Interferometric laser speckle contrast imaging system and method

Abstract

An interferometer laser speckle contrast optics system is provided, configured to image only the thin, curved object layer of a selected object by limiting the depth of field, thereby distinguishing it from the surrounding, substantially unimaged curved object layer. This system employs a novel 5F optical system in the sample arm of the interferometer, improving spatial resolution and reducing the signal-to-noise ratio of the imaging process by substantially matching the curvature of the illumination plane with the curvature of the target object layer. Used as part of an ophthalmoscope, it can measure hemodynamic changes with capillary-level resolution to establish baseline values ​​for retinal neurovascular function.

Description

Technical Field

[0001] (Cross - reference to related applications) This international application claims priority based on U.S. Provisional Application No. 63 / 430,080, filed on December 5, 2022, and incorporates the entire disclosure thereof herein by reference.

[0002] (Statement regarding federally - sponsored research or development) This project has received funding and approval under grant R01EY027767 from the National Eye Institute. The government has certain rights in this invention.

Background Art

[0003] The present invention relates to laser speckle imaging, and more particularly, to a method of scanning interference optical imaging of a target with limited longitudinal spatial resolution, which intentionally avoids collecting optical information provided by the object space adjacent to the target, and at the same time expands the effective field of view of an imaging device by spatially adapting or matching the spatial distribution of illumination irradiated on an object through an optical system not statically but dynamically to the surface of the object to be imaged.

[0004] Laser speckle contrast imaging (LSCI), also called laser speckle imaging (LSI), is an image diagnostic method that analyzes the blurring effect of a speckle pattern. In LSCI, generally, light generated from a coherent light source is used to irradiate a rough object surface over a wide field of view. Next, an image is taken from the laser speckle pattern generated by the interference of coherent light using a photodetector (e.g., a CCD camera or a CMOS sensor, etc.). (In certain cases for biomedical applications, to increase the penetration depth of light into the target tissue, the coherent light is usually in the red or near - infrared spectral region.)

[0005] In this respect, LSCI is a promising but underutilized non-invasive and non-contact imaging technique that can create wide-field blood flow maps for quantifying retinal hemodynamics without the need for exogenous contrast agents. As with other applications of LSCI, illuminating retinal blood vessels with light generated from a coherent light source, for example, creates a random "speckle pattern." Here, the intensity of each pixel arises from the coherent summation of backscattered light with different optical path lengths. Motion within the field of view (FOV) (e.g., moving blood cells) causes temporal and spatial variations in the speckle pattern. The rate at which the intensity of each pixel changes over time is characterized by the decorrelation time of the speckle autocorrelation function. When this dynamic speckle pattern is recorded over a finite integration time set by the camera exposure time, the integration time is longer than the decorrelation time, resulting in a speckle blur effect (the degree of which is called speckle contrast K). Speckle contrast K is usually quantified as the ratio of the standard deviation of the time-integrated speckle intensity to the mean intensity (Equation 1). This ratio is used, for example, when high temporal resolution is required within a small spatial window of 5x5 or 7x7 pixels (referred to here as "spatial processing"), or when high spatial resolution is required at the same pixel position over time (referred to here as "temporal processing").

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[0006] One common reason why existing LSCI devices cannot adequately analyze the movement of particles / elements within an object is that the range in the longitudinal direction of the object (axial direction, measured along the inspection ray) is extremely small, and the useful signal information received from the object is significantly lost due to light reflected from the surrounding space to the optical imaging system. A specific example of a biomedical application is that existing human LSCI devices cannot analyze and evaluate hemodynamic changes in the microvascular system. (For example, see Patel, DD et al., "Development of a Preclinical Laser Speckle Contrast Imaging Instrument for Assessing Systemic and Retinal Vascular Function in Small Rodents," Translational Vision Science & Technology 10, 19 2021; Cho, KA et al., "Portable, non-invasive video imaging of retinal blood flow dynamics," Scientific Reports, 10, 20236, 2020; Feng, X et al., "Functional imaging of human retina using integrated multispectral and laser speckle contrast imaging," J Biophotonics, e202100285, 2021) This represents a significant technological gap that prevents the effective use of LSCI as a diagnostic tool in a situation where vascular dysfunction in Alzheimer's disease (AD) and its comorbidities primarily affects small vessels such as capillaries first or exclusively. [Overview of the Initiative]

[0007] Multiple embodiments of the present invention provide a system having an optical imaging device. The optical imaging device comprises an optical interferometer having a sample arm and a reference arm, and an optical relay subsystem in the sample arm. Such an optical relay subsystem has a first lens and a second lens (separated in the axial direction by a distance exceeding the sum of the focal lengths of the first and second lenses, which in one case necessarily exceeds), and is configured to form a spatially curved image plane having corresponding curvatures that are variable as a function of the distance. In at least one case, the system has a full field of view of at least 15 degrees and / or at least 30 degrees, and / or the first lens and the second lens are each an optical doublet (in a particular embodiment, multiple lenses may be configured as substantially similar optical doublets). In substantially each realization, the system is configured as an ophthalmoscope and may further have a light source (having a coherence length substantially included in the range of about 200 microns to about 450 nanometers). Alternatively or additionally, and substantially in each embodiment, the system may have a light source and be configured to irradiate an object with light formed at the output of the light source device and to register laser speckles representing the object with an optical detector of the system. (In at least one case, such a light source may be configured to interchangeably form or generate the light as a first light or a second light, the first light and the second light having different corresponding degrees of temporal coherence.) Alternatively or additionally, and substantially in each embodiment, the system may have a multiport optical device, a light emitter (e.g., such as a laser diode) optically coupled to a first port of the multiport optical device, an optical reflector optically coupled to a second port of the multiport optical device, and optical switches optically coupled to both the second and third ports of the multiport optical device.Alternatively or additionally, and substantially in each embodiment, the system has or is characterized by a light source having an input section (defined by an emitter having a first spectral bandwidth), an intermediate section of the light source, and an output section (defined by an optical switch optically separated from the input section by the intermediate section). In such a case, the intermediate section is configured to transmit light from the input section to the output section along a first optical path and a second optical path (where the first optical path has an optical reflector and is configured to transmit first light having a bandwidth substantially equal to the first bandwidth from the emitter to the output section, and the second optical path is configured to transmit second light having a spectral bandwidth substantially equal to the spectral bandwidth of the optical reflector from the emitter to the output section). In one or more of the above embodiments, the light source is configured to transmit optical outputs, interchangeably formed in a first optical output mode and a second optical output mode, toward an optical interferometer (where the spectral bandwidth of the optical output in the first output mode is at least 10 times narrower than the spectral bandwidth of the optical output in the second output mode). Alternatively or additionally, and substantially in each embodiment, the system may include an optical circulator, an optical reflector, an optical amplifier, and an optical switch optically isolated from the optical circulator by the optical circulator, the optical reflector, and the optical amplifier, respectively. Optionally, each implementation of the system may be implemented by a programmable data processing electronic circuit (or, simply put, a processor) operably connected to the optical detector and tangible non-temporary storage medium of the system. Such a storage medium contains program code thereon, which is configured to determine a motion index (the object or its interior illuminated by light passing through the optical interferometer) in an object illuminated by light passing through the optical interferometer, at least partially based on the speckle contrast characteristics of at least one optical image of an object formed by the optical detector.Optionally, such an object may be represented by a retinal layer or a choroidal layer (in which case the program code is configured to determine the blood flow velocity in a reference vessel in the retinal layer or choroidal layer as the object).

