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1From the Institutes of Physiology and 2Medical Physics, University of Vienna, Vienna, Austria.
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Abstract |
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METHODS. Ultrahigh-resolution OCT images were acquired with 1.4-µm axial x 3-µm transverse resolution from in vitro posterior eyecup preparations of the domestic pig. Frozen sections were obtained in precise alignment with OCT tomograms, by using major blood vessels as orientation markers and were counterstained with cresyl violet or unstained and examined by differential interference contrast microscopy. Micrographs from histologic sections were linearly scaled to correct for tissue shrinkage and compared with OCT tomograms.
RESULTS. In the proximal retina, ultrahigh-resolution OCT signal bands directly corresponded to the main retinal layers. For the wavelength region used (
800 nm), axodendritic layers (nerve fiber layer, inner and outer plexiform layers) were more reflective than cell body layers (ganglion cell layer, inner nuclear layer, outer nuclear layer). In the distal retina, substructures of the photoreceptor layer such as the interface between inner and outer segments were visualized, and the retinal pigment epithelium, the choriocapillaris, and superficial choroid layers were resolved. In addition, the time sequence of a retinal detachment event was monitored by ultrahigh-resolution OCT.
CONCLUSIONS. In vitro ophthalmic ultrahigh-resolution OCT imaging reveals retinal morphology with unprecedented detail. The specific assignment of OCT signal patterns to retinal substructures provides a basis for improved interpretation of in vivo ophthalmic OCT tomograms of high clinical relevance.
The goal of the present study was to compare cross-sectional images of the retina obtained by ultrahigh-resolution OCT with those obtained by light microscopy, to identify the morphology visualized in OCT tomograms. We demonstrated in the current study that ultrahigh-resolution OCT can be a powerful tool for ophthalmic diagnosis by enabling optical biopsy of the retina—that is, the visualization of retinal microarchitecture, which previously has been possible only with histopathology.
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Materials and Methods |
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Ocular Tissue
All animals were handled in accordance with the ARVO Statement for the Use of Animals in Ophthalmic and Vision Research. Eyes were enucleated from domestic pigs that were used for unrelated experiments, either shortly before or immediately after death. After immersion in cooled oxygenated 0.01 M phosphate-buffered saline (PBS, pH 7.4), eyes were transferred to the laboratory within 30 minutes, and the cornea, lens, and vitreous were removed. The reason for removing the anterior eye segment and the vitreous was to obtain high transverse resolution that would be limited by ocular aberration in case of using the intact eye. From the eyecup, a horizontal strip including the optic disc was prepared, the remaining vitreous removed, and the fundus digitally photographed before transferring the sample to the ultrahigh-resolution OCT setup.
Ultrahigh-Resolution OCT
A new generation of a compact ultrahigh-resolution OCT system was developed and used in the present study. The system consists of a high-speed scanning unit (up to 250 Hz, 400 mm/s) integrated in a fiber optic-based Michelson interferometer using a compact, user-friendly, state-of-the-art sub-10-femtosecond titanium:sapphire laser (800-nm center wavelength, up to 170-nm [full width at half maximum; FWHM], optical bandwidth, 400-mW output power; Compact Pro; Femtosource, Vienna, Austria). The interferometer was interfaced to a microscope delivery system. Both the fiber-optic interferometer and the optical components of the microscope were designed to support the propagation of very broad bandwidth light throughout the OCT system and to compensate for any polarization and dispersion mismatch between the sample and reference arms of the interferometer.12 To achieve high transverse resolution, a specially designed achromatic objective with 10 mm focal length and a numerical aperture of 0.30 was used, achieving 3-µm free-space transverse resolution, resulting in a confocal parameter of approximately 40 to 60 µm in air, degrading the OCT image outside the focused zone. To overcome the depth-of-field limitation and to maintain high transverse resolution at various depths through the image, a zone focus and image fusion technique was used.12 