Devices and methods for in vivo measurement of corneal biomechanical responses

Abstract

An apparatus and method for non-contact in vivo measurement of one or more properties of the cornea or tear film with spatial resolution are presented. In certain embodiments, the cornea / tear film is probed at substantially normal incidence with a converging array of sub-beams from a multi-wavelength light source, and the reflected light is analyzed interferometrically to produce a time series of pachymetry maps. Measuring and analyzing thickness changes caused by differences between external and internal intraocular pressures, such as from eye pulsations or externally applied pressure changes, can obtain information about the biomechanical response of the cornea. In a preferred embodiment, the temporal changes in tear film thickness are measured and subtracted to produce normalized pachymetry data for biomechanical analysis. In certain embodiments, the apparatus is configured to measure the dynamics and distribution of the tear film using a converging or substantially parallel array of sub-beams.

Description

Technical Field

[0001] The present invention relates to apparatus and methods for optical metrology, in particular apparatus and methods for measuring the biomechanical response of the human cornea in vivo. However, it should be understood that the invention is not limited to this particular field of use.

[0002] Related Applications

[0003] This application claims priority to Australian Provisional Patent Application No. 2018902018 filed on 5 June 2018, the contents of which are incorporated herein by reference. Background Art

[0004] Any discussion of the prior art throughout the specification should in no way be considered as an admission that such prior art is widely known or forms part of the common general knowledge in the field.

[0005] Keratoconus is a degenerative disease in which local thinning and reduced stiffness cause corneal deformation, which directly impairs the quality of vision. Although the corneal deformation characteristics of more advanced keratoconus can be easily detected by corneal topography or thickness measurement, it is preferred that the disease can be detected at an earlier stage. For example, this will allow screening of people at risk of developing keratoconus, so that management strategies for the disease can be implemented before permanent damage occurs, and patient screening can be performed before refractive surgery. It is believed that early detection of keratoconus and other corneal diseases can be effectively achieved by measuring the biomechanical properties of the eye and looking for local weakening of the cornea. Specifically, the focal area of ​​the cone of the keratoconus is weakened and has different biomechanical properties from other areas of the cornea. This method can provide a distinction from other corneal perturbations, which may complicate diagnosis based solely on geometric features such as corneal elevation and thickness maps.

[0006] One technique for measuring the mechanical response of human tissues such as the cornea is optical coherence elastography (OCE), described, for example, in published U.S. Patent Application No. 2017 / 0290503 A1 entitled "Optical coherence elastography to assess biomechanics and detect progression of ocular and other tissues degenerative diseases". Vibrations in the tissue are excited by, for example, air puffs, ultrasound, or mechanical contact, and the mechanical response is measured by optical coherence tomography (OCT). The difficulty in using OCE for corneal measurements is the need to separate the effects of changes in intraocular pressure (IOP) from corneal abnormalities.

[0007] Brillouin microscopy has been proposed as a technique for mapping the mechanical strength of the cornea at least in vitro. For example, as described in Scarcelli et al'Biomechanical characterization of keratoconuscorneas ex vivo with Brillouin microscopy', Investigative Ophthalmology & Visual Science 55(7), 4490(2014), Brillouin shift measurements can provide information about the longitudinal modulus of the cornea. However, the equipment is relatively expensive due to the need for a high-resolution spectrometer. In addition, the technique is time-consuming due to the scanning requirements and requires high intraocular light intensity, which poses a challenge for in vivo use.

[0008] Several types of pachymeters for measuring corneal thickness are known, for example, based on ultrasound techniques such as corneal waveforms or optical techniques such as OCT, slit scanning, and Scheimpflug imaging. However, these techniques may not have sufficient accuracy to measure small spatial or temporal variations in thickness associated with corneal biomechanical responses, with repeatability reported to be about ±5 μm for many commercially available instruments, see, for example, McAlinden et al. "A comprehensive evaluation of the precision (repeatability and reproducibility) of the Oculus Pentacam HR", Investigative Ophthalmology & Visual Science 52 (10), 7731 (2011) and Correa-Perez et al. "Precision of high definition spectral-domain optical coherence tomography for measuring central corneal thickness", Investigative Ophthalmology & Visual Science 53 (4), 1752 (2012). Optical reflectometry techniques for measuring tear film thickness have a higher precision, on the nanometer level, especially when measuring over large areas of the cornea, but are less suitable for measuring corneal thickness that is more than about two orders of magnitude thicker than the tear film.

[0009] Studies of corneal pressure-induced deformation have shown that the eye and cornea can creep in shape due to changes in IOP of approximately ±3-6 mm Hg, with a variety of factors, including heart rate, changes in posture, fluid intake, circadian cycle, and certain medications. These shape changes can be measured over time periods of seconds or longer using conventional topographic techniques, such as Placido disc topography. It is also known that IOP fluctuates with ocular pulsation, as reported in a published U.S. Patent Application No. 2015 / 0313573 A1 entitled "Ophthalmic Elastography" using contact ultrasound technology applied in vitro to simulate pulsation. However, these pulsation-related shape changes are typically an order of magnitude smaller than those caused by the more gradual intraocular pressure changes mentioned above, and it is difficult to perform non-invasive in vivo measurements of corneal thickness at the sensitivity level required to evaluate the actual biomechanics of the cornea.

[0010] The corneal tear film is the first refractive surface encountered by light when entering the eye, and therefore plays an important role in eye health and vision, with abnormal tear film breakup leading to dry eye disease and abnormal vision. As recently reviewed in King-Smith et al "Mechanisms, imaging and structure of tear film breakup", The Ocular Surface 16, 4 (2018), the dynamics and causes of tear film breakup have been studied for many years. The thickness and surface shape of the tear film are important for determining tear film dynamics, but current imaging techniques are limited to measuring only one of the thickness or surface shape. Spectral domain OCT has been used to measure tear film thickness, for example, see dos Santos et al'In vivo tear film thickness measurement and tear film dynamics visualization using spectral domain optical coherence tomography', Optics Express 23 (16), 21043 (2015), but does not provide information about the surface shape. Therefore, there is a need for a device that can measure tear film thickness and dynamics over an extended area in which the shape and position of the eye can be taken into account.

[0011] Unless the context clearly requires otherwise, throughout the specification and claims, the words "include", "comprising", etc. should be interpreted in an inclusive sense, rather than an exclusive or exhaustive sense. In other words, they should be interpreted in the sense of "including, but not limited to".

[0012] Purpose of the Invention

[0013] It is an object of the present invention to overcome or ameliorate at least one limitation of the prior art, or to provide a useful alternative. It is an object of the present invention to provide, in a preferred form, an apparatus for rapid in vivo measurement of one or more corneal properties at multiple points within the cornea. It is another object of the present invention to provide, in a preferred form, an apparatus for in vivo measurement of temporal changes in corneal thickness or strain. It is another object of the present invention to provide, in a preferred form, a method for measuring tear film dynamics within an extended region of the cornea. Summary of the invention

[0014] According to a first aspect of the present invention, there is provided an apparatus for measuring one or more characteristics of a cornea, the apparatus comprising:

[0015] a first optical system including a light source and a spatial sampling element for generating a converging array of beamlets configured to simultaneously impinge upon at least a portion of the anterior surface of the cornea; and

[0016] The second optical system is used for:

[0017] capturing reflected or scattered light from the anterior surface and reflected or scattered light from a second surface or interface of the cornea;

[0018] measuring the relative phase between reflected or scattered light from the front surface and reflected or scattered light from the second surface or interface in the portion of the cornea illuminated by the sub-beam; and

[0019] The relative phase is monitored over time to obtain information about one or more properties of the cornea within the illuminated portion.

[0020] The apparatus is preferably configured so that, in use, the angle of incidence of the sub-beams on the front surface is within 3 degrees of normal incidence.

[0021] Preferably, the spatial sampling element comprises a lenslet array. In some embodiments, reflected or scattered light from the front surface and from the second surface or interface is captured by the spatial sampling element. In other embodiments, reflected or scattered light from the front surface and from the second surface or interface is captured by the second spatial sampling element.

[0022] Preferably, the apparatus comprises a processor for: generating a relative phase map of the illuminated portion of the cornea from the relative phase measurements; and monitoring the relative phase over time to determine temporal changes in the map.

[0023] The apparatus preferably comprises an interferometer for interfering reflected or scattered light from the front surface and from a second surface or an interface with a reference beam to produce one or more interference patterns. Preferably, the processor is configured to track the position of the sub-beam on the front surface using the one or more interference patterns to register two or more maps of relative phase acquired at different times.

[0024] In a preferred embodiment, the light source comprises a multi-wavelength light source, and the processor is preferably configured to calculate a tomographic profile of the cornea from the relative phase map. The tomographic profile may include one or more of amplitude, phase, or optical path length between the anterior surface and a second surface or interface. Preferably, the second surface or interface comprises the posterior surface of the cornea, such that the optical path length comprises a measure of corneal thickness.

[0025] In preferred embodiments, the processor is configured to determine the biomechanical response of the cornea to the relative difference between the intraocular pressure and the external pressure on the cornea from the temporal change in the optical path length. In certain embodiments, the processor is configured to determine the biomechanical response of the cornea to periodic intraocular pressure changes associated with eye pulsation. In other embodiments, the device is configured to change the external pressure on the cornea. In certain embodiments, the device is configured to change the external pressure by applying a source of distributed acoustic waves or by changing the ambient pressure at the cornea.

[0026] In certain embodiments, the processor is configured to determine, from the temporal change in optical path length, a biomechanical response of the cornea to a perturbation applied by one or more of: a jet source; an ultrasound source; or an acoustic radiation pressure source.

