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Transscleral Optical Phase Imaging of the Human Retina

In-vivo observation of the human retina at the cellular level is crucial to detect the first signs of retinal diseases and properly treat them. Despite the phenomenal advances in adaptive optics (AO) systems, clinical imaging of many retinal cells is still elusive due to the low signal-to-noise ratio induced by transpupillary illumination. We present a transscleral optical phase imaging (TOPI) method, which relies on high-angle oblique illumination of the retina, combined with AO, to enhance cell contrast. Examination of eleven healthy volunteer eyes, without pupil dilation, shows the ability of this method to produce in-vivo images of retinal cells, from the retinal pigment epithelium to the nerve fibre layer. This method also allows the generation of high-resolution label-free ex-vivo phase images of flat-mounted retinas. The 4.4°x 4.4° field-of-view in-vivo images are recorded in less than 10 seconds, opening new avenues in the exploration of healthy and diseased retinas.

. In-vivo TOPI images of two distinct retinal layers of two healthy volunteers S4 (12° eccentricity from the fovea) and S11 (8° and 5° eccentricity from the fovea).  Fig. 4 In-vivo retinal pigment epithelium TOPI quantification of eleven healthy volunteers (S1 to S11). (A) Quantification of RPE cell area versus the eccentricity with respect to the fovea. Quantification of RPE cell density versus the eccentricity with respect to the fovea (B) and age of the participants (C). The phototype of the subjects ranged from 1 to 6 on the Fitzpatrick scale 26 .

Supplementary Fig. 5. Fourier analysis of an RPE layer image centered at 7° from the fovea. (Left)
Dark-field image that was high-pass filtered to enhance the visualization. (Center) Axial profile of the spectrum. (Right) Spectrum of the left image cropped at a row to row spacing of 6.8 µm. The peak signature of the RPE signal was located at 13.8 µm, which is consistent with the values found in the literature.

Supplementary Note 1. ex-vivo validation of the proposed phase imaging modality
Our experimental phase microscope is illustrated in Supplementary Fig. 6. In a first series of experiments, it has been configured to obtain similar optical conditions to those of the in-vivo implementation in order to validate the potential of phase imaging with oblique illumination, without the artefacts induced by eye movements and aberrations. For this purpose, a 0.25-NA objective was selected to match the maximum possible numerical aperture of a fully dilated human eye (0.24). Four light emitting diodes (LEDs) with a center wavelength of 650 nm and a 50 nm bandwidth were used to illuminate the retina. The ex-vivo image reconstruction is described in the Material and Methods section. To mimic the scattering effect of the sclera, a white paper sheet was placed between the LEDs and the samples ( Supplementary Fig. 6D).

Supplementary Note 2. Optical characterization of ex-vivo images
We first measured the modulation transfer function (MTF) resulting from the incoherent illumination ( Supplementary Fig. 7A). Then, we performed imaging of the frontal frozen sections of a pig neuroretina to compare our phase imaging method with digital holographic microscopy (DHM). For phase imaging, a scattering surface (standard printer white paper) was attached to the bottom side of the glass slide in order to simulate the backscattered light (Supplementary Fig. 6B). DHMs produce true metrological phase images, allowing for a quantitative comparison with the proposed method ( Supplementary Fig. 7B).
The images from the DHM were taken with a 0.4-NA microscope objective and with coherent light illumination. Because our method uses incoherent light, the cut-off spatial frequency was equal to 2 ⁄ = 0.5⁄ [ !" ], with l being the central illumination wavelength. Thus, our phase imaging method produces images with a resolution similar to the 0.4-NA DHM images taken with coherent illumination and with a sharp cut-off spatial frequency of Finally, we compared our phase imaging modality with reflectance confocal microscopy using a human retina-choroid complex. The back illumination was provided by the scattering of the RPE-choroid layers ( Supplementary Fig. 6C), and the region of interest was selected using blood vessels as landmarks. Supplementary Fig. 7C shows the intensity images taken with a confocal microscope and 0.8-NA (left) and 0.3-NA (center) objectives.
Our phase image (right), which was recorded at the same depth, exhibits better SNR and