Separate images with different focal depths of the optics were recorded, while maintaining the same interferometer delay depth (2 mm). These tomograms were then fused together. This technique is similar to C-mode scanning used in ultrasound imaging.20 Up to 80- to 100-µm imaging depth was obtained without significant image degradation. This image fusion technique would not be necessary in case of in vivo ultrahigh-resolution OCT imaging. Due to ocular aberration the best transverse resolution possible in the living human retina is limited to 10 to 15 µm, resulting in a more than 500-µm depth of focus to cover the whole retinal thickness. Special single-mode fibers (570-nm cutoff wavelength) and special broad band, wavelength-flattened, 3-dB fiber couplers were used to maintain ultrabroad bandwidth and single-mode propagation. Applying laser light centered at 800 nm with up to a 170-nm bandwidth (FWHM), axial resolution of 2.0 µm in air, corresponding to 1.4 µm in biological tissue, was achieved with this system. A signal-to-noise ratio of 105 dB was achieved at 1 MHz carrier frequency by using an incident power of 5-mW, using dual-balanced detection. Although applied in ex vivo tissue, retinal exposure must be taken into account in studies using the ultrabroad-bandwidth light generated by a titanium:sapphire laser. The American National Standards Institute (ANSI) standards for retinal exposure account for wavelength, exposure duration, and multiple exposures of the same spot of the retina. Because the laser source generates femtosecond pulses, the laser output was coupled into a 100-m-long optic fiber that was used to provide dispersive stretching of the pulse duration to hundreds of picoseconds. This reduces the peak pulse intensities by several orders of magnitude and, because the laser operates at an 80 MHz repetition rate, the output can be treated as a continuous wave. Persistent illumination of the retina with laser light centered around 800 nm with 500 µW is allowed for only 20 seconds. Therefore the microscope OCT system has been designed to avoid direct illumination of the focused beam into the eye. Full interference fringe signal OCT data were digitized with a high-speed (10 megasamples/s) and high-resolution (16-bit) analog-to-digital (A/D) converter followed by software demodulation.
During OCT imaging, real-time imaging display enabled simultaneous, immediate cross-sectional visualization of the imaged area. Using a scanning frequency of up to 130 Hz resulted in a measurement time of approximately 16 seconds for an OCT tomogram consisting of 2000 A-scans. Except for image fusion, no other technique was used to generate OCT tomograms. Position, orientation, and length of OCT scanned cross sections were recorded on the digital fundus micrographs and used to achieve matching orientation of specimens in subsequent histologic sectioning.
Histologic Preparation
OCT-imaged tissue was fixed in 4% paraformaldehyde and 0.1 M PBS (pH 7.4) for 12 to 72 hours, cryoprotected in an ascending series of sucrose and PBS, infiltrated in 20% sucrose and PBS (two parts) and optimal cutting temperature medium (one part; Miles, Elkhart, IN) for 18 hours, flash frozen, and mounted to receive vertical sections matching the plane of the OCT scans. Series of 12-µm frozen sections were collected onto chrome-alum gelatin-coated slides, air dried, and stained with cresyl violet or left unstained for differential interference contrast (DIC) microscopy.
Data Analysis
Sections matching the position of OCT scans were identified by using blood vessels as landmarks and photographed with a camera (NU-200 CCD; Photometrics, Tuscon, AZ) attached to a microscope (Eclipse 600; Nikon, Tokyo, Japan). Image-analysis software (Photoshop 5.5; Adobe Systems, San Jose, CA) was used for linear scaling of micrographs to correct for volume changes of the tissue that occurred in the course of histologic processing, and the micrographs were overlaid on OCT images to evaluate their correlation. OCT image enhancement was applied when appropriate and included gradient subtraction and noise or median filtering (Image Processing Tool Kit, Reindeer Graphics Inc., Asheville, NC). Shadow extending from blood vessels and nerve fiber bundles was reduced by orientational fast Fourier transform (FFT) masking (Digital Micrograph; Gatan Inc., Warrendale, PA). To obtain averaged density profiles, pixel-line projections were performed along the radial axis of OCT images in Image SXM (http://reg.ssci.liv.ac.uk/; developed by Steve Barrett, University of Liverpool, Liverpool, UK, available in the public domain).