[0027] In certain embodiments, the device is configured to measure the temporal variation of tear film thickness on the cornea. Preferably, the processor is configured to: measure the temporal variation of tear film thickness on the cornea; and subtract the measured temporal variation of tear film thickness from the optical path length to provide a normalized measurement of the corneal optical path length.

[0028] According to a second aspect of the present invention, there is provided a method for measuring one or more characteristics of a cornea, the method comprising the following steps:

[0029] generating a converging array of beamlets configured to simultaneously impinge upon at least a portion of an anterior surface of a cornea;

[0030] capturing reflected or scattered light from the anterior surface and reflected or scattered light from a second surface or interface of the cornea;

[0031] measuring the relative phase between reflected or scattered light from the front surface and reflected or scattered light from the second surface or interface in the portion of the cornea illuminated by the sub-beam; and

[0032] The relative phase is monitored over time to obtain information about one or more properties in the illuminated portion of the cornea.

[0033] Preferably the method further comprises the steps of: generating from the relative phase measurements a relative phase map throughout the illuminated portion of the cornea; and monitoring the relative phase over time to determine temporal changes in the map.

[0034] Preferably, the method also includes the following steps: using a reference beam to interfere with reflected or scattered light from the front surface and from the second surface or interface to generate one or more interference patterns; and using one or more interference patterns to track the position of the sub-beam on the front surface for aligning two or more relative phase images acquired at different times.

[0035] In a preferred embodiment, the sub-beams are generated by a multi-wavelength light source and the relative phase map preferably provides a tomographic profile of the cornea. The tomographic profile may include one or more of amplitude, phase, or optical path length between the anterior surface and the second surface or interface. Preferably, the method also includes the step of determining the biomechanical response of the cornea to the relative difference between the intraocular pressure and the external pressure on the cornea from the temporal change of the optical path length. In certain embodiments, the biomechanical response of the cornea to periodic intraocular pressure changes associated with eye pulsation is determined.

[0036] In some embodiments, the method further comprises the following steps: applying a disturbance to the cornea, including one or more of air blowing, ultrasound or acoustic radiation pressure; and determining the biomechanical response of the cornea to the disturbance based on the temporal variation of the optical path length.

[0037] In certain embodiments, the method further comprises the step of measuring the temporal variation of tear film thickness on the cornea.The measured temporal variation of tear film thickness is preferably subtracted from the optical path length to provide a normalized measure of corneal optical path length.

[0038] According to a third aspect of the present invention, there is provided an apparatus for measuring one or more characteristics of a cornea, the apparatus comprising an optical system for:

[0039] generating a converging array of beamlets configured to simultaneously impinge upon at least a portion of a first surface or interface of the cornea;

[0040] capturing reflected or scattered light from the first surface or interface of the cornea and reflected or scattered light from a second surface or interface;

[0041] measuring a relative phase between first and second surfaces or interfaces on a portion of the cornea illuminated by the sub-beam; and

[0042] The relative phase is monitored over time to obtain information about one or more properties in the illuminated portion of the cornea.

[0043] In some embodiments, the optical system is configured to measure the phase of the first surface and the second surface or interface relative to a reference beam. In other embodiments, the optical system is configured to measure the phase of the first and second surfaces or interfaces relative to a reflection from a tear film on the cornea. The first surface or interface may include an air / tear film interface.

[0044] Preferably, the apparatus comprises a processor for: generating a relative phase map in the illuminated portion of the cornea from the relative phase measurements; and monitoring the relative phase over time to determine temporal changes in the map. The optical system preferably comprises a multi-wavelength source for generating the sub-beams, and the processor is preferably configured to calculate a tomographic profile of the cornea from the relative phase map.

[0045] According to a fourth aspect of the present invention, there is provided a method for measuring one or more characteristics of a cornea, the method comprising the following steps:

[0046] generating a converging array of beamlets configured to simultaneously impinge upon at least a portion of a first surface or interface of the cornea;

[0047] capturing reflected or scattered light from the first surface or interface and reflected or scattered light from a second surface or interface of the cornea;

[0048] measuring the relative phase between the first and second surfaces or interfaces in the portion of the cornea illuminated by the sub-beam; and

[0049] The relative phase is monitored over time to obtain information on one or more properties in the illuminated portion of the cornea.

[0050] In some embodiments, the phase of the first and second surfaces or interfaces is measured relative to a reference beam. In other embodiments, the phase of the first and second surfaces or interfaces is measured relative to reflection from a tear film on the cornea. The first surface or interface may include an air / tear film interface.

[0051] Preferably, the method further comprises the steps of: generating a relative phase map in the illuminated portion of the cornea from the relative phase measurements; and monitoring the relative phase over time to determine temporal changes in the map. Preferably, the sub-beams are generated from a multi-wavelength light source, and the relative phase map preferably provides a tomographic profile of the cornea.

[0052] According to a fifth aspect of the present invention, there is provided a device for inspecting a tear film on a cornea, the device comprising:

[0053] an irradiation system for irradiating the tear film or the anterior surface of the cornea at multiple points; and

[0054] a capture optical system for capturing a return signal including a super-reflection signal from the tear film or scattered light from the front surface at the plurality of points, the capture optical system having a capture angle,

[0055] The illumination system is configured, in use:

[0056] illuminating a first group of the plurality of points with light incident on the tear film or the anterior surface at an angle of incidence sufficiently close to normal incidence so that the super-reflection signal is within the capture angle, resulting in a group of higher intensity return signals; and illuminating a second group of the plurality of points with light incident on the tear film or the anterior surface at an angle of incidence sufficiently far from normal incidence so that the super-reflection signal is not within the capture angle, resulting in a group of lower intensity return signals;

[0057] And wherein the device further comprises a processor for:

[0058] processing the higher intensity and lower intensity return signal groups to obtain an optical coherence tomography measurement; and

[0059] A measure related to the thickness of the tear film is calculated from optical coherence tomography measurements of selected sets of higher intensity and lower intensity return signals.

[0060] In certain embodiments, the processor is configured to calculate a metric related to tear film thickness by fitting a surface to optical coherence tomography measurements of a group of lower intensity return signals; and calculating a difference between the surface of higher intensity return signals and a selected optical coherence tomography measurement. In other embodiments, the processor is configured to calculate a metric related to tear film thickness by fitting a first surface to optical coherence tomography measurements of higher intensity return signals; fitting a second surface to optical coherence tomography measurements of lower intensity return signals; and calculating a deviation between the first and second surfaces. The processor is preferably configured to monitor temporal changes in measurements related to tear film thickness.

[0061] In some embodiments, the processor is configured to determine a boundary between a group of higher intensity return signals and a group of lower intensity return signals. The processor can be configured to obtain information related to the thickness, quality or distribution of the lipid layer of the tear film from the size or shape of the boundary, or from its temporal variation.

[0062] Preferably the illumination system is configured to illuminate the front surface of the tear film or cornea at multiple points simultaneously. More preferably the illumination system is configured to illuminate the front surface of the tear film or cornea using an array of substantially parallel sub-beams.

[0063] In a preferred embodiment, the illumination system is configured to illuminate the first set of points with light that impinges on the tear film or anterior surface at an angle of incidence of less than 15 degrees, more preferably less than 8 degrees, and most preferably less than 4 degrees.

[0064] In a preferred embodiment, the illumination system is configured to illuminate the second set of points with light incident on the tear film or anterior surface at an angle of incidence greater than 4 degrees, more preferably greater than 8 degrees, and most preferably greater than 15 degrees.

[0065] According to a sixth aspect of the present invention, there is provided a method for examining a tear film on a cornea, the method comprising the following steps:

[0066] irradiating the tear film or the anterior surface of the cornea at a plurality of points;

[0067] capturing return signals using a capture optical system having a capture angle, the return signals comprising super-reflection signals from the tear film or scattered light from the front surface at the plurality of points, wherein a first group of the plurality of points is illuminated with light incident on the tear film or the front surface at an incident angle sufficiently close to normal incidence so that the super-reflection signals are within the capture angle, producing a group of return signals with higher intensity, and a second group of the plurality of points is illuminated with light incident on the tear film or the front surface at an incident angle sufficiently far from normal incidence so that the high-reflection signals are not within the capture angle, producing a group of return signals with lower intensity;

[0068] processing the higher intensity and lower intensity return signal groups to obtain an optical coherence tomography measurement; and

[0069] A measure related to tear film thickness is calculated from optical coherence tomography measurements of selected sets of higher intensity and lower intensity return signals.

[0070] In certain embodiments, the calculating step comprises: fitting a surface to an optical coherence tomography measurement of a lower intensity return signal; and calculating a difference between the surface of a higher intensity return signal and a selected optical coherence tomography measurement. In other embodiments, the calculating step comprises: fitting a first surface to an optical coherence tomography measurement of a higher intensity return signal; fitting a second surface to an optical coherence tomography measurement of a lower intensity return signal; and calculating a deviation between the first and second surfaces. Preferably, the method further comprises the step of monitoring temporal changes in a measure related to tear film thickness.

[0071] In some embodiments, the method further comprises the step of determining a boundary between a group of higher intensity return signals and a group of lower intensity return signals. The method may further comprise the step of obtaining information related to the thickness, quality or distribution of the lipid layer of the tear film from the size or shape of the boundary, or from its temporal variation.

[0072] Preferably, the front surface of the tear film or cornea is illuminated at multiple points simultaneously. More preferably, the front surface of the tear film or cornea is illuminated with an array of substantially parallel sub-beams.

[0073] In a preferred embodiment, the first set of points is illuminated with light incident on the tear film or anterior surface at an angle of incidence of less than 15 degrees, more preferably less than 8 degrees, and most preferably less than 4 degrees.

