 12, the depth-related signal (15) from the spectrometer (38) is analyzed to adapt the wavefront corrector (32) to focus on the desired retinal layer.

[0105] The depth-related signal (15) may be obtained by, but is not limited to, a Fourier domain setup combined with a wavefront probing source (18).

[0106] The transscleral-based images are processed using, but not limited to, time correlation techniques to extract functional images of blood flow.

[0107] According to FIG. 11, an OCT system (7) implemented as a full-field OCT obtains a depth-related signal (15) using a transpupillary flood illumination source (44).

[0108] According to FIG. 10, the beam directed towards the sclera (2) is used to provide: - Transscleral wide-field retinal anatomy imaging (26) - Transscleral wide-field retinal angiography images (27) - Transscleral high-resolution retinal anatomy images (28) - Transscleral high-resolution retinal angiogram (29).

[0109] Those skilled in the art will understand that the invention described herein is susceptible to variations and modifications other than those specifically described. It is to be understood that the invention includes all such variations and modifications without departing from its spirit or essential characteristics. The invention also includes all steps, features, compositions and compounds mentioned or shown in this specification, individually or collectively, and any and all combinations or any two or more of said steps or features. Therefore, the present disclosure should be considered as not limiting in all exemplified aspects, and the scope of the invention is indicated by the appended claims, and all changes that come within the meaning and range of equivalents are intended to be embraced therein.

[0110] Various references are cited throughout this application, each of which is incorporated herein by reference in its entirety.

[0111] [Table 1] [Table 2]

Claims

1. 1. An ophthalmic illumination system comprising: an oblique light delivery system (2) having one or more light sources (3) for providing oblique illumination of the fundus (1) and emitting transscleral or transpalpebral illumination light toward the sclera (4) of the eye (6) or the skin (5) surrounding the eye (6) to be measured, respectively; an optical coherence tomography (OCT) system (7) directed at a pupil (8) of an eye (6) to be measured, the optical coherence tomography (OCT) system (7) comprising an OCT light source (9), a reference arm (10), a sample arm (11) and a detection arm (14); the system further comprises an optical imaging system (17) for collecting light of the oblique illumination scattered by the fundus (1) and for producing one or more en-face images (51) of the fundus (1); 13. An ophthalmic illumination system, characterized in that the optical imaging system further comprises a focusing system configured to adjust a depth of an imaging plane of the optical imaging system in response to a depth-related signal provided by the OCT system (7).

2. The optical coherence tomography system (7) comprises: The system of claim 1 , further configured to generate a one-dimensional (16), two-dimensional (17) or three-dimensional (18) OCT image of the fundus (1).

3. The system of claim 1 or 2, wherein the optical imaging system (19) further comprises one or more light-sensitive detectors or cameras (35, 36) for providing the en face image (51) of the fundus (1).

4. 4. The system of claim 3, wherein the sequence of frontal images (51) is analyzed and processed to extract time-correlated information and enhance contrast of time-varying biological features such as blood vessels (52).

5. The system according to any of the preceding claims, wherein the depth-related signal (15) provides information of the depth of the front-facing image (51) within the tissue of the fundus.

6. The system of claim 5, wherein the depth-related signals (15) are processed to provide real-time closed-loop feedback (56) for controlling the depth of imaging of the front-facing image (51).

7. The system of claim 5, wherein the depth-related signals (15) are processed to provide open-loop control of the depth of imaging of the front-facing image (51).

8. The system according to any one of claims 3 to 7, further comprising correction means for correcting optical aberrations of the eye for at least one of said front-facing images (51).

9. The system of claim 8 , wherein the correction means is selected from among a static optical element or a computational means.

10. 9. The system according to claim 8, characterized in that the correction of the optical aberrations is performed in real time using an adaptive optics closed loop comprising a transpupillary probing light source (30), a wavefront sensor (31) and a wavefront corrector (32) capable of spatially shaping the wavefront of the light forming the front-facing image (51).

11. The system of claim 10, characterized in that the transpupillary probing light source (30) is the same as the OCT light source (9).

12. The system of any one of claims 1 to 11, further comprising a transpupillary flood illumination source (44) and an imaging system for generating a front image (51) of the fundus (1) from backscattered light (23) derived from the transpupillary flood illumination source (44).

13. The system according to any of claims 1 to 12, wherein the transscleral light delivery systems (2) providing transscleral oblique illumination of the fundus (1) have different wavelengths.

14. 14. The system of claim 13, wherein the different wavelengths provide functional information selected from the list comprising blood flow oxygenation and retinal pigment epithelial cell activity.

15. An ophthalmic illumination and imaging device, comprising a transscleral light delivery system (2) in combination with an OCT system (7) according to any one of claims 1 to 14, said ophthalmic illumination and imaging apparatus comprising: a scanning system (45) for scanning the fundus (1) using the OCT system (7); an aberration correction system including a probing light source (30), a wavefront sensor (31) and a wavefront corrector (32); A system for high-resolution transscleral anatomical or angiographic imaging (28, 29) using a high-resolution camera (36); A system for wide-field transscleral anatomical or angiographic imaging (26, 27) using a wide-field camera (35); A system for transpupillary anatomical or angiographic imaging (24) including a transpupillary flood illumination source (21) and a high resolution camera (36); 1. An ophthalmic illumination and imaging device comprising:

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