[0008] Multiple embodiments of the present invention further perform at least the following steps by substantially using the systems according to each of the embodiments described above: (a) dynamically matching (or spatially confirming with respect to such first spatial curvature) a first spatial curvature of a curved illumination surface (formed by illumination light propagated from the light source of the system through the illumination subsystem) with a second spatial curvature of a spatially curved object layer of material, in other words, a spatially curved layer of an object (where the illumination subsystem has a sample arm of an optical interferometer); (b) illuminating the spatially curved object layer of the material with the illumination light by substantially spatially superimposing the curved illumination surface with the spatially curved object layer of the material; and (c) forming an optical image of the curved object layer by spatially superimposing, in an optical detector of a light collection subsystem, sample light (returned from the spatially curved object layer irradiated with the illumination light) onto a portion of the illumination light delayed with respect to the sample light. In at least one embodiment, the dynamic matching can be configured to substantially match the first spatial curvature to the second spatial curvature over at least 15 degrees of the entire field of view (FOV) of the illumination subsystem, and / or over at least 20 degrees of the entire field of view (FOV) of the illumination subsystem, and / or over at least 30 degrees of the entire field of view (FOV) of the illumination subsystem. Optionally, the method is characterized by at least one of the following: (i) the dynamic matching step is performed substantially concurrently with the illumination step; (ii) the illumination surface is substantially optically conjugate to the light source; and (iii) the illumination step includes illuminating the spatially curved object layer of the material with illumination light having a coherence length that does not necessarily exceed the thickness of the spatially curved object layer of the material, and / or is substantially equal to the thickness. In particular, in substantially each implementation of the method, the spatially curved object layer of the material has a spatially curved laminate of a plurality of material layers.Optionally, the dynamically matching step of at least one realization of the method may include axially repositioning the first lens of a multi-lens optical relay system contained within the sample arm. Alternatively or additionally, and substantially in each embodiment, the step of forming an optical image may include forming an interference image of only the spatially curved object layer of the material (and not an interference image of other parts of the object space adjacent to the spatially curved object layer of the material) by optically interfering the sample light with a portion of the illumination light in an optical detector. Substantially, each embodiment of the method may optionally include the step of generating first and second images of the spatially curved object layer of the material, representing the curved layer at different depths, respectively, by varying the delay between the sample light and the portion of the illumination light. (In one particular implementation of the method, which includes the step of generating a first image and a second image, the spatially curved object layer of the material may be selected to include only one and no more structural layers among a plurality of structural layers located at the back of the eyeball, in which case the generating step is configured to include imaging only one of the plurality of structural layers in the depth direction and not imaging the other structural layers.) The step of generating the optical image may include forming an optical image that simultaneously represents the microvessels of the retina of the eye over a field of view of at least 15 degrees and / or a field of view of at least 20 degrees and / or a field of view of at least 30 degrees. Alternatively or additionally, and substantially in each embodiment, the method may include the step of additionally forming the illumination light interchangeably (as a first illumination light or a second illumination light) by transmitting the light emitted by the light emitter to an optical switch that optically separates the light emitter from the optical interferometer (where the first illumination light and the second illumination light correspond to different first and second bandwidths, respectively, and are characterized by differing by at least an order of magnitude in amplitude to ensure the ability to illuminate / irradiate an object with substantially incomparable degrees of light in one particular case).When the illumination light is thus interchangeably formed, the method may further include forming the second illumination light by at least partially spatially superimposing (i) a first portion of the light emitted by the light emitter and reflected by an optical reflector, and (ii) a second portion of the light emitted by the light emitter. (Optionally, the first and second portions of the light emitted by the light emitter may be further amplified after spatial superposition.) The spatial superposition process may include transmitting both the first and second portions through the same port of a multiport optical device optically separated from the optical switch by the optical reflector. Multiple embodiments of the method may further include transmitting the light emitted by the light emitter to the optical switch along spatially distinct first and second optical paths (the first optical path passing through an optical circulator and a fiber Bragg grating, and the second optical path passing through the optical circulator and an optical amplifier). Alternatively or additionally, and substantially in each embodiment, the method may include a step performed using a programmable data processing electronic circuit (simply put, a processor) operably connected to the optical detector, such a step being to determine an index of motion occurring in the spatially curved object layer, at least in part on the speckle contrast characteristics of the optical image of the spatially curved object layer. Optionally, when such a determination occurs, the method may be complemented by generating a visually perceptible output representing the dynamic change of motion over a predetermined period of time, at least based on the determination. It should be understood that, if the curved object layer of the material is a layer of biological tissue, or when it is a layer of biological tissue, the index of motion may be a parameter of blood flow in the biological tissue. For example, when the curved object layer of the material is a layer of the retina or choroid of the eye, determining the index of motion may include determining the blood flow velocity of a reference vessel in the curved object layer of the material.(In this case, the method may be further complemented by generating a visually perceptible output showing a change in the quantification of retinal hemodynamics over a predetermined period, at least based on the determination.)

[0009] Multiple embodiments of the present invention further include computer program products incorporating program code that embodies various realizations of the methods described above.