[0074] In a preferred embodiment, the second set of points is illuminated with light incident on the tear film or anterior surface at an angle of incidence greater than 4 degrees, more preferably greater than 8 degrees, and most preferably greater than 15 degrees.

[0075] According to a seventh aspect of the present invention, there is provided an article of manufacture comprising a non-transitory computer usable medium having a computer readable program code configured to operate an apparatus according to the first, third or fifth aspect, or to implement a method according to the second, fourth or sixth aspect. BRIEF DESCRIPTION OF THE DRAWINGS

[0076] Preferred embodiments of the present invention will now be described, by way of example only, with reference to the accompanying drawings, in which:

[0077] Figure 1A A spectral domain OCT device for measuring one or more characteristics of the cornea in vivo at multiple points with phase accuracy, i.e., nm-level accuracy, is shown in schematic form according to an embodiment of the present invention;

[0078] Figure 1B The schematic diagram shows Figure 1A Alternative configurations of the sample arm optics of an OCT device.

[0079] Figure 1C The schematic diagram shows Figure 1A Alternative configurations of the sample arm optics of an OCT device.

[0080] Figure 1D An alternative configuration for generating an array of beamlets and collecting return signals is shown in schematic form;

[0081] Figure 2 The structure of the tear film and human cornea is shown schematically.

[0082] Figure 3 The effect of changes in the axial position of the eye to the device on the apparent corneal thickness is shown.

[0083] Figure 4A and 4B The expected temporal variation of the reflected sub-beam power in multiple discrete wavelength bins is shown for six different starting tear film thicknesses ranging from 6 μm to 1 μm.

[0084] Figure 5A and 5BThe expected variation in power in a sub-beam reflected from the tear film over six seconds in multiple discrete wavelength bins for seven radial positions of the corneal apex is shown.

[0085] Figure 6 Depicted are plots of tear film thickness relative to the radial position of the corneal apex at various times from zero to six seconds after a blink.

[0086] Figure 7 An in vivo reflectivity image of a portion of the cornea illuminated with an array of beamlets is shown.

[0087] Figure 8 Schematic diagram showing the use of Figure 7 Methods for obtaining measurements related to tear film thickness from OCT data calculated from reflectance images;

[0088] Fig. 9 Schematically shows the Figure 7 A model of specular reflection and scattering that is consistent with the basic binary intensity distribution seen in ; and

[0089] Fig.10 Illumination of multiple points on the tear film or cornea is schematically shown. DETAILED DESCRIPTION

[0090] Figure 1A A spectral domain optical coherence tomography (OCT) device 100 suitable for in vivo measurement of one or more properties of a cornea 102 at multiple points with phase accuracy, i.e., nanometer-level accuracy, is shown in schematic form in accordance with an embodiment of the present invention. Light 104 from a broadband light source 106, such as a superluminescent diode having a central wavelength of 840 nm and a bandwidth of 40 nm, is collimated by a collimating element 108, such as a lens or parabolic mirror, linearly polarized by a polarizer 110, and then split into a reference beam and a sample beam 114, 116 by a polarization beam splitter cube (PBS) 112. A reference arm 117 includes a mirror 118, a movable shutter 120 for blocking the reference beam 114 when the device is not operating with a reference beam, and a quarter wave plate 122 for polarization conversion, so that light reflected from the mirror 118 passes through the PBS 112 and enters the detection arm 121. The reference arm 117 may also include relay elements and dispersion matching components for compensating for the dispersion of the optical devices in the sample arm 123. The mirror 118 can be moved axially to adjust the path length of the reference arm relative to the sample arm, for example, to match different eye positions or to obtain information from structures at different depths of the eye. Alternatively or additionally, the entire device 100 can be moved axially relative to the cornea 102 to adjust the distance from the eye to the device and, therefore, the path length of the sample arm 123.

[0091] The sample arm includes a quarter wave plate 138, a spatial sampling element in the form of a two-dimensional (2D) lenslet array 124 to produce from the sample beam 116 a 2D array of sample sub-beams 126 that are relayed to the cornea 102 via the lens system 128. In the illustrated embodiment, the lens system is non-telecentric and is designed so that the central rays of the relayed sub-beams 130 are incident at near normal incidence on the anterior surface 132 of the cornea, or more specifically, the air / tear film interface as explained below. The central rays of the converging array of relayed sub-beams 130 can, for example, converge at a point 134 that is approximately 8 mm beyond the focal plane 135 (i.e., beyond the surface where the sub-beam waists are located). In a preferred embodiment, the lens system 128 is designed so that the focal plane 135 is substantially spherical as shown, with the convergence point 134 of the sub-beams 130 being approximately at the center of curvature of the surface. Figure 1B In the illustrated alternative embodiment, the sample arm includes a telecentric or 4F lens system 170 designed to produce an array of relay beamlets 172 that propagate to the cornea 102 in a substantially parallel manner, in which case the focal planes of the beamlets will be substantially planar. To simplify the illustration, the lenses in the relay lens systems 128 and 170 are depicted as simple single element lenses, but in a preferred embodiment they have multiple elements to reduce distortion of the relay beamlets within the signal bandwidth. Figure 1C In yet another embodiment shown, the sample arm includes a lens system 174 that includes a conventional lens 176 and a compound lens 178. The compound lens includes a shorter focal length portion that directs an inner subset of the sub-beams 130 onto the cornea 102 at normal or near normal incidence, and a longer focal length portion that directs an outer subset 180 of the sub-beams onto the anterior sclera 182 or the limbus 184.

[0092] Light scattered or reflected from the anterior or posterior corneal surface 132, 136, or from other interfaces in the cornea 102 or from deeper ocular structures, passes back through the relay lens system 128, 170 or 174, is captured by the sub-lens array 124 and is reflected by the PBS 112 to the detection arm 121 after polarization transformation at the quarter wave plate 138. In general, the number of sub-beams 126 that can be relayed to the cornea 102 depends on the design of the 2D lenslet array 124, and in some embodiments, there can be, for example, about 100 or 1000 sub-beams in a square or rectangular pattern, with a density of 4-100 sub-beams / mm2 at the nominal focal plane 135, i.e., at the waist of the sub-beams 130 or 172. Figure 1A As shown, in use, the device is preferably positioned so that the nominal focal plane 135 is within or very close to the cornea 102. To enhance the relatively weak reflection from the posterior corneal surface 136, it may further be preferred that the nominal focal plane 135 is close to the posterior corneal surface 136.

[0093] If a reference beam 114 is present, it is combined at the PBS 112 with the reflected sample sub-beam 140 and the resulting combined beam analyzed by the polarizer 142 to interfere with the light from the sample and reference paths. If the reference beam 114 is blocked by the shutter 120, an interference signal is generated between the light reflected or scattered from two or more surfaces or interfaces of the eye, such as the air / tear film interface and the posterior corneal surface 136. Regardless of the source of the interference signal, the resulting interference pattern, containing information about the relative phase between the light reflected or scattered from two or more surfaces or interfaces in the eye, is relayed by the lens system 144 and an optional aperture 146 to eliminate stray light for spectral analysis in a spectrometer 148 at a grid of spatial locations determined by spatial sampling elements in the form of a 2D lenslet array 150 and a corresponding 2D aperture array 152.

[0094] The spectrometer 148 can analyze multiple grid points, beams or sub-beams simultaneously or at least within a single frame of the 2D sensor array 154 for snapshot acquisition. After entering the spectrometer 148, the interfering sub-beams are redirected by the PBS 158 to the lens 160, which collimates the sub-beams for dispersion by the grating 156 and then passes through the quarter wave plate 162 twice by reflection from the mirror 164 to rotate the polarization state by 90 degrees. After passing through the PBS 158, the dispersed spectral components are imaged by the lens 160 onto the 2D sensor array 154, such as a CMOS camera, to extract or measure the relative phase between the light reflected or scattered from two or more surfaces or interfaces in the eye, especially from two or more surfaces or interfaces in the cornea or tear film. In a preferred embodiment, the grating 156 is oriented relative to a grid of spatial positions determined by the 2D lenslet array 150 and the corresponding 2D aperture array 152 so that each combined sub-beam entering the spectrometer 148 is dispersed over a separate set of pixels of the 2D sensor array 154, as described in published U.S. Patent Application No. US 2016 / 0345820 A1, entitled "High resolution 3-D spectral domain optical imaging apparatus and method," the contents of which are incorporated herein by reference. As explained in more detail below, the relative phase between light reflected or scattered from two or more surfaces or interfaces in the cornea or tear film, or more simply, the relative phase between two or more surfaces or interfaces in the cornea or tear film, can be monitored over time in a series of snapshot measurements of the 2D sensor array 154 to obtain information about one or more characteristics of the cornea 102.

[0095] In some embodiments, the sample arm relay system 128, 170 or 174 also includes a scanning element 168, such as a MEMS mirror, for translating the array of relay sub-beams 130 or 172 across the cornea 102 in one or two dimensions, such as by "filling" the gaps between the sub-beams of the sub-beam array to create a dense map over a large area of ​​the cornea. This dense map is preferably time-averaged over many snapshots to average out time-dependent contributions to the measured thickness, such as from tear film dynamics and heart-related IOP fluctuations, and can be used as a reference or template for correcting eye movement artifacts, as described below. To simplify the illustration, the MEMS mirror 168 is shown as transmissive rather than reflective.