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Results |
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Recording of Local Retinal Detachment
In a series of OCT scans, the initiation of a retinal detachment event was monitored within a time frame of 30 minutes (Fig. 4) . Ultrahigh-resolution OCT visualized a focal elevation of the neural retina concomitant with an increase in subretinal space (Fig. 4A , arrow). Fifteen minutes later, alterations were observed within the monolayered band of the PE signal. Although still continuous, the PE signal appeared triple layered at the initial locus of detachment, with a stripe of bright signal framed by two darker bands (Fig. 4B , arrowheads). After an additional 15 minutes, all retinal layers were observed to be bent inward, and measurements of their relative thicknesses (not shown) indicated increased thickness of the proximal retinal layers. In the PE signal, the bright inclusion had increased, whereas the innermost aspect of the signal appeared eroded (Figs. 4C 4D , arrow). Histologic examination of the matching retinal position demonstrated a significantly extended region of detachment (Fig. 4E) . The pigment epithelium was lesioned at the initial locus of detachment, and fragments of tissue were dislocated in the subretinal lumen (Fig. 4E , asterisk).
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Discussion |
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Several factors further complicated the correlation of structural detail with OCT images. Inherent in optical imaging techniques is the degradation of signal contrast with distance from the focus level. We compensated for this partly by combining multiple scans acquired at different focal levels. Mismatches between histology and OCT images resulted from the limits of precision in selecting sections closest to the OCT plane from an entire series, possible deviations from perpendicular orientations of both OCT images and histologic sections, and volume changes in the tissue after scanning and during histologic processing. A particular problem is the frequent detachment along the PE/photoreceptor border with subsequent buckling of the retina. With the enhanced resolution of ultrahigh-resolution OCT, however, positional mismatches between histology and OCT signal provided a source of information to evaluate artifactual modification of the tissue in the course of histologic processing. In histologic preparations, epiretinal blood vessels were observed to protrude into the vitreous (Fig. 4E , V). They appeared smoothly embedded in the inner retinal surface in the OCT tomograms (Fig. 4D) . Choroidal lacunae were clearly visible in OCT scans (Figs. 3 4) , whereas in the course of tissue processing they frequently collapsed. This further helps to discriminate procedural artifacts from pathologic alterations.
Assignment of Signal to the Inner Retinal Layers
Taking into account these limitations, our approach allows reliable correlation of all main retinal layers with specific bands of the OCT signal. Ultrahigh-resolution OCT imaging precisely distinguishes the NFL from the GCL. OCT scans performed perpendicular to the papillary radiation allow evaluation of the full cross-sectional status of nerve fiber bundles (Figs. 2B 2C) . We did not resolve individual ganglion cell somata, although the size of the large alpha ganglion cells is well within the range of resolution of the technique. Unequivocal confirmation of the representation of individual somata in an ultrahigh-resolution OCT tomogram requires correlation at the cytological level and was beyond the scope of this study. The inhomogeneous appearance of OCT signal corresponding to the IPL and the INL implies that with further refinements of image acquisition and processing, substructures within both layers (IPL sublayers, capillaries) will become identifiable.
Assignment of Signal to the Photoreceptor-Pigment Epithelium-Choroid Complex
The detailed evaluation of the photoreceptor layer, the pigment epithelium, and the choroid is of prime interest for clinical diagnosis. Ultrahigh-resolution OCT distinguishes these layers. The most intense signal deriving from the outer retina can be safely correlated with the position of the pigment epithelium, thus providing a landmark for the delineation of the retina versus the choroidal layers. This is confirmed by our record of a progressive retinal detachment. As the neural retina increasingly detached, additional alterations affected the pigment epithelium signal, which split at the site of detachment with a brighter cleft of approximately 5 to 8 µm framed by two darker bands. Although the present data do not suffice to resolve the cytological equivalent of the cleft (i.e., whether the pigment epithelium is lesioned between villous processes and cell bodies or at Bruch’s membrane), the observation demonstrates the resolving power of the technique.