[0010] This invention can be better understood by referring to the following detailed description in conjunction with the drawings. [Brief explanation of the drawing]

[0011] [Figure 1] This is a schematic diagram of the eyeball. [Figure 2] An optical imaging system according to a generalized embodiment of the present invention is schematically shown, and its use demonstrates the feasibility of the proposed method. [Figure 3] Figure 4 shows the optical layout of a conventional 4F optical relay compared to the optical layout of an optical relay according to one embodiment of the optical imaging system of the present invention, which is used in the sample arm of an interferometer. [Figure 4] This shows the optical layout of an optical relay according to one embodiment, used in the sample arm of an interferometer in an optical imaging system according to one embodiment of the present invention. [Figure 5A-5B] It exhibits the various image field curvatures mentioned above. [Figure 6A-6B] The present invention provides a spot diagram comparing two different viewing angles and characterizing an optical relay configured according to one embodiment of the present invention, as well as a conventional 4F type optical relay. [Figure 7] This is a plot of the optical path-length difference (OPLD) of light propagating through one embodiment of the optical subsystem 110, showing a round-trip OPLD of less than ±0.1 mm over a half-FOV of approximately 15 degrees. [Figure 8A]Figure 4 shows a specific version of a generalized embodiment of the optical system of the present invention, characterized by the same performance characteristics as those described with reference to the generalized embodiment in Figure 4. [Figures 8B-8D] Figure 8A shows the various parts of the optical train according to the embodiment shown. [Figure 9] Figure 8A shows the modeled reference wavefront on the surface of a CMOS according to a specific embodiment, demonstrating that the wavefront error in PV (peak-to-valley) is less than 0.16λ. [Figure 10] The left side shows the illumination path through the curved surface layer of the object (in this non-limiting example, the curved surface layer of the eye), and the right side shows the focusing path of light due to reflection (or scattering) from the curved surface layer of the object. Both figures show how the light ray revolves around the center of curvature of the curved surface layer of the object. [Figure 11] Figure 8A shows both a graph representing the modulation transfer function (MTF; upper part of the figure) and a spot diagram (lower part of the figure) that demonstrate the diffraction-limited performance according to the embodiment when imaging the retina of the eye onto a CMOS sensor. [Figure 12] This is a schematic diagram of one particular embodiment of a light source that can actually complement the optical system according to one embodiment of Figure 4 and / or Figure 8A. [Figure 13] Figure 12 is a graph showing a typical optical spectrum of the light output generated by a light source according to one embodiment. [Modes for carrying out the invention]

[0012] Generally, the size and relative scale of elements in drawings may be set differently from reality to adequately facilitate the conciseness, clarity, and understanding of the drawings. For the same reason, not all elements present in one drawing are necessarily shown in another. Certain embodiments are shown in the drawings with the understanding that the disclosure is illustrative, but these particular embodiments are not intended to limit the scope of the invention described and illustrated herein.

[0013] In accordance with the concept of the present invention, embodiments of the LSCI apparatus and related methods are realized by employing interferometric imaging to intentionally and necessarily limit the depth of field to a substantially comparable length in the spatial range of the object being imaged along the axis of the inspection ray. By implementing the concept of the present invention, it is possible to determine the parameters of motion occurring in the object without considering optical information received from adjacent spatial portions of the object, thereby effectively improving the signal-to-noise ratio of the measurement. In an unlimited case, for example, when applied to biological tissue such as the retina, embodiments of the proposed LSCI method can be used to perform quantitative measurements of hemodynamics, including changes in blood flow and vascular function, on a very short spatial scale. (As the retina is an extension of the central nervous system and neurodegeneration progresses in AD, imaging of retinal blood vessels may offer a promising alternative approach to assessing neurovascular health in dementia patients. Importantly, because retinal blood vessels can be visualized directly and non-invasively through the pupil, it is expected that even slight structural or functional abnormalities can be detected, even in the pre-clinical disease stage, thus providing an unparalleled opportunity to diagnose AD early, assess its progression over time, or monitor the effectiveness of therapeutic interventions.) However, as any skilled operator would readily understand, any use and / or reference of any part of the eye in the following discussion should be understood to be merely specific examples, and the proposed apparatus and methodology should be considered applicable to general optical imaging.

[0014] The need to configure each embodiment of the present invention to intentionally limit the depth of field is, in contrast to existing LSCI systems and almost all full-field OCT systems, due to the multilayer structure of various objects (as an example without specific limitations, the posterior part of the eye, for example, as schematically shown in FIG. 1, the choroid, sclera, and retinal material layers in the posterior part of the eye are explicitly shown), the recognition that the ability of conventional imaging systems to have a signal-to-noise ratio (SNR) exceeding a specific threshold level is necessarily limited. (As an example without specific limitations that are selected, an example of imaging the eye, for example, imaging only the blood vessels of one of the choroid and retina and not imaging the other.) In fact, the optical interference signals arriving from adjacent layers (in the selected example, the other of the choroid and retina) necessarily reduce the actually achievable SNR and complicate the measurement of changes in blood dynamics that should be measured at least at the capillary level of resolution.

[0015] In accordance with the idea of the present invention, the formation of a desired and intended shallow depth of field is performed by intentionally reducing and / or limiting the coherence length of the light for investigating the sample / object to a geometric range equal to or shorter than the thickness (axial range) of a specific object (incidentally, making the coherence length so selected more generally object-dependent).

[0016] Furthermore, each embodiment of the present invention is configured to change the axial position of the region of the object space imaged within an intentionally limited shallow depth of field by a scanning operation performed by adjusting a part of an optical interferometer that is part of the optical imaging system of the embodiment in accordance with the idea of the present invention.

[0017] Furthermore, in contrast to currently available LSCI techniques, the proposed embodiments of the LSCI apparatus are configured to take into account the spatial curvature of the object (in the case of imaging the blood vessels of the choroid and / or retina, the spatial curvature of these ocular structural layers). This practical advantage provided by the discussed embodiments cannot be simply overstated. In the design of conventional LSCI systems, the imaging plane of the system is substantially flat, and only a small region of a curved object (in one case, the retina, choroid) that occupies the center of a few degrees of angular space lies in the exact imaging plane. Therefore, the natural curvature of the imaged object necessarily severely limits the LSCI field of view (FOV). In contrast to what is available in the related art, embodiments of the present invention are configured to dynamically adjust (i.e., vary) the curvature of the image plane of the optical imaging system according to the embodiment without changing the set of optical elements or components included in the embodiment.