[0096] Figure 1A Several variations of the device 100 shown are possible. For example, separation and recombination of the sample and reference beams 116, 114 may be achieved using fiber couplers or non-polarizing beam splitters, or a 2D array of sample sub-beams 126 may be generated by a spatial sampling element in the form of an aperture mask, a MEMS mirror array, or a diffractive optical element instead of a lenslet array 124. In yet another variation, a 1D array of sample sub-beams may be generated using a 1D lenslet array or similar form of spatial sampling element, but a 2D array is generally preferred to obtain data over a larger area of ​​the cornea 102 in a single frame. It should be understood that as Figure 1D As shown, the array of sample sub-beams 126 may alternatively be formed by a first lenslet array 124 or other spatial sampling element placed before the beam splitter 112, and the reflected signal is captured by a second lenslet array 124-A, or other spatial sampling element located after the beam splitter 112 in the detection arm 121. In yet another variation, the lenslet array 124 is omitted and the cornea 102 is illuminated by an unstructured wave edge, but generally, it is preferred to illuminate the cornea with multiple discrete sub-beams in order to improve collection efficiency and reduce crosstalk generated by multiple scattering.

[0097] When measuring the eye in vivo, the cornea 102 is always covered by a tear film, in which case the first reflection will come from the air / tear film interface. Figure 2As shown schematically, the tear film 200 has multiple layers, including a thin outer lipid layer 202 and an aqueous layer 204 that contacts the anterior surface 132 of the cornea 102 via a mucus layer (not shown). It should be noted that the thickness 206 of the tear film is exaggerated relative to the thickness 208 of the cornea. Table 1 summarizes the main reflective surfaces of the corneal structure and calculates the nominal Fresnel reflection at normal incidence from the relevant refractive indices. In practice, the air / tear film reflectivity is determined by the aqueous layer, because the lipid layer is very thin and is typically slightly above 2% at normal incidence, with the intensity modulated by the structure and thickness of the lipid layer 202. Obviously it remains the strongest reflection, but reflections can also be detected from other surfaces or interfaces including the posterior corneal surface 136 and possibly from intracorneal structures such as the Bowman's layer 214. For the purposes of this specification and the appended claims, the term "anterior surface of the cornea" refers to the air / tear film interface 212 or the actual anterior surface 132 of the cornea 102, depending on whether a tear film 200 is present. The term "anterior surface of the cornea" refers specifically to the physical anterior surface 132 of the cornea, ie, the tear film / epithelial interface.

[0098]

[0099] Table 1

[0100] Recalling that the interference signal from the cornea 102 contains information about the relative phase between light reflected or scattered from two or more surfaces or interfaces in the cornea 102 or tear film 200, as previously described, the relative phase can be monitored over time in a series of measurements to obtain information about one or more properties of the cornea 102. In a preferred embodiment, the interference pattern detected by the 2D sensor array 154 is read out in a single frame for subsequent analysis by a processor 166 equipped with suitable computer readable program code to obtain spatially resolved measurements, i.e., maps, within each portion of the cornea 120 illuminated by the sub-beam 130. By reading out the sensor array 154 in a series of frames or snapshots over time, the processor 166 can monitor the relative phase over time to determine temporal changes in the relative phase map to obtain information about one or more properties of the cornea, such as thickness or biomechanical response, such as strain. In certain embodiments, the processor 166 uses the well-known Fourier transform-based OCT technique to obtain a map of the cornea 102 in the form of a depth-resolved image, also known as a tomogram or tomogram profile. The tomogram may, for example, include one or more of amplitude, phase, or optical path length between two or more corneal or tear film surfaces or interfaces at a grid of points determined by the positions of the relayed sub-beams 130 on the cornea 102. It should be understood that the optical path length between two corneal or tear film surfaces or interfaces is approximately equal to the product of the physical distance between those surfaces or interfaces and the effective refractive index, typically with a small deviation due to phase changes associated with reflection.

[0101] In certain embodiments, Figure 1A The spectral domain OCT device 100 shown is used in a snapshot multi-probe interferometry technique to determine nanometer-scale, extremely small temporal changes in corneal thickness at multiple points within the cornea 102 in vivo and to register the locations of the measurements on the cornea. Spatially resolved information about the biomechanical response of the cornea, such as metrics related to Young's modulus, can then be obtained from the measured thickness changes through finite element analysis. Although it has been demonstrated that the tear film 200 can be resolved over a range of thicknesses using OCT using a sufficiently broad spectrum light source 106, see, for example, dos Santos et al Optics Express 23(16), 21043 (2015), the tear film thickness 206 is close to its axial resolution limit of ~1 μm, which is not ideal for measuring spatial or temporal thickness changes. Therefore, in a preferred embodiment, we measure the corneal / aqueous interface 136 relative to the air / tear film interface 212, i.e., the combined tear film+corneal thickness 210, and track the changes in this combined thickness over time over a series of frames. In the absence of external pressure changes or perturbations, in general, a plot of combined thickness 210 versus time will show a gradual decrease over the seconds between blinks due to tear film flow or evaporation, with superimposed periodic fluctuations on the order of ~1 second due to corneal strain response to eye pulsation. These sources of temporal variation are uncorrelated and can be separated, for example, using standard curve fitting and subtraction techniques.

[0102] In a preferred embodiment, multiple pachymetry maps, i.e., measurements of tear film + corneal thickness 210 at multiple points within the cornea, are acquired over a few seconds at an appropriate frame rate. After the on-eye location of the pachymetry map is taken into account in the data analysis described below, the tear film changes are separated from the periodic fluctuations associated with the heartbeat to provide a map of corneal deformation versus time that can be related to the heartbeat. The typical rate of change of tear film thickness over five seconds is about 1 μm, corresponding to a phase change of about 1.7 degrees per frame at a frame rate of 100 Hz. Therefore, phase wrapping issues generally do not need to be considered, and the accuracy of the measurement can be maintained by tracking the phase over time. Therefore, by making ultra-sensitive in vivo measurements of the corneal biomechanical response to periodic IOP fluctuations caused by blood flow synchronized with the heartbeat, we can detect spatial changes in corneal elasticity.

[0103] In other embodiments, the device or method can be used to provide spatially resolved information about the biomechanical response of the cornea to external stimuli such as ultrasound, air puffs, or acoustic radiation pressure. Such external stimuli are typically localized. Alternatively, the device or method can be used to provide spatially resolved information about the biomechanical response of the cornea to distributed stimuli such as changes in ambient air pressure or distributed acoustic wave sources. The ambient pressure on the cornea can be changed by, for example, goggles or the like placed over the eye being tested. The device or method can also be applied to monitor changes in the biomechanical response over longer time frames, such as over longer periods of time, for detecting long-term corneal regression or for evaluating the effectiveness of clinical cross-linking treatments aimed at increasing corneal hardness.

[0104] In certain embodiments, the pachymetry map is generated with the device 100 operating as a standard Michelson interferometer, where reflections from interfaces such as the air / tear film interface 212 and the posterior corneal surface 136 are referenced to the reference beam 114. However, in a preferred embodiment, the device 100 is used as a common-path interferometer, where the reference beam 114 is blocked and instead uses reflections from the anterior corneal surface, typically the air / tear film interface 212, as a reference for reflections or scattering from other interfaces or surfaces, preferably including the posterior corneal surface 136. We note that the phase and intensity of the reflected "reference" light may be affected by the thickness of the lipid layer and its variations, and this effect can be simulated if necessary. Since the thin lipid layer 202 tends to affect the intensity of the average tear film reflection over the wavelength bandwidth employed, accurate calibration of the slope of the reflected intensity relative to the cornea relative to an incident beam of known reflection can also provide information about the thickness of the lipid layer. Although the signal-to-noise ratio of a common-path interferometer is slightly inferior to that of a standard interferometer, it has excellent phase stability and low noise during phase determination, providing high measurement accuracy. Furthermore, since all measured interfaces move together, common-path interferometry measurements are virtually unaffected by axial eye motion.

[0105] In a preferred embodiment, using Figure 1AThe array of converging sub-beams 130 shown, i.e., sub-beams incident at substantially normal incidence on the anterior surface of the cornea 102, generates a pachymetry map. That is, the angle of incidence of the central ray of the sub-beam 130 on the anterior surface of the cornea 102 is preferably within 3 degrees, more preferably within 2 degrees, and most preferably within 1 degree of normal incidence. This is particularly important for a common-path interferometry configuration because it provides a consistent specular reflection over a large area of ​​the cornea, from which reflections from other interfaces or surfaces can be referenced. Specular reflections can be captured from sub-beams incident on the cornea at other angles, but this will require additional optics to capture the reflected sub-beams. The preferred combination of common-path interferometry and a converging array of sub-beams incident at substantially normal incidence allows for phase-resolved corneal thickness to be measured in a spatially resolved manner, with sufficient sensitivity to detect very small changes in corneal thickness, and thus small changes in corneal elasticity.

[0106] In an alternative embodiment, using Figure 1B The array of substantially parallel sub-beams 172 shown generates a pachymetry map, although the signal intensity from the interface of interest beyond the apex of the cornea is typically strongly attenuated because strong specular reflections are not captured, impairing the accuracy of the phase measurement. Another difficulty when using conventional OCT is that the intensity of the tear film reflection at the corneal apex is typically comparable to the intensity of the reference beam 114, potentially resulting in multiple ghost reflections, which can complicate accurate reconstruction of the scattering distribution. This is particularly true if the signal intensity causes the detector to saturate. In conventional OCT, it is typically preferred to interfere the weak reflection signal from the sample with the stronger reference signal to provide phase and depth information from each scattering point in the A-scan. However, as described below, probing the eye with an array of substantially parallel sub-beams 172 can provide additional information about the tear film, including the thickness and quality of the lipid layer.

