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      A Method for Combined Retinal Vascular and Tissue Oxygen Tension Imaging

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          Abstract

          The retina requires adequate oxygenation to maintain cellular metabolism and visual function. Inner retinal oxygen metabolism is directly related to retinal vascular oxygen tension (PO 2) and inner retinal oxygen extraction fraction (OEF), whereas outer retinal oxygen consumption (QO 2) relies on oxygen availability by the choroid and is contingent upon retinal tissue oxygen tension (tPO 2) gradients across the retinal depth. Thus far, these oxygenation and metabolic parameters have been measured independently by different techniques in separate animals, precluding a comprehensive and correlative assessment of retinal oxygenation and metabolism dynamics. The purpose of the current study is to report an innovative optical system for dual oxyphor phosphorescence lifetime imaging to near-simultaneously measure retinal vascular PO 2 and tPO 2 in rats. The use of a new oxyphor with different spectral characteristics allowed differentiation of phosphorescence signals from the retinal vasculature and tissue. Concurrent measurements of retinal arterial and venous PO 2 , tPO 2 through the retinal depth, inner retinal OEF, and outer retinal QO 2 were demonstrated, permitting a correlative assessment of retinal oxygenation and metabolism. Future application of this method can be used to investigate the relations among retinal oxygen content, extraction and metabolism under pathologic conditions and thus advance knowledge of retinal hypoxia pathophysiology.

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          Most cited references 21

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          Oxygen distribution and consumption within the retina in vascularised and avascular retinas and in animal models of retinal disease.

          Maintenance of an adequate oxygen supply to the retina is critical for retinal function. In species with vascularised retinas, such as man, oxygen is delivered to the retina via a combination of the choroidal vascular bed, which lies immediately behind the retina, and the retinal vasculature