[0018] Overall, as will be understood by a person skilled in the art from this disclosure, the problem that existing LSCI techniques cannot simultaneously generate a snapshot of an image of a spatially curved object configured as a material layer of limited thickness and spatially resolve different depths of that object in each image (while also negating optical information reaching from parts of the object space surrounding the object) is solved by devising a Michelson interferometer-based scanning LSCI apparatus. This apparatus is configured to image the object with light having a coherence length equal to or shorter than substantially the axial range of the object and to match (i.e., substantially match) the curvature of the illumination plane generated by the apparatus to that of the object.

[0019] The following discussion regarding the application of the proposed methodological embodiments includes a discussion regarding the imaging of the human visual system, but such an application is merely a specific example chosen because there are multiple spatially curved layers in that visual system. A person skilled in the art will clearly understand that the use of the proposed methodological embodiments is applicable to biological objects in the same way as to inanimate objects.

[0020] Figure 1 provides a diagram of the eyeball, a specific object, where some of the objects of interest are identified, represented by the spatially curved layers of the choroid and / or retina of the eye. [Examples]

[0021] (Example 1) Figure 2 shows a generalized schematic diagram of one embodiment 200 of the laser speckle imaging apparatus of the present invention, in which a custom-configured optical system 210 is incorporated into the sample arm of a free-space interferometer (shown in this particular case as a Mickelson interferometer). When the object being imaged 216 is a part of the eye, this embodiment may be called an interferometric laser speckle contrast ophthalmometer, or ILSCO. The optical system 210 is configured to produce a curved imaging plane (occupying at least 15 degrees, preferably 30 degrees of FOV, in some cases) with a shallow, object-dependent depth of field limited to an axial range of the object (about 250 microns to about 450 microns in the case of the retina and / or choroid). The object-dependent imaging field can be centered on the object (in a selected example, either the neuroretina or the choroid) through adjustment of the reference arm of the apparatus 200. The reference arm is shown to include several optical elements (as shown in the figure: ND, neutral density filter; L2, optical lens; RF, reflector driven at least axially by a micropositioner; PZT, piezo). The apparatus 200 may further include another amplitude and / or spectral filter F between it and a light source 220 (generally including an emitter and optionally including additional constituent optical components necessary to properly configure the light supplied to the interferometer, shown simply as a superluminescent diode, SLD) configured to produce light L (wavelength about 780 nanometers) at a desired low coherence length. The light L is substantially collimated by a collimating optical system (not shown) and then directed through lens L1 to a beam splitter BS and an auxiliary collimating lens CL, and the spatially overlapping portion of the light from the reference arm and sample arm of the interferometer apparatus passes through the auxiliary collimating lens CL to the photodetection system 230.

[0022] Compared to most full-field OCT systems or conventional LSCI systems of related technologies (which utilize light with a coherence length of at least a few microns), the selection of a light source, referred interchangeably here as light source 220 or a combination of light source 220 and filter F (e.g., a notch filter), is configured to have a coherence length long enough to cover virtually all thicknesses of the retina (average approximately 250 to 350 microns) and to produce light short enough for the device 200 to interferentially cancel out light reflected from the choroid (typically about 200 to 450 microns thick), and vice versa. Since the coherence length is related to the Fourier transform of the spectrum of light transmitted to the object 216, in this embodiment of the example, a custom-made optical bandpass filter applied to the light emitted from the narrowband SLD 226 can be used to select a desired coherence length value. A skilled operator can easily understand that the intentionally limited coherence length of the light used to image the spatially curved object 216 generates axial cross-sections of the object in which different sublayers (or different parts of the object located at different depths) of the object 216 are imaged in different LSCI images acquired using the optical detection system 230 at different lengths of the reference arm of the apparatus 200 (indicated by arrow 226) during the operation.

[0023] An additional operational feature of Embodiment 200 (whose need is not considered or anticipated by the LSCI systems of the related technology) is that the device 200 is configured to form a spatially curved imaging plane (or an illumination plane that overlaps with the object during imaging). In particular, referring to the specific example of imaging the posterior part of the eye, it is possible in principle to carefully select and position the constituent optical system to match (i.e., substantially match) a single retinal curvature; however, natural variations in human anatomy inevitably lead to differences in the focal length, refractive index of the eye's natural lens, the shape of the eye, and the curvature of the choroid / retina from subject to subject. Thus, an immutable solution remains substantially impractical.

[0024] To address the need to dynamically and in real time change the curvature of the illumination surface, the optical system 210 is configured to variably match the curvature of the retina by moving a single constituent lens of the optical system 210 (in one implementation, this may be controlled by an adjustment knob by an operator or by piezo-based repositioning) and / or by adjusting the working distance (i.e., the nearest separation between the optical system 210 and the object relative to the object objective lens).

[0025] The concept of the proposed solution is illustrated with reference to Figures 3 and 4. Figure 3 schematically shows an embodiment of a conventional so-called 4F optical system, which includes a combination of two lenses that perform a cascade of the Fourier transform of light passing through that combination (essentially a telescope with a finite conjugate positioned to the left of the objective lens 304 and to the right of the condensing lens 308, with one focal length to the left). Figure 4 shows an embodiment of optical system 410 (representing optical system 210 in Figure 2), whose working length is approximately 5F compared to related technologies.

[0026] In the conventional 4F design of the optical system 310 in Figure 3, the intermediate image plane IM-310 is designed to be as close to the telecentric position as possible. However, in the substantial 5F design according to the embodiment in Figure 4, the image plane curvature is intentionally guided to the intermediate image plane IM-410 (see Figure 5A). When this intentionally formed additional image plane curvature, which was not present in the operation of the conventional 4F optical system, is imaged onto an object (e.g., the curved retinal layer of the eye, RD in Figure 5B), an illumination plane is created that better matches the curvature of the retina, minimizing the shift in focus across the entire FOV (see Figure 5B).

[0027] Returning to Figures 2 and 4, in one realization, the constituent lenses 404 and 408 of Embodiments 410 and 210 were custom Prussel eyepieces separated by a distance greater than the sum of their focal lengths. When properly designed, this arrangement produces a curved image plane behind the eye and minimizes the optical pathlength difference (OPLD) across half the field of view (see Figure 7), which is important for the ophthalmic application of the device 100. The curvature of the posterior focal plane and the OPLD plane can be adjusted by changing the spacing between PE1 and PE2 and refocusing the camera 230 (maintaining a constant working distance).