[0107] Although eye movement has little effect on phase stability when measuring corneal thickness maps using the device 100 configured for common-path interferometry, it can still affect measurement accuracy. For example, changes in the axial position of the eye relative to the device will affect the apparent curvature of the corneal surface. In addition, because the thickness of a healthy cornea increases gradually from the vertex to the periphery, typically varying by ~100 μm within a 4 mm radius, a lateral change in the position of the sub-beam, such as from translation or rotation of about 40 μm, will cause a corneal thickness change of ~1 μm. Both of these effects must be compensated to ensure sub-micron accuracy of the resulting interferometric corneal thickness measurement. In a preferred embodiment, a weak reference beam 114 is introduced for one or more conventional interferometry measurements to track the position of the tear film surface in a series of thickness maps. This makes it possible to align the thickness maps, thereby allowing correction of phase changes associated with eye movement. Relative to the frequency of common-path interferometry measurements, the frequency of acquiring these conventional interferometry measurements can be selected based on circumstances such as the angle of eye movement or the required measurement accuracy. To properly register the common-path pachymetry maps, in most cases it is sufficient to acquire regular interferometric measurements occasionally, e.g., once every five, ten, or twenty pachymetry measurements, optionally interpolating correction values ​​in each pachymetry measurement between consecutive registration measurements. To avoid saturating the sensor array 154, the intensity of the reference beam 114 in the registration measurement is preferably weaker than the intensity of the captured reflection of each beamlet, e.g., ~1% weaker than the ~2% specular reflection of the tear film.

[0108] Reference Figure 3 The registration process is explained by simulated interferometer data plotted in Figure 2, which shows how changes in the eye-to-device axial position, such as those caused by eye movement, affect the apparent curvature of various corneal interfaces. Figure 3 , the x-axis represents the radial position from the corneal vertex in mm, and the y-axis represents the optical path length from the anterior surface, typically the position 300 of the air / tear film interface 212, in μm. Using the device 100 configured for common-path interferometry, the position of the posterior surface 136 of the cornea relative to the anterior surface is measured as a function of radial position from two different eye-to-device axial positions, obtaining traces 302-A and 302-B. Since the position 300 of the anterior surface coincides with the x-axis, traces 302-A and 302-B represent a measure of the optical path length thickness 304 of the cornea as a function of radial position, which can be measured using a one-dimensional array of beamlets, although as previously described, the array of beamlets is preferably two-dimensional. Trace 306 depicts the Bowman's layer, which can be measured using Figure 1A Another interface measured by the apparatus 100 is shown.

[0109] In principle, the curvature of a trace such as 302-A or 302-B represents a gradual increase in corneal thickness away from the vertex, however, from the slightly different curvatures between these two traces 302-A and 302-B, it should be understood that changes in the eye-to-device axial position will affect the measurement of corneal thickness. When the device 100 is reconfigured for conventional interferometry using the reference beam 114, the position of the anterior surface of the cornea is measured for each of the two eye-to-device axial positions, thereby generating traces 308-A and 308-B. Importantly, the curvature of these traces 308-A and 308-B represents the apparent curvature of the anterior surface of the cornea relative to the planar reference mirror 118, depends on the optical path length difference between the reference and sample paths, and is therefore sensitive to the eye-to-device axial position. Therefore, the difference in curvature between these traces 308-A and 308-B allows a correction to be calculated and applied to the apparent curvature difference between the traces 302-A and 302-B. Figure 3 In FIG. 1 , traces 308 -A and 308 -B have been shifted on the y-axis relative to the other traces for ease of display, but in practice the actual relative positions of the traces are used to calculate the correction.

[0110] Despite its simplicity, Figure 3 Only the effect of changes in the axial position of the eye with respect to the device on the corneal thickness measurement is shown, but the same principles apply to corrections for changes in the curvature, shape or slope of the interference trace caused by translation or rotation of the eye relative to the device. Once the position of the eye is registered to the device using a registration frame obtained by conventional interferometry, small changes in apparent corneal thickness due to eye movement can be corrected. If necessary, geometry and Snell's law can be used to account for smaller terms in the deformation due to changes in the angle of incidence of the sub-beams on the anterior surface of the cornea. Advantageously, the use of e.g. Figure 1C For the lens system 174 shown in , the registration frame includes at least data from the anterior sclera 182 or the corneal limbus 184 to assist in interpreting displacement and rotation, as explained in published PCT patent application No. WO 2018 / 136993 A1 entitled “Optical coherence metrology and tomography with improved registration.”

[0111] If conventional interferometry is used rather than common-path interferometry to obtain corneal measurements, then the above-described registration procedure based on additional measurements using reference beam 114 is not required, although information about the position of the sub-beams on the eye needs to be processed. The above-described registration procedure can also be omitted if the cornea can be registered to itself, for example, using an existing accurate pachymetry map obtained using the MEMS mirror 168 described previously, or if eye motion can be tracked using a camera and MEMS mirror 168 adjusted to lock the position of sub-beam 130 on the eye to stabilize individual measurements.

[0112] A preferred approach to using the apparatus 100 for in vivo measurement of corneal properties such as thickness or biomechanical response can be summarized as follows:

[0113] a) Blocking the reference beam 114, preferably using Figure 1A The array of converging sub-beams 130 shown in FIG. 1C generates a map of the combined tear film + corneal thickness 210 represented by the interference trace 302-A, i.e., a thickness map, but other methods may also be used. Figure 1B An array of substantially parallel beamlets 172 is shown.

[0114] b) Unblocking the reference beam 114 generates a map of the tear film position relative to the device 100 represented by the interference trace 308-A.

[0115] c) For each subsequent pachymetry measurement or set of measurements 302-B, a new tear film position 308-B is determined.

[0116] d) Based on the apparent change in tear film position, i.e., comparison of tear film traces 308-A and 308-B, a correction for eye movement can be calculated and applied to a subsequent pachymetry map (or set of maps) 302-B. Any remaining differences between pachymetry maps 302-B and 302-A can be assigned to actual changes in the cornea 102 or tear film 200.

[0117] e) By acquiring additional pachymetry maps and correcting them for eye motion, changes in the combined tear film + corneal thickness 210 at multiple points throughout the cornea 102 can be tracked in time. For phase changes between measurements that are significantly less than π, if pachymetry maps are acquired at a high enough frequency, e.g., 100 Hz or higher, the relative phase between light reflected from the air / tear film interface 212 and the posterior corneal surface 136 can be tracked without accounting for phase wrapping.

[0118] f) Independent analysis of the contributions of the time-varying pachymetric data to (i) tear film flow or evaporation and (ii) strain response to heartbeat-related IOP fluctuations or external stimuli to provide spatially resolved information about tear film dynamics and corneal biomechanical response. For example, the gradual change in tear film thickness 206 can be subtracted from the pachymetric data to provide a normalized measure of corneal optical path length, i.e., thickness 208, and the strain response analyzed to provide a metric related to Young's modulus or some other stiffness or elasticity-related parameter at multiple points on the cornea 102.

[0119] Since the radius of curvature of the cornea changes from the apex toward the periphery, it may not be possible to capture the spectral reflectance corresponding to a complete map of the cornea within the numerical aperture of the lenslet array 124. Population-based calibration of the focal plane 135 can be designed into the relay lens, for example, Figure 1A 128 in the lens system. Alternatively, the device can be moved axially relative to the eye to optimize the capture of light reflected or scattered from areas of different radii of curvature. The above embodiments have been described for the case where the device 100 includes a multi-wavelength light source, such as a broadband source 106 that emits light in a continuous wavelength band. This makes it possible to obtain a tomographic profile of the cornea 102, preferably including a measure of corneal thickness. However, information about one or more characteristics of the cornea can also be obtained by probing the cornea with an array of sub-beams generated from a monochromatic light source. Monochromatic light only provides information about changes in the relative optical path length of the cornea 102 or the tear film 200 over time or between sub-beams, and it may be necessary to monitor the return light regularly to avoid phase wrapping artifacts. However, the information about the changes in relative optical path length obtained thereby can still infer properties at multiple points on the cornea in some low-cost embodiments, such as changes in relative strain or tear film thickness 206.

[0120] In other embodiments of the invention, where the high resolution lens relay 128 provides specular reflection over a large area of ​​the cornea 102, Figure 1A The device 100 is used to determine the tear film thickness dynamics, so that the tear film thickness 206 can be measured absolutely with sub-micron accuracy and nm-level relative accuracy, which is significantly better than the accuracy achievable with conventional OCT. In some embodiments, the reference beam 114 is preferably blocked by a shutter 120, and the wavelength-resolved signals read from each sub-beam 140 reflected or scattered by the illumination point on the cornea 102 by a suitably programmed processor 166 from the 2D sensor array 154 are each divided into, for example, six or seven 5 nm wide wavelength bins within a plurality of consecutive frames. Data is preferably collected within a time period that allows at least one interferometric measurement cycle, which corresponds to a period greater than λ / (2*n 泪 ) tear film thickness changes. For a broadband light source 106 with a central wavelength λ = 840 nm, and assuming that the tear film refractive index n 泪= 1.337, which is equivalent to a thickness change of at least 0.31 μm. From the typical thickness loss rate of the precorneal tear film 200 between blinks, the corresponding minimum data collection time can be estimated and is usually no more than a few seconds.

