An imaging modality that allows for fast, simultaneous, noninvasive probing of both three-dimensional (3D) cellular resolution retinal morphology and depth-resolved function could substantially improve the early diagnosis of various retinal diseases that are the leading causes of blindness worldwide and could contribute to a better understanding of retinal pathogenesis and enhanced therapy monitoring. In addition to user friendliness, reliability, and cost, the key technological parameters of any imaging technique that can markedly influence its clinical feasibility are axial (depth) and transverse image resolution, measurement time, detection sensitivity, penetration depth in tissue, and image contrast. Advances in photonics technology, including the development of ultrabroad bandwidth and high-speed tuneable light sources and high-speed detection techniques, have enabled a considerable improvement in the visualization capability of optical coherence tomography (OCT) in the past decade, establishing it as a state-of-the-art, noninvasive, complementary ophthalmic diagnostic methodology. Axial image resolution has been a key parameter for ophthalmic imaging because of the stratified organization of the retina. In contrast to standard or confocal microscopy, axial and transverse OCT resolution are decoupled, with the axial being mainly determined by the optical bandwidth of the used light source and the transverse by the focusing quality of the measurement beam onto the imaged tissue. In this sense, OCT bridges the gap between the high resolution and limited penetration of confocal microscopy and the low resolution and high penetration of ultrasound. These properties make OCT a unique ophthalmic diagnostic modality, in which high axial resolution, despite a long depth of focus (field)—a situation encountered in retinal imaging in vivo —can be accomplished. Furthermore, the ocular media are essentially transparent, transmitting light with minimal optical attenuation and scattering, to provide easy optical access to the retina. As a consequence, there have been numerous recent developments in OCT technology and considerable interest in this topic, especially in the field of ophthalmology. Objectively, this interest is evidenced by the great increase in publications, patents, and companies involved in the field of OCT in recent years. The market for OCT equipment is predicted to grow at a compound annual rate of more than 30% in the next 4 years, reaching Graphic200 million by 2011.1 It is noteworthy that approximately 50% of all OCT publications so far have been in ophthalmology journals, demonstrating the major impact of this technique in this field. Another 25% have been published in optical journals, reflecting the numerous technical advances that have been accomplished.
Since its invention in the late 1980s2 3 4 5 and early 1990s,6 7 8 the original idea of OCT was to enable noninvasive optical biopsy (i.e., the in situ imaging of tissue microstructure with a resolution approaching that of histology, but without the need for tissue excision and postprocessing). A major limitation in this approach might be the lack of optical contrast between cellular components.
A first step toward OCT’s acting as a noninvasive optical biopsy method was the introduction of ultrahigh-resolution (UHR) OCT (Fig. 1A) enabling a noticeably superior visualization of all major intraretinal layers, especially the photoreceptor layer, because of the improved axial OCT resolution from 10 to 15 ?m to 2 to 3 ?m.9 10 11 12 Since this approach was based on a classic technique known as time-domain OCT, it was limited in that it allowed only for two-dimensional (2D) UHR retinal imaging. With the introduction of frequency-domain (also referred to as Fourier- or spectral-domain) OCT, data-acquisition speed was greatly improved, and three-dimensional (3D) UHR OCT was achieved (Fig. 1B) .13 14 Nevertheless 2D and 3D UHR OCT in this configuration could deliver only ultrahigh axial resolution, with a mismatch between axial and transverse resolution of approximately one order of magnitude. The next major advance came with the use of adaptive optics (AO), with deformable mirror technology used to correct higher order ocular aberrations during OCT image acquisition—so-called AO UHR OCT—recently allowing in vivo acquisition of retinal images with cellular resolution (Fig. 1C) .15 16 The development of light sources emitting at alternative wavelengths (e.g., ?1050 nm) enabled not only unprecedented 3D OCT with enhanced choroidal visualization, due to enhanced penetration below the retina, but also improved OCT performance in patients with cataract because there was less scattering losses in this wavelength region (Fig. 1D) .17 18 19 Finally, extensions of UHR OCT have been developed that enable noninvasive depth-resolved functional imaging of the retina, providing spectroscopic,20 21 polarization-sensitive blood flow or physiologic22 tissue information. These extensions of OCT should not only improve image contrast, but should also enable the differentiation of retinal diseases via localized metabolic properties or functional (physiologic) state (Fig. 1E) .
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