[0028] Figures 5A and 5B are plots showing the empirically and / or theoretically determined curvatures of the intermediate image planes / surfaces IM-310, IM-410 and illumination planes (final image planes) SI-224, SI-228 in the conventional 4F optical system of Figure 3 used in the embodiment of Figure 2 and in the embodiment of Figure 4 used in the embodiment of Figure 2, respectively. The slight negative curvature of the spatial light distribution generated on the intermediate image plane IM-210 by the conventional system of Figure 3 is attributable to at least lens aberrations.

[0029] In practice, both systems in Figures 3 and 4 were implemented using the same commercially available lenses (Edmund Optics, Barrington, N.J., and ThorLab, Newton, N.J.), optimized with ray tracking software (RadiantXemax, Redmond, Washington) and the Goncharov and Dainty eye model, which was established as an adult eye model for non-wide-field systems (see A.V. Goncharov and C. Dainty, "Wide-field schematic eye models with gradient-index lens," J.Opt.Soc.Am.A24(8), 2157-2174, 2007, the disclosure of which is incorporated herein by reference). Refractive errors were modeled by changing the axial length of the eye model (see A. Dubra and Y. Sly, “Reflective afocal broadband adaptive optics scanning ophthalmoscope,” Biomed.Opt.Express 2(6), 1757–1768, 2011, the disclosure of which is incorporated herein by reference).

[0030] The design of embodiment 410 of system 210 (see Figure 4) was optimized so that the Strehr ratio is maintained above 0.7 within a 30-degree FOV and corrected refractive error range. In both the conventional 4F system in Figure 3 and the new systems 410 and 210 in Figure 4, moving the corresponding collimating lenses (denoted as 308 and 408, respectively) changes the amount of field curvature correction.

[0031] Both systems 310 and 410 had the same diffraction-limited resolution (Airy radius of 12.0 micrometers), but the 410, a substantial 5F design of system 210, produced a diffraction-limited spot over a field of view of approximately 30 degrees (the full angle, limited by clipping at the lens aperture), whereas the 4F design in Figure 3 produced a diffraction-limited spot over a field of view of only approximately 16 degrees (see Figures 6A and 6B).

[0032] Embodiments of the optical system 410,210 (located within the sample arm of the interferometer of apparatus 100) are configured in accordance with the concept of the present invention to dynamically correct a reference radius of curvature of 12 millimeters for the object being imaged (e.g., the retina or choroid of the eye) and to dynamically adjust the working distance, for example, between about 11 millimeters and about 14 millimeters (thus covering the typical curvature range of an adult retina), thereby achieving a spatial resolution of 8 microns (Airy radius) over a full FOV of at least 15 degrees (and in certain related embodiments, 30 degrees).

[0033] Those skilled in the art who benefit from this disclosure will readily understand that embodiments of the present invention provide a method for canceling out-of-plane signals using temporal coherence gating, which generates an interference signal when light emitted from a coherent light source (e.g., a laser diode) passes through a sample path and a reference path, and the optical path lengths of the sample path and the reference path match (within a specific length known as the coherence length) upon recombination. By shortening the coherence length to be substantially comparable to or smaller than the axial range of the object, and by using a custom optical relay incorporated into the optical interferometer, embodiments of the present invention generate a curved imaging plane (at least 15 degrees of full FOV, or at least 20 degrees of full FOV, or even at least 30 degrees of full FOV) and a shallow depth of field (between about 250 microns and about 500 microns, depending on the selection of the coherence length of light measured in the middle of the object / sample, taking into account the group refractive index of the sample medium), which is sufficient for LSCI-based imaging of the motion of elements of the curved object, while substantially canceling out the light scattered by the surrounding volume in object space and returned to the optical imaging system. In certain embodiments, this cancels out the light reflected from the basal choroid, making it possible to detect only the flow information from the retinal microvessels, or vice versa. Accordingly, the realization of the idea of ​​the present invention appears in a system comprising an optical device including (i) an optical interferometer having a sample arm and a reference arm, and (ii) an optical relay system in the sample arm, the optical relay system being configured to a) include the first lens and the second lens separated axially by a distance exceeding the sum of the focal lengths of the first and second lenses, and b) to form a spatially curved image plane having a curvature that is necessarily variable as a function of the distance and the working distance of the imaging device.

[0034] For LSCI imaging of the human visual system, there is no need to be concerned with axial resolution, but only with axial cross-section. In other words, as an option, according to the embodiments of the apparatus described above, when imaging the posterior part of the eye during operation, it is only necessary to cancel out the light signals returned from (e.g.) the choroidal signal, and it is not necessary to analyze individual blood vessels in the retina axially. In fact, in some embodiments, it may be preferable not to analyze individual blood vessels axially. Indeed, in some realizations, it is preferable not to analyze individual blood vessels axially because such an axial resolution requirement adds an additional dimension (i.e., depth coordinate) to the recorded image set, dramatically increasing the amount of data that needs to be stored and processed. A preferred realization in some situations of the proposed LSCI apparatus is configured to detect light reflected from the retina and cancel out light reflected from the choroid, while generating unanalyzed images with two-dimensional depth at a high frame rate (100 frames per second).

[0035] Referring again to Figure 2, in one implementation, the optical detection system 230 includes a Lucid Vision 2k×2k monochrome camera capable of providing critical sampled LSCI images with a spatial resolution of 8 microns and an FOV of at least 15 degrees (at least 30 degrees in relevant embodiments) at 480 fps. Four LSCI frames are required to reconstruct a coherent image, and therefore the system can, for example, provide quantitative flow measurements of blood in some blood vessels of the eye at 120 Hz across the entire 15-degree (or 30-degree) FOV, and can capture human retinal hemodynamics quickly enough.

[0036] This new instrument design allows for precise axial cross-sections of retinal or choroidal blood vessels using the LSCI modality, enabling independent measurement of hemodynamic changes in one or the other tissue. This has a profound impact on the diagnosis and clinical management of diseases including (but not limited to) diabetic retinopathy, age-related macular degeneration (AMD), hypertension, and dementia (including Alzheimer's disease), which cannot be addressed with current imaging modalities, particularly in hemodynamic changes in choroidal vessels (AMD) or retinal microvessels (other diseases).