[0121] The processor 166 then calculates the temporal variation of the integrated power for each wavelength bin. Since the signal power within each bin is relatively high due to the return beamlet 140 having been specularly reflected from the cornea 102, a more accurate phase measurement can be achieved by taking advantage of the high signal-to-noise ratio and knowledge of the structure of the tear film 200. The combined reflection signal from each tear film layer is the main signal that is not averaged over the wavelength range of the wavelength bin and therefore has variations that depend on the tear film thickness 206, as shown below. Even without numerical analysis, we can clearly identify micron-level variations based on the propagation of the intensity plots of the wavelength bins over time. However, in order to measure the distribution of the tear film 200 within the cornea 102, we can also use phase information by tracking the phase changes between spatial sampling points. In a specific embodiment, the two-dimensional lenslet array 124 and relay optical device 128 provide sampling points on a 250 μm-spaced square or rectangular grid at the nominal focal plane 135 (i.e., the waist of the beamlet 130).

[0122] Figure 4A and 4B Plots 402, 404, 406, 406, 408, 410, and 412 of the expected temporal variation of the power in the reflected sub-beam in each of six 5 nm wide wavelength bins centered at 0.82, 0.825, 0.83, 0.835, 0.84, and 0.845 μm, respectively, are shown for six initial tear film thicknesses from 6 μm to 1 μm, assuming a constant rate of change of the tear film thickness 206. Each plot is calculated within 35 frames (i.e., within 3.5 seconds) measured at a 10 Hz frame rate, and the power variation in each of the six wavelength bins during the measurement period may be slightly more than one cycle.

[0123] Figure 5A and Figure 5BPlots 502, 504, 506, 506, 508, 510, 512 and 514 of the expected change in power in a sub-beam reflected over six seconds in each of seven 5 nm wide wavelength bins centered at 0.82, 0.825, 0.83, 0.835, 0.84, 0.845 and 0.85 μm, respectively, are shown for seven radial positions r measured from zero to 3.0 mm from the corneal vertex. These plots were generated for a tear film 200 that was initially 5 μm thick at the vertex (after a blink), and the model assumes that the tear film thickness 206 across the cornea is weakly parabolic and that the rate of loss increases with distance (r) from the vertex. These chosen assumptions are not necessarily realistic, although there is some evidence in fluorescein imaging of tear dynamics that tear film breakup typically occurs away from the vertex, which means that the initial thickness is smaller or the rate of thickness loss is higher. The main purpose of this assumption is to show how changes in parameters such as the rate of thickness loss can be revealed in this wavelength bin analysis. For example, for the r = 3.0 mm curve, the temporal power variation in each wavelength bin can be seen to cycle faster than in the curve at the apex.

[0124] Advantageously, using this approach, once we have specular back reflections, the tear film dynamics at specific locations or regions on the cornea 102 can be reliably analyzed over time. To improve phase stability, it is preferred to block the reference beam 114, i.e., use common path interferometry for measurements, since the tear film thickness 206 is less likely to be overly sensitive to small changes in position caused by eye movement. Alternatively, measurements can be made with the presence of a weak reference beam 114. Taking into account the power, relative position of the sub-beam waists and the angle of incidence on the tear film 200 and the spectral distribution of the light 104, the received signal can be normalized to improve the coupling efficiency. The effect of the lipid layer 202 can also be taken into account, which mostly appears as an attenuation term, since the bandwidth of its reflectivity distribution will typically be much wider than the bandwidth of the light source 106.

[0125] Although a series of experimental measurements at intervals of 250 μm or less in two dimensions can be made using the apparatus 100, depending on the design of the lenslet array 124 and the lens relay 128, the radial positions at intervals of 0.5 mm in only one axis in the cornea were calculated. Figure 5A and 5Bseries of seven figures shown in . Using the assumed continuity of the tear film thickness 206 as a function of small changes in tear film thickness over time and radial position intervals, the path of the descending profile can be selected using phase shifts of less than π / 2 between sample points to eliminate any phase ambiguity, allowing us to obtain an unambiguous tear film distribution over time, with a resolution limited only by the signal-to-noise ratio. Given the strong signal from specular reflection in each spectral band or wavelength bin, we expect that the temporal evolution of the tear film thickness 206 can be measured in vivo with an accuracy of a few nm. The previously described model or some other model can be applied to the data to determine the radial distribution of the tear film 200 at different time points. This Figure 6 As shown in , the tear film thickness (in μm) at t=0, 1, 2, 3, 4, 5 and 6 seconds after blinking is plotted against the radial position (in mm) from the corneal vertex, and the plots labeled 602 and 604 depict the tear film distribution at 0 seconds and 6 seconds, respectively.

[0126] The parameters of the selected model may also be adjusted to provide non-constant tear film dynamics and identify tear film breakup. The selected model may also include a factor to account for changes in lipid layer thickness, which as previously described generally acts to change the intensity of all spectral components over time.

[0127] The dynamics and distribution of the precorneal tear film 200 are of interest in providing information about the impact of tear film quality and consistency on the refractive properties of the eye. Tear film distribution (i.e., shape) is not typically captured in OCT images of non-specular topography, but is important for determining the refraction of the eye. Therefore, the additional information about tear film distribution provided by our analysis can lead to improved refraction estimates compared to refraction information obtained from corneal topography alone.

[0128] It is noteworthy that the detected return sub-beams 140 can be analyzed in the processor 166 using conventional OCT techniques, i.e., without the wavelength bin analysis described above. For example, the device 100 can be configured for common path interferometry, where the air / tear film interface 212 provides a common path reference beam, and various layers of the cornea 102, such as the anterior or posterior surfaces 132, 136, provide smaller reflections that can be detected by the edges. However, because the tear film 200 typically has a thickness 206 of only a few microns, and because it can be important to measure the tear film thickness to sub-micron levels during breakup, a very wide spectrum is required to separate the reflection peaks from the air / tear film interface 212 and the tear film / cornea interface 132. The required spectral width far exceeds the 40 nm bandwidth of the 840 nm light source 106 illustrated in the device 100. In contrast, wavelength binning analysis requires only a model with a priori information about the expected tear film structure and the temporal variation of the phase of light reflected from the tear film / corneal interface 132, and can provide sub-micron accuracy for tear film thickness 206 using an instrument with a much narrower spectrum, such as a 40 nm bandwidth. The same information can also be provided by analyzing the temporal variation of the phase and intensity of the Fourier components of the returned sub-beams 140, especially the lowest few spectral Fourier components. For simplicity, we describe the analysis of the model with respect to wavelength-dependent fringes, where the sensitivity to sub-wavelength shifts can be easily visualized and plotted, but this is not a limitation of the method.

[0129] Because the dynamics of tear film changes are on the order of seconds, and the frame rate of the spectrometer 148 is up to 300 Hz, the sampling density on the cornea can be increased by dithering the position of the sub-beam array 130 into a pattern with a repetition rate of 5 Hz. For the case of a 250 μm two-dimensional grid spacing on the cornea 102, we can use the MEMS mirror 168 to dither the sub-beam array with a peak-to-peak equivalent displacement on the axis connecting the grid points on the cornea, such as 300 μm, to provide a series of "B-scans" with some oversampling. This allows for full continuity of phase between points in space while still allowing the tear film dynamics to be captured at 5 Hz. As a potentially useful benefit of this approach, a measure of epithelial roughness can be derived or an epithelial distribution can be provided under the reasonable assumption that the tear film thickness 206 is a smooth function of position before any breakup occurs, so that any microstructure observed in the series of B-scans comes from the underlying roughness of the tear film / epithelial interface 132. This information gives nanometer-resolved roughness that can be of diagnostic value in refractive surgeries such as photorefractive keratectomy (PRK), where it is important to understand epithelial regrowth and how this affects the tear film and ocular refraction.

[0130] To recover the topography of the anterior corneal surface 132, the time-averaged decay of the tear film thickness is subtracted from the derived phase for each wavelength bin, noting that for tear film thicknesses of a few microns, at least some of the wavelength bin maps will typically have components in sensitive regions (i.e., away from the turning point) for most frames acquired. Thus, as a series of closely spaced B-scans, a measure of the surface roughness or even nanotopography distribution of the anterior corneal surface 132 can be provided along with the tear film distribution. It is noted, for example, in King-Smith et al'Tear film interferometry and corneal surface roughness', Investigative Ophthalmology & Visual Science 55(4), 2614 (2014) that the variability or roughness of the corneal surface distribution limits the ability of interferometric spectroscopy measurements, particularly in the visible to near infrared, to achieve high contrast levels. Notably, the use of a small focused spot in the present invention, and the ability to ensure that the spot size is maintained by accurately positioning the device 100 relative to the tear film 200 using standard OCT with a reference beam 114, should help overcome this limitation. In some embodiments, it may be advantageous to utilize a longer wavelength bandwidth, such as about 1550 nm, or to have additional longer wavelength bandwidths to enhance the contrast of the received signal.

[0131] In addition to providing information about tear film dynamics, the wavelength binning method also provides an alternative to the previously described curve fitting method for subtracting the contribution of tear film thickness 206 from the pachymetry map, i.e., the combined tear film + corneal thickness 210 at multiple points in the cornea 102. This ensures that the phase changes in the pachymetry map can be normalized at each time point to account for tear film thickness, thereby ensuring nanometer-level accuracy of corneal thickness 208, which is important for elastic imaging measurements of the cornea.