To assign substructures within the photoreceptor layer at a micrometer scale is challenging. Artifactual alterations of fragile photoreceptor outer segments in the course of tissue processing interferes with direct alignment, and it is likely that disproportionate vertical representation due to refractive index variation further complicates the assignment of signal. Apparently, the complex structural subtiering of the photoreceptor layer is not reflected by an equivalent number of bands in the OCT tomogram. For example, in the myoid portion of the cone inner segments (IS) cresyl violet contrasts with a rich Nissl substance, the light microscopic equivalent of the endoplasmic reticulum at the electron microscope level (Fig. 3C) .21 This zone appears to have no OCT correlate. Therefore, in an attempt to assign observed bands of OCT signal to specific components of the photoreceptors, we considered their optical properties. The ONL comprises two to four rows of rod somata and a monolayer of cone cell bodies,22 located proximal to the ELM. The regular arrays of cone somata and the tight association of photoreceptor myoids and microvillous processes of Müller cells adjacent to the proximal and distal border of the ELM, respectively, may provide for enhanced transparency and similar refractive properties of the tissue and therefore be represented as the delicate light band discernible at the outermost aspect of the ONL (Figs. 1 3) . This interpretation is supported by DIC microscopy. Proximal and distal to the ELM, corresponding to the location of cone cell somata and the photoreceptor inner segment myoid portion, respectively, DIC microscopy identified two bands of high transparency but low relief (Fig. 1B) , indicating a region of similar transmissive and refractive properties. Evidently, the light signal band would then include the ELM, which seems to give no separate signal (Fig. 3B , elm). An alternative interpretation would correlate the borderline between high and low signal to the ELM. However, this would leave a very small radial representation of the ONL. We consider this unlikely for both optical and morphologic reasons.
Using DIC optics, the ellipsoid portions of the cone inner segments were clearly distinguished by their high relief (Fig. 1B) . OCT imaging identified this zone as a high-signal band. In pig, cone inner segment ellipsoids comprise approximately 70% of the cross-sectional light-capture area.23 Their paraboloid morphology and their high refractive index may result in periodical alterations of reflectivity within this zone, which is consistent with the speckled appearance of the OCT signal.
Photoreceptors attain specific shapes beyond their myoid portion (rod inner and outer segments [IS and OS]: cylindrical; cone OS: conical, cone IS ellipsoids: paraboloid).24 They are supposed to constitute individual optical elements, with refractive indices (n) of 1.4 or more separating them from the surrounding interphotoreceptor matrix (n = 1.34). Under physiological conditions, particularly the cone ellipsoids guide light toward the photopigments located in the OS.25 Further, photoreceptor OS consisting of densely stacked disc membranes have high refractive indices.26 27 The transition zone to the OS appears to produce a reflective signal that is more prominent in the all-cone foveal photoreceptor layer.14 Of interest, in macaque fovea, approximately 20 tapering calycal processes arise from the ellipsoid surrounding the cone outer segment base as a dense collar.28 29 The processes are supposed to provide structural support or semioccluded periciliary compartmentation. These processes are less numerous around the base of the longer rod outer segments. It is possible that cone calycal processes contribute to the optical properties of the IS-OS transition zone. In pig and human retina, the photoreceptor layer is tiered with fat, short cone IS collecting major portions of the incoming light at the basal aperture.30 The cone OS are tapered and possibly distribute nonabsorbed light from their shorter tips to the surrounding rods.23 24 Cone IS are shorter than rod IS, and their short, tapered OS lead to the positioning of cone OS tips just above the rod OS-IS transition.