[0037] (Example 2) Figure 8A provides a schematic diagram of an optical imaging device 800, which is operationally comparable to the above embodiment of a system structured according to the concept of the present invention. In embodiment 800, at least the optical system of the interferometer's sample arm is modified somewhat compared to that described in Example 1. Furthermore, as will be understood from the following discussion, the adjustment of at least the temporal coherence of the light transmitted from the light source through lens L1 in Figure 8A (indicated by the arrow) to the optical interferometer is performed by the light source itself, compared to the use of filter F in Example 1. Figures 8B, 8C, and 8D complement Figure 8A and schematically show parts of embodiment 800 of the optical imaging device that are easily identifiable by a skilled operator, showing the combination of the device's illumination unit and the sample arm of the configuration interferometer (see Figure 8B), the combination of the device's illumination unit, the reference arm of the configuration interferometer, and the acquisition optical system marked as a camera lens (see Figure 8C), and the combination of the configuration interferometer's sample arm and camera lens (see Figure 8D).

[0038] A complete and detailed description of the design of the optical system of this optical imaging device is not provided here to avoid unnecessarily complicating the disclosure. However, relevant data that may inform the operator about the design details of the optical system combination shown in Figure 8D is provided in the appendix below to provide the necessary written explanations and to allow the operator to understand the design details of Example 2 by referring to Figure 8A. Herein lies some preliminary note. In particular, the data presented in the appendix focuses primarily on providing an overview of the optical surfaces of the combination of elements in Figure 8D. The numbering of each surface begins with "10" (surfaces "1" through "9" and "15" through "20" are surfaces of other parts of the overall optical system, see Figure 8A). This is a de facto standard representation for the Zemax® software on which this design was performed. Glass notations are from the Schott® glass catalog. Details that are not substantially important to the purpose of this disclosure, such as vignette coefficients, surface data details, edge thickness data of constituent lens elements, refractive index data, global vertex coordinates, orientation, and rotation / offset matrices generated by Zemax®, are omitted for the sake of brevity of the explanation.

[0039] Figure 9 shows a modeled reference wavefront on the surface of a CMOS according to a specific embodiment of Figure 8, exhibiting a wavefront error of less than 0.16λ peak-to-valley. Figure 10 provides on the left a diagram of the path of illumination to a curved layer of an object (selected as the curved layer of an eye in this unrestricted example), and on the right a diagram of the path of light collection by reflection (or scattering) from such a curved layer of an object. Both diagrams show rays rotating through the center of curvature of the curved layer of the object. Figure 11 shows a plot representing the modulation transfer function (MTF; top of the figure) and a spot diagram (bottom) showing the diffraction-limited performance of the embodiment in Figure 8A when imaging the retina of an eye onto the CMOS.

[0040] As those skilled in the art will readily understand, other operating characteristics / parameters of Embodiment 800 are substantially similar to or substantially equal to those of the optical imaging apparatus of Example 1.

[0041] At the same time, the light source (which can be equipped in the optical imaging device 800 of this embodiment to form the system of the present invention) can have a different structure from conventional ones so that the coherence of the light transmitted through the lens L1 is appropriately controlled. For this purpose, Figures 12 and 13 provide information showing an embodiment of such a light source that is suitably used in an embodiment of the optical imaging device of the present invention.

[0042] For example, as shown in Figure 12, a polarization-maintaining (PM) fiber-coupled light emitter, in this non-limiting example, operates at approximately 850 nanometers and is represented by a superluminance diode (SLD) with an FWHM bandwidth of approximately 27 nanometers. It directs light from the emitter to a PM multiport optical device (represented here as an optical circulator, CIRC), and then directs the light through the corresponding ports of the multiport optical device to an optical reflector. In the specific case shown in Figure 12, the optical reflector is selected as a custom PM fiber Bragg grating (FBG). In this specific case, the FBG has a peak reflectivity of 93% at 851.92 nanometers and an FWHM of 0.47 nanometers.

[0043] Light reflected from the FBG returns to the circulator and is led to a semiconductor optical amplifier (SOA). The output from the SOA and the output (throughput) from the optical reflector are both led to an optical switch (here a MEMS switch), whose output can be quickly switched / changed / selected between the low-time coherence output of the optical reflector (equivalent to the notched SLD output) or the designed coherence output of the SOA (see Figure 13). The SOA output is measured with an optical spectrum analyzer (OSA) and has an FWHM bandwidth of 0.46 nanometers, which is approximately the same as the bandwidth of the optical reflector (here FBG). The gain of the SOA was set so that the output stabilized at 20 milliwatts.

[0044] Therefore, depending on the specific implementation of the system of the present invention, it can be understood that the optical imaging device (including the optical interferometer as described above) may be complemented by any one or any combination of the following: An optical circulator, an optical reflector, an optical amplifier, and an optical switch (optically isolated from the optical circulator by the optical circulator, optical reflector, and optical amplifier, respectively); The light source comprises a light-emitting element optically coupled to the first port of a multiport optical device, an optical reflector optically coupled to the second port of the multiport optical device, and an optical switch optically coupled to both the second and third ports of the multiport optical device; A light source comprising an input section defined by a light emitter having a first spectral bandwidth, an intermediate section of the light source, and an output section defined by an optical switch optically separated from the input section by the intermediate section. The intermediate section is configured to transmit light from the input section to the output section along a first optical path and a second optical path, the first optical path containing an optical reflector and configured to transmit first light having a bandwidth substantially equal to the first bandwidth from the light emitter to the output section, and the second optical path configured to transmit second light having a spectral bandwidth substantially equal to the spectral bandwidth of the optical reflector from the light emitter to the output section; A light source configured to transmit optical outputs alternately formed in a first optical output mode and a second optical output mode toward an optical interferometer, wherein the spectral bandwidth of the optical output in the first output mode is at least 10 times narrower than the spectral bandwidth of the optical output in the second output mode.