[0132] As explained previously, to measure corneal thickness, it is preferred to use a Figure 1A The array of converging sub-beams 130 shown, i.e., probing the eye with sub-beams incident on the front surface of the cornea 102 at substantially normal angles of incidence, provides a uniform specular reflection over a large portion of the cornea, against which reflections from other interfaces or surfaces can be referenced. Surprisingly, we have found that using the Figure 1B The array of substantially parallel sub-beams 172 shown probing the eye provides a wide range of incident angles on the cornea 102 useful for studying the tear film 200 , and in particular the lipid layer 202 . Figure 7An in vivo reflectivity image 700 of the cornea of ​​a portion of an eye of approximately 2 mm in diameter is shown by illuminating multiple points using a 12×24 array of substantially parallel sub-beams and integrating the reflected sub-beam power over a depth range. The array of sub-beams was generated using light from a (840±15) nm superluminescent diode sampled with a 2D lenslet array and extending to an area of ​​approximately 11 mm×14 mm. Image 700 shows a substantially binary intensity distribution with a central region 702 of high reflectivity and a rapid transition to an outer region 704 of lower reflectivity. The small dark square directly above the higher intensity region 702 is an artifact caused by a defective camera pixel. The shape and size of the higher intensity region 702 varies between individuals and for individuals over time, which is believed to be caused by changes in the thickness, quality, or distribution of the lipid layer 202.

[0133] In some embodiments, the reflectance image 700 is processed to delineate an inner region 702 of higher intensity and an outer region 704 of lower intensity, for example using a bimodal segmentation algorithm with a selected threshold to generate a boundary 706. Figure 8 As shown in FIG. 1 , depth data 804-H, 804-L in the higher and lower intensity regions 702, 704, calculated using standard optical coherence tomography techniques, such as from phase measurements relative to the reference beam 114, reveal a clear transition 806 in height around the boundary 706, typically 1 μm-6 μm. The magnitude of this transition 806, together with the Figure 7 The fact that the essentially binary intensity distribution shown in is not seen in test subjects such as the model eye, strongly suggests that the effect is related to the tear film. Therefore, the difference measurement between the selected depth data 804-H, 804-L in the higher and lower intensity regions 702, 704 provides a metric related to the thickness of the tear film. We note that although the axial imaging resolution is about 10 μm, by using sub-pixel sampling techniques to find edges and fit surfaces that allow averaging of a sufficiently large number of data points 804-H or 804-L, a height accuracy of better than 1 μm can be obtained.

[0134] In some embodiments, the first and second surfaces 800, 802 are fitted to the depth data 804-H, 804-L in the higher and lower intensity regions 702, 704, respectively, thereby allowing us to obtain a measure related to the tear film thickness from the offset 808 between the first and second surfaces 800, 802. In other embodiments, the surface 802 is fitted to the depth data 804-L in the lower intensity region 704, and the difference between the surface 802 and the selected depth data 804-H in the higher intensity region 702 provides a measure related to the tear film thickness.

[0135] The height difference or offset between the two surfaces 800, 802 or between the surface 802 and the selected depth data 804-H can be calculated at multiple locations, such as in the higher reflectivity region 702 or along the boundary 706, to provide a spatially resolved measure of the tear film thickness in the region or boundary, which can be averaged to provide a single tear film thickness measurement. Then, by offsetting the measurement points 804-H of the inner region 702 by the tear film thickness before merging the measurement points 804-H of the inner region 702 with the measurement points 804-L of the outer region 704, and fitting a surface through the combined points, the averaged or additional tear film thickness measurements can be used to calculate a corrected corneal topography 704. Advantageously, our edge finding method with a substantially binary intensity distribution eliminates the difficulties encountered by the previously mentioned standard OCT image segmentation techniques in separating the air / tear film interface from the tear film / cornea interface at a typical axial resolution of 5-10 μm.

[0136] exist Figure 7 The basic binary intensity distribution observed in Fig. 9 explain, Fig. 9 The interaction of two substantially parallel sub-beams 172-1, 172-2 (indicated by their central ray paths) with the lipid 202 and aqueous layers 204 of the tear film 200 and the anterior surface 132 of the cornea 102 is shown. Fig. 9 As schematically depicted in FIG. 2 , the lipid layer 202 has more texture than the aqueous layer 204. In a preferred embodiment, the sub-beams 172-1, 172-2 are as follows: Figure 1B Two of the multiple substantially parallel sub-beams produced by the combination of the 2D lenslet array 124 and the telecentric lens relay 170 are shown. One of the representative sub-beams 172-1 is incident on the tear film 200 and the cornea 102 at an angle of incidence 900 that is close to normal incidence, while the other representative sub-beam 172-2 is incident on the tear film 200 and the cornea 102 at an angle of incidence 902 that deviates significantly from normal incidence. For each sub-beam, a large portion of the light will experience a primary specular reflection 904 from the tear film 200 within a cone or angular range 906 that is largely determined by the textural properties of the lipid layer 202. A much smaller portion of the light in each sub-beam is scattered at the anterior corneal surface 132, and the scattering 908 is substantially isotropic. In addition, there will be a small amount of isotropic scattering from the lipid layer 202 and a weak specular reflection from the anterior corneal surface 132. These small components are not shown. Fig. 9 because they do not affect Figure 7 An explanation for the essentially binary intensity distribution seen in .

[0137] Reference Figure 1A and 1B, it should be understood that the 2D sensor array 154 will only detect return light from the cornea 102 or tear film 200 that is within the capture angle of the optical system used to capture the return signal. Whether the reflection 904 from the sub-beam 172 is detected depends on the curvature of the cornea, i.e., the size of the sample eye, the numerical aperture of the sub-beam 172, and the numerical aperture of the capture optical system, which in the illustrated embodiment includes the lens relay system 170 and the small lens array 124. For a sub-beam such as the representative sub-beam 172-1, which is incident on the tear film 200 at an incident angle 900 that is sufficiently close to zero (i.e., close to normal incidence), the detected return signal is dominated by the specular reflection 904 within the angle cone 906, resulting in the generation of a signal such as Figure 7 702 We will hereinafter refer to this brighter captured light from the combination of the tear film surface structure and specular reflection as the hyper-reflective signal 910. On the other hand, for beamlets incident on the tear film 200 at an angle of incidence 902 significantly greater than zero (i.e., away from normal incidence), such as the representative beamlet 172-2, no hyper-reflective signal 910 will be captured, and the main contribution to the detected return signal will be the isotropic scattering 908 from the anterior corneal surface 132, resulting in Figure 7 The lower intensity outer region 704 is seen in FIG.

[0138] In an alternative embodiment, the reflectance image 700 is processed using a segmentation algorithm with two thresholds. In the region 702 depicted by data points with intensities exceeding the higher threshold, the return signal is dominated by the hyper-reflection signal 910 affected by the lipid layer and can be used to fit the surface 800 corresponding to the air / tear film interface. In the outer region 704 depicted by data points with intensities below the lower threshold, the return signal is dominated by scattering 908 from the anterior corneal surface 132 and can be used to fit the surface 802 corresponding to the anterior corneal surface 132. When fitting either surface 800, 802, data points with intensities between the two thresholds that generally fall in the narrow band between the regions 702, 704 are not used. However, once the thickness of the tear film is determined, these intermediate points can be used as part of the height data by interpolating based on their offsets relative to the intensities of the two thresholds.

[0139] The observed variability in the shape and size of the bright central region 702 between individuals and for individuals over time is due to changes in the thickness, quality, or distribution of the lipid layer 202, which will affect the angular cone 906 of the specular reflection 904, and thereby the high reflection signal 910. Therefore, the shape or size of the bright central region 702 and changes in shape or size over time can be a useful indicator of the thickness, quality, or distribution of the lipid layer 202. Together with tear film thickness, this may prove useful in distinguishing different types of dry eye such as, for example, aqueous-deficient dry eye and evaporative dry eye.

[0140] In certain embodiments, tear film breakup or health is assessed by the dynamics of thickness and topology derived in or at the high reflectivity region 702. For example, machine learning techniques such as convolutional neural networks can be used in conjunction with large datasets of normal and diseased states of the eye to aid in the diagnosis and treatment of eye diseases, particularly dry eye disease. Once a sufficiently large database of existing eye health indicators is established, Figure 7 The association between the intensity distribution seen in (including the high reflective signal from the tear film on the one hand, and the health of the tear film and lipid layer on the other hand) is expected to yield important correlations or predictive value.

[0141] In certain embodiments, and with reference to Figure 8 , 9 and 10, a method for obtaining measurements related to the thickness of the tear film 200 on the cornea 102 by implementing:

[0142] (i) irradiating the tear film or the anterior surface of the cornea at a plurality of points 1000;

[0143] (ii) capturing return signals at a plurality of points 1000 using a capture optical system having a capture angle, the return signals including a super-reflection signal 910 from the tear film 200 or scattered light 908 from the front surface 132 of the cornea 102, wherein a first group 1002 of the plurality of points is illuminated by light 172-1 incident on the tear film or the front surface of the cornea at an incident angle 900 sufficiently close to normal incidence such that the super-reflection signal 910 is within the capture angle, resulting in a group of return signals with a higher intensity, and a second group 1004 of the plurality of points is illuminated by light 172-2 incident on the tear film or the front surface of the cornea at an incident angle 902 sufficiently far from normal incidence such that the super-reflection signal 910 is not within the capture angle, resulting in a group of return signals with a lower intensity;

[0144] (iii) processing the return signals of the higher intensity and lower intensity groups to obtain optical coherence tomography measurements 804-H, 804-L; and

[0145] (iv) Calculating a measurement 808 related to the thickness of the tear film 200 from selected optical coherence tomography measurements of the higher intensity and lower intensity groups of return signals.