Together, these observations suggest that interactions of the OCT beam with the outer retina are less homogeneous than in the proximal retina. The interpretation proposed herein attempts a coarse correlation of photoreceptoral subtiers with the OCT image. Further studies are needed to clarify how the various subcellular components of the photoreceptors contribute to the OCT signal. We may expect that, beyond the ELM, OCT signal patterns are different in cone-prominent retinas (as in the current study), rod dominant retinas, and the fovea, with its homogeneous array of elongated cones. Evaluation of these differences may allow the interpretation of pathologic conditions, such as congenital or progressive cone dystrophies.
Although the pig retina may well approximate the human peripheral and extrafoveal retina, we advise caution in directly transferring our layering assignment to the human fovea. There are no rods in the fovea. Both cone IS and OS have rodlike morphology.29 The refractive index of the elongated foveal outer segments has been estimated (n = 1.419) to be higher than in peripheral retina.24 Finally, foveal cones have been reported to exert a spatial-frequency filter effect31 for coherent light with wavelengths from 410 to 654 nm (where two waveguide modes are carried) and a flat response for wavelengths greater than 654 nm (the single-mode region). Together, the specific morphologic and optical properties of the foveal receptors may significantly alter the banding pattern of the OCT signal, particularly at the level of their IS and OS, and our layering assignment may need specific adaptation for reliable interpretation of ultrahigh-resolution OCT images of the normal and pathologic fovea.
In summary, this study demonstrates that ultrahigh-resolution OCT enables unprecedented visualization of retinal microarchitecture. A time-lapse sequence OCT recording of a progressive retinal detachment demonstrates the potential of the technique to monitor dynamic processes in the retina at sufficient resolution to track the fate of specific retinal layers. Preliminary in vivo results using a laboratory prototype laser system demonstrated recently that the quality and performance of in vivo retinal ultrahigh-resolution OCT images in normal subjects is comparable to the present results, as far as axial resolution and sensitivity are concerned14 : axial resolution of 3 µm and a sensitivity of only 5 to 7 dB less than was achieved in the present ex vivo study. This axial resolution was a factor of two less, mainly due to the chromatic aberrations of ocular media, but was sufficient to visualize all main retinal layers similar to what can be achieved in histopathology and to what is presented in the present ex vivo study. Transverse OCT imaging resolution is much worse in studies in vivo, because of corneal aberrations that limit the best possible transverse resolution on the retina to 10 to 15 µm. Interfacing adaptive optics to the ultrahigh-resolution ophthalmic OCT system may improve transverse resolution. The lower sensitivity in the in vivo measurements is mainly due to the lower power (500–800 µW compared with 5 mW) necessary for safety reasons, but is sufficient to achieve comparable sensitivity and intraretinal layer visualization in vivo.
In addition, a clinically viable ultrahigh-resolution ophthalmic OCT system has been developed recently and used in clinical imaging in 56 eyes of 40 selected patients with different macular diseases and has enabled unprecedented visualization of intraretinal morphology comparable to the results presented in the present ex vivo study.32 The ultimate clinical availability of this ultrahigh-resolution OCT technology will depend on the availability of ultrabroad bandwidth light sources that are suitable for OCT applications. The principal disadvantage of current femtosecond laser technology is its extremely high cost. With continuing research, more compact and less expensive light sources for ultrahigh-resolution OCT imaging can be expected in the near future and therefore ultrahigh-resolution OCT may provide a powerful tool for the diagnosis of retinal disorders at both the photoreceptor and the ganglion cell levels.
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Acknowledgements |
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Footnotes |
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Submitted for publication July 2, 2002; revised October 1, 2002; accepted November 2, 2002.
Disclosure: M. Gloesmann, None; B. Hermann, None; C. Schubert, None; H. Sattmann, None; P.K. Ahnelt, None; W. Drexler, Carl Zeiss Meditec (F)
The publication costs of this article were defrayed in part by page charge payment. This article must therefore be marked "advertisement" in accordance with 18 U.S.C. 
1734 solely to indicate this fact.
Corresponding author: Wolfgang Drexler, Institut für Medizinische Physik, Universität Wien, Währinger Strasse 13, A-1090 Vienna, Austria; wolfgang.drexler{at}univie.ac.at.
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). Scale bars, 100 µm.