[0045] In at least one case, the control, image acquisition, and data processing of optical mechanical components may be performed using custom software. Therefore, at least one embodiment may include an electronic circuit / processor controlled by instructions stored in memory. The memory may be random access memory (RAM), read-only memory (ROM), flash memory, or other memory, or a combination thereof, suitable for storing control software or other instructions and data. Those skilled in the art will also readily understand that the instructions or programs defining the functions of the present invention may be delivered to the processor in a variety of forms, including but not limited to information permanently stored in a non-writable storage medium (e.g., a read-only memory device in a computer such as ROM, or a device readable by a computer I / O attachment such as a CD-ROM or DVD disc), information variably stored in a writable storage medium (e.g., a floppy disk, removable flash memory, and hard drive), or information transmitted to a computer via a communication medium, including a wired or wireless computer network. Furthermore, while the present invention can be embodied in software, the functions necessary to carry out the present invention may also be embodied in part or in whole using, optionally or alternatively, combinational logic, application-specific integrated circuits (ASICs), field-programmable gate arrays (FPGAs), firmware and / or hardware components, or other hardware, or a combination of hardware, software and / or firmware components.

[0046] While the present invention has been described through the exemplary embodiments described above, it will be understood by those skilled in the art that modifications and changes can be made to the illustrated embodiments without departing from the concept of the invention disclosed herein. For example, an LSCI apparatus related to the present invention was configured to image moving elements of an object at a field of view of 30 degrees (15 degrees in another case) in the eye of a mouse. The apparatus achieved a frame rate of up to 376 fps across the entire field of view and enabled resolution of pulsating flow even when the mouse's heart rate increased (up to 840 bps).

[0047] Wherever the terms “one embodiment,” “an embodiment,” “related embodiment,” or similar terms are used throughout this specification, it means that any particular feature, structure, or characteristic described in relation to such “embodiment” is included in at least one embodiment of the present invention. Therefore, wherever the terms “one embodiment,” “an embodiment,” and similar terms are used throughout this specification, they do not necessarily all refer to the same embodiment, although they may all refer to the same embodiment. It should be understood that no part of the disclosure is intended to fully describe all the features of the present invention, either by itself or, in some cases in conjunction with the figures.

[0048] In this disclosure and the accompanying claims, the use of “substantially,” “approximately,” “about,” and similar terms with respect to descriptors of values, elements, properties, or features at hand is intended to emphasize that the values, elements, properties, or features referred to are not necessarily exactly as stated, but are practically considered to be as stated by those skilled in the art. When applied to a particular property or quality descriptor, these terms reasonably indicate approximations, meaning “almost,” “mainly,” “quite,” “generally,” “essentially,” “mostly or to a considerable extent,” and “mostly, not necessarily exactly the same,” and describe the particular property or descriptor so that its range is understood by those skilled in the art. In one particular case, when the terms “approximately,” “substantially,” and “about” are used with respect to a numerical value, they represent a range of plus or minus 20%, more preferably plus or minus 10%, even more preferably plus or minus 5%, and most preferably plus or minus 2% from the given value. As an example without limitation, two values ​​being “substantially equal” means that the difference between the two values ​​is within plus or minus 20% of the values ​​themselves, preferably within plus or minus 10% of the values ​​themselves, more preferably within plus or minus 5% of the values ​​themselves, and even more preferably within plus or minus 2% or less of the values ​​themselves. The use of these terms when describing selected properties or concepts does not imply or provide any basis for ambiguity or numerical limitations of that property or descriptor. As a person skilled in the art will understand, the actual deviation between the exact value or property of such a value, element, or property and the stated value or property may vary, while remaining within a numerical range defined by the experimental measurement error that typically occurs when using measurement methods accepted in the art for that purpose.

[0049] The use of these terms when describing selected characteristics or concepts does not imply or provide any basis for any ambiguity or numerical limitations of those characteristics or descriptors. As a person skilled in the art will understand, the actual deviation between the exact value or characteristic of such a value, element, or characteristic and the value or characteristic described may vary, while remaining within the numerical range defined by the typical experimental measurement error when using measurement methods accepted for such purposes in the art.

[0050] The term "A and / or B" or similar terms are defined as meaning "A only, B only, or A and B together" and are interchangeable with the term "at least one of A and B."

[0051] The term "image" is defined as an ordered representation of detector signals corresponding to spatial locations. For example, an image may be an array of values ​​in electronic memory, or it may be a visual or visually perceptible image formed on a display device such as a video screen or printer.

[0052] The real-time performance of a system is understood and defined as the performance that depends on the operational timeframe from a particular event to the system's response to that event. For example, the real-time extraction of optical information (e.g., the irradiance distribution from an optical detector or sensor placed on a surface characterized by such an irradiance distribution in an image formed by an optical imaging device) may be a process that is triggered by a user or processor and executed simultaneously and without interruption with the optical imaging process in which such an image is being acquired.

[0053] Although the present invention has been described through the above-described exemplary embodiments, those skilled in the art will understand that modifications and changes can be made to the illustrated embodiments without departing from the concept of the invention disclosed herein. The disclosed embodiments, or any part thereof, can be combined in ways not listed above. Therefore, the present invention should not be construed as being limited to the disclosed embodiments. [Table 1-1] [Table 1-2] [Table 1-3]

Claims

1. A system including an optical imaging device, wherein the optical imaging device, An optical interferometer having a sample arm and a reference arm, The optical relay system in the sample arm, wherein the optical relay system is a) A first lens and a second lens, the first lens and the second lens being separated in the axial direction by a distance exceeding the sum of the focal lengths of the first lens and the second lens, b) A system comprising an optical relay system configured to form a spatially curved image plane having a curvature that is necessarily variable as a function of the distance and / or the working distance of the optical imaging device.

2. The system according to claim 1, wherein the system has a full field of view of at least 15 degrees and / or at least 30 degrees.

3. The system according to claim 1 or claim 2, wherein the first lens and the second lens are each an optical doublet.

4. The system according to claim 3, wherein the first lens and the second lens are substantially the same optical doublet.

5. The system according to any one of claims 1 to 4, wherein the system is configured as an ophthalmoscope and further comprises a light source device having a coherence length necessarily falling within the range of about 200 microns to about 500 nanometers.

6. The system according to any one of claims 1 to 5, comprising a light source, configured to irradiate an object with light formed by the output of the light source device, and to register laser speckles representing the object with an optical detector of the system.

7. The system according to claim 6, wherein the light source is configured to interchangeably form the light as a first light or a second light, and the first light and the second light have different corresponding temporal coherence degrees and / or different corresponding spatial coherence degrees.

8. A light-emitting element optically coupled to the first port of a multiport optical device, An optical reflector optically coupled to the second port of the multiport optical device, The system according to any one of claims 1 to 7, comprising a light source having an optical switch optically coupled to both the second port and the third port of the multiport optical device.