[0146] The limiting angle of incidence for depicting the first and second groups of points 1002, 1004, i.e., the maximum angle of incidence beyond which the super-reflection signal 910 will not be captured, depends on many factors. These include the numerical aperture of the illuminating sub-beam 172 and the numerical aperture or capture angle of the optical system used to capture the return signal from the tear film 200 or cornea 102. The smaller the numerical aperture in any case, the smaller the limiting angle will result, or equivalently, the smaller the high-intensity central area 702. Importantly, the limiting angle or size of the central area 702 also depends on the characteristics of the tear film 200, thereby generating diagnostic value. The limiting angle of incidence is typically 4 degrees to 8 degrees, but may reach 15 degrees for some tear films. Therefore, an array of sub-beams 172 should be generated and directed onto the sample cornea 102 so that at least some of the sub-beams 172-1 have an angle of incidence 900 less than 15 degrees, more preferably 8 degrees and most preferably less than 4 degrees. Additionally, at least some of the sub-beams 172-2 should have an angle of incidence 902 greater than 4 degrees, more preferably greater than 8 degrees, and most preferably greater than 15 degrees.

[0147] In the above embodiment, Figure 7 The reflectance image 700 is obtained by illuminating the tear film 200 or cornea 102 at multiple points 1000 simultaneously with an array of sub-beams 172. Although this is preferred for the purposes of acquisition speed and minimization of eye movement artifacts, it is also possible to illuminate the tear film or cornea at multiple points in sequence using, for example, a scanning beam OCT device, followed by subsequent analysis of the reflectance image 700 or return signal in an equivalent manner.

[0148] Although the invention has been described with reference to specific embodiments, it will be appreciated by those skilled in the art that the invention may be embodied in many other forms.

Claims

1. An apparatus for measuring one or more properties of a cornea, the apparatus comprising: a first optical system including a light source and a spatial sampling element for generating a converging array of beamlets configured to simultaneously impinge upon a plurality of points within at least a portion of an anterior surface of the cornea; and The second optical system is used for: capturing reflected or scattered light from the anterior surface and reflected or scattered light from a second surface or interface of the cornea; measuring the relative phase between reflected or scattered light from the front surface and reflected or scattered light from the second surface or interface in the portion of the cornea illuminated by the sub-beam; and The relative phase is monitored over time to obtain information about one or more properties of the cornea in the illuminated portion.

2. The device according to claim 1, wherein: The apparatus is configured such that, in use, the angle of incidence of the sub-beams on the front surface is within 3 degrees of normal incidence.

3. The device according to claim 1 or claim 2, wherein: The spatial sampling element includes a lenslet array.

4. The device according to claim 1 or claim 2, wherein: Reflected or scattered light from the front surface and from the second surface or interface is captured by the spatial sampling element.

5. The apparatus according to claim 1 or claim 2, wherein: Reflected or scattered light from the front surface and from the second surface or interface is captured by a second spatial sampling element.

6. The apparatus according to claim 1 or claim 2, wherein: The device comprises a processor configured to: generating, from the measurements of the relative phase, a map of the relative phase in the illuminated portion of the cornea; and The relative phase is monitored over time to determine temporal changes in the graph.

7. The device according to claim 6, wherein: The apparatus comprises an interferometer for interfering reflected or scattered light from the front surface and from the second surface or interface using a reference beam to produce one or more interference patterns.

8. The device according to claim 7, wherein: The processor is configured to track the position of the sub-beam on the front surface using the one or more interference patterns to register two or more relative phase maps acquired at different times.

9. The device according to claim 6, wherein: The light source comprises a multi-wavelength light source, and wherein the processor is configured to calculate a tomographic profile of the cornea from the map of relative phases.

10. The device according to claim 9, wherein: The tomographic profile comprises one or more of amplitude, phase or optical path length between the front surface and the second surface or interface.

11. The device according to claim 10, wherein: The second surface or interface comprises the posterior surface of the cornea such that the optical path length comprises a measurement of corneal thickness.

12. The device according to claim 10, wherein: The processor is configured to determine, from the temporal change in the optical path length, a biomechanical response of the cornea to a relative difference between intraocular pressure and an external pressure on the cornea.

13. The device according to claim 12, wherein: The processor is configured to determine a biomechanical response of the cornea to periodic intraocular pressure changes associated with ocular pulsations.

14. The apparatus according to claim 12, wherein: The device is configured to vary the external pressure on the cornea.

15. The device according to claim 14, wherein: The device is configured to change the external pressure by applying a distributed source of acoustic waves or by changing the ambient pressure at the cornea.

16. The apparatus according to claim 10, wherein: The processor is configured to determine, from the temporal change in the optical path length, a biomechanical response of the cornea to a perturbation applied by one or more of: an air insufflation source; or an ultrasound source.

17. The apparatus according to claim 1, wherein: The device is configured to measure temporal changes in the thickness of the tear film on the cornea.

18. The apparatus according to claim 10, wherein: The processor is configured as follows: measuring temporal changes in thickness of a tear film on the cornea; and The measured temporal variation in tear film thickness was subtracted from the optical path length to provide a normalized measure of corneal optical path length.

19. A method for measuring one or more properties of a cornea, the method comprising the steps of: generating a converging array of beamlets configured to simultaneously impinge upon a plurality of points within at least a portion of an anterior surface of the cornea; capturing reflected or scattered light from the anterior surface and reflected or scattered light from a second surface or interface of the cornea; measuring the relative phase between reflected or scattered light from the front surface and reflected or scattered light from the second surface or interface on the portion of the cornea illuminated by the sub-beam; and The relative phase is monitored over time to obtain information about one or more properties of the cornea in the illuminated portion.

20. The method according to claim 19, further comprising the steps of: generating a map of relative phase in an illuminated portion of the cornea from the measurements of relative phase; and The relative phase is monitored over time to determine temporal changes in the graph.

21. The method according to claim 20, further comprising the steps of: Using a reference beam to interfere with reflected or scattered light from the front surface and from the second surface or interface to produce one or more interference patterns; and using the one or more interference patterns to track the position of the sub-beam on the front surface for aligning two or more relative phase images acquired at different times.

22. The method of claim 20 or claim 21, wherein: The sub-beams are produced by a multi-wavelength light source, and wherein the map of relative phases provides a tomographic profile of the cornea.

23. The method according to claim 22, wherein: The tomographic profile comprises one or more of amplitude, phase or optical path length between the front surface and the second surface or interface.

24. The method of claim 23, further comprising the step of determining, from the temporal variation of the optical path length, a biomechanical response of the cornea to a relative difference between intraocular pressure and external pressure on the cornea.

25. The method according to claim 24, wherein: The biomechanical response of the cornea to periodic intraocular pressure changes associated with ocular pulsation is determined.

26. The method according to claim 23, further comprising the steps of: Applying a disturbance including one or more of air blowing or ultrasound to the cornea; and determining a biomechanical response of the cornea to the disturbance based on the temporal change of the optical path length.

27. The method of claim 19, further comprising the step of measuring temporal changes in thickness of the tear film on the cornea.

28. The method according to claim 23, further comprising the steps of: measuring temporal changes in thickness of a tear film on the cornea; and The measured temporal variation in tear film thickness was subtracted from the optical path length to provide a normalized measure of corneal optical path length.

29. An apparatus for measuring one or more properties of a cornea, the apparatus comprising an optical system for: generating a converging array of beamlets configured to simultaneously impinge upon a plurality of points within at least a portion of a first surface or interface of the cornea; capturing reflected or scattered light from the first surface or interface and reflected or scattered light from a second surface or interface of the cornea; measuring a relative phase between a first surface or interface and a second surface or interface in a portion of the cornea illuminated by the sub-beam; and The relative phase is monitored over time to obtain information about one or more properties of the cornea in the illuminated portion.

30. The apparatus of claim 29, wherein: The optical system is configured to measure a phase of the first surface or interface and a phase of the second surface or interface relative to a reference beam.

31. The apparatus of claim 29, wherein: The optical system is configured to measure a phase of the first surface or interface and a phase of the second surface or interface relative to reflection from a tear film on the cornea.

32. The apparatus of claim 31, wherein: The first surface or interface comprises an air / tear film interface.

33. Apparatus according to any one of claims 29 to 32, wherein: The device comprises a processor configured to: generating a map of relative phase in an illuminated portion of the cornea from the relative phase measurements; and The relative phase is monitored over time to determine temporal changes in the graph.

34. The apparatus of claim 33, wherein: The optical system comprises a multi-wavelength source for generating the sub-beams, and wherein the processor is configured to calculate a tomographic profile of the cornea from the map of relative phases.

35. A method for measuring one or more properties of a cornea, the method comprising the steps of: generating a converging array of beamlets configured to simultaneously impinge upon a plurality of points within at least a portion of a first surface or interface of the cornea; capturing reflected or scattered light from the first surface or interface and reflected or scattered light from a second surface or interface of the cornea; measuring a relative phase between the first surface or interface and the second surface or interface in a portion of the cornea illuminated by the sub-beam; and The relative phase is monitored over time to obtain information about one or more properties of the cornea in the illuminated portion.

36. The method of claim 35, wherein: The phase of the first surface or interface and the phase of the second surface or interface are measured relative to a reference beam.

37. The method of claim 35, wherein: The phase of the first surface or interface and the phase of the second surface or interface are measured relative to reflection from a tear film on the cornea.

38. The method of claim 37, wherein: The first surface or interface comprises an air / tear film interface.

39. The method according to any one of claims 35 to 38, further comprising the steps of: generating a map of relative phase in an illuminated portion of the cornea from the relative phase measurements; and The relative phase is monitored over time to determine temporal changes in the graph.

40. The method of claim 39, wherein: The sub-beams are produced by a multi-wavelength light source, and wherein the map of relative phases provides a tomographic profile of the cornea.

41. A computer-readable storage medium storing a computer program, wherein: When the computer program is executed by a computer, it is configured to operate the apparatus according to any one of claims 1 to 18 or 29 to 34, or to implement the method according to any one of claims 19 to 28 or 35 to 40.

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