9. A light source having an input section defined by a light emitter having a first spectral bandwidth, an intermediate section of the light source, and an output section defined by an optical switch optically separated from the input section by the intermediate section, The intermediate section is configured to transmit light from the input section to the output section along the first optical path and the second optical path. The first optical path is configured to transmit a first light having a bandwidth substantially equal to the first bandwidth from the light emitter to the output unit, and the second optical path is configured to transmit a second light having a spectral bandwidth substantially equal to the spectral bandwidth of the optical reflector from the light emitter to the output unit. The system according to any one of claims 1 to 8.

10. The system according to any one of claims 6 to 9, wherein the light source is configured to transmit an optical output, which is interchangeably formed in a first optical output mode and a second optical output mode, to an optical interferometer, and the spectral bandwidth of the optical output in the first output mode is at least 10 times narrower than the spectral bandwidth of the optical output in the second output mode.

11. The system according to any one of claims 1 to 5, further comprising an optical circulator, an optical reflector, an optical amplifier, and an optical switch optically isolated from the optical circulator by each of the optical circulator, the optical reflector, and the optical amplifier.

12. The system further includes an optical detector and a programmable data processing electronic circuit operably connected to a tangible non-temporary storage medium, The storage medium includes program code, The program code is configured to determine a motion index in an object illuminated by light that has passed through the optical interferometer, at least partially based on the speckle contrast characteristics of at least one optical image of the object formed by the optical detector. The system according to any one of claims 1 to 11.

13. The object includes a retinal layer or a choroidal layer, The program code is configured to determine the blood flow velocity in a reference blood vessel in the retinal layer or the choroidal layer, which is the object. The system according to claim 12.

14. By using the system described in any one of claims 1 to 13, The first spatial curvature of the arc-shaped illumination surface formed by illumination light propagating from the light source of the aforementioned system through the illumination subsystem including the sample arm of the optical interferometer is dynamically matched with the second spatial curvature of the spatially curved material layer. By substantially overlapping the arc-shaped illumination surface with the spatially curved object layer of the material, the spatially curved object layer of the material is irradiated with the illumination light. A method for forming an optical image of a spatially curved object layer of a material by spatially superimposing sample light returned from a spatially curved object layer of the material irradiated with illumination light and a portion of illumination light delayed relative to the sample light, in an optical detector of a light collection subsystem.

15. The method according to claim 14, wherein (15A) the dynamic matching is performed substantially simultaneously with the illumination, and / or (15B) the illumination surface is substantially optically conjugate to the light source.

16. The method according to claim 14 or 15, wherein the irradiation comprises irradiating the spatially curved object layer of the material with illumination light having a coherence length that does not necessarily exceed the thickness of the spatially curved object layer of the material and / or substantially equal to the thickness.

17. The method according to claim 16, wherein the spatially curved object layer of the material has a laminate of a plurality of material layers that are spatially curved.

18. The method according to any one of claims 14 to 17, wherein the dynamic matching includes axially repositioning the first lens of a multi-lens optical relay system contained within the sample arm.

19. The method according to any one of claims 14 to 18, wherein forming the optical image includes, in the optical detector, optically interfering the sample light with a portion of the illumination light to form an interference image of only the spatially curved object layer of the material, and not an interference image of other portions of the object space adjacent to the spatially curved object layer of the material.

20. The method according to any one of claims 14 to 19, further comprising generating a first image and a second image of a spatially curved object layer of the material, representing the curved layer at different depths, by varying the delay between the sample light and a portion of the illumination light.

21. The spatially curved material layer includes only one of several structural layers located at the back of the eyeball. The above generation includes imaging only one of the multiple structural layers in the depth direction, and not imaging the other structural layers. The method according to claim 20.

22. The method according to any one of claims 14 to 21, wherein the substantially matching includes substantially matching the first spatial curvature with the second spatial curvature over at least a 15-degree field of view (FOV) of the lighting subsystem and / or over at least a 20-degree field of view (FOV) of the lighting system and / or over at least a 30-degree field of view (FOV) of the lighting subsystem.

23. The method according to any one of claims 14 to 21, wherein generating the optical image comprises forming an optical image that simultaneously represents the microvessels of the retina of the eye over a field of view of at least 15 degrees and / or a field of view of at least 20 degrees and / or a field of view of at least 30 degrees.

24. The method according to any one of claims 14 to 23, comprising transmitting light emitted by a light emitter to an optical switch that optically separates the light emitter from the optical interferometer, thereby forming the illumination light interchangeably as a first illumination light or a second illumination light having corresponding first and second spectral bandwidths that differ from each other by at least one order of magnitude in amplitude.

25. The method of claim 24, comprising (i) forming the second illumination light by at least partially spatially superimposing (i) a first portion of the light emitted by the light emitter and reflected by an optical reflector, and (ii) a second portion of the light emitted by the light emitter.

26. The method according to claim 25, further comprising amplifying both the first and second parts.

27. The method according to claim 25 or 26, wherein the spatial superposition includes transmitting both the first and second parts through the same port of a multiport optical device optically separated from the optical switch by the optical reflector.

28. The light emitted by the light-emitting element is transmitted to an optical switch along a spatially distinct first optical path and a second optical path, The first optical path passes through an optical circulator and a fiber Bragg grating. The method according to any one of claims 24 to 27, wherein the second optical path passes through the optical circulator and the optical amplifier.

29. The method according to any one of claims 14 to 28, further comprising determining an index of motion occurring in the spatially curved object layer based at least in part on the speckle contrast characteristics of the optical image of the spatially curved object layer, by using a programmable data processing electronic circuit operably connected to the optical detector.

30. The method according to claim 29, further comprising generating a visually perceptible output representing the dynamic change of the motion over a predetermined period of time, based at least on the determination.

31. The method according to claim 29, wherein the curved object layer of the material is a layer of biological tissue, and the indicator of movement is a parameter of blood flow in the biological tissue.

32. The curved material layer is the retina layer or the choroid layer. Determining the indicator of the aforementioned motion includes determining the blood flow velocity in the material of a curved object layer of a reference blood vessel from an optical image of the curved object layer of the material, The method according to claim 29 or claim 31.

33. The method according to claim 32, further comprising generating a visually perceptible output showing a change in quantification of retinal hemodynamics over a predetermined period of time, based at least on the aforementioned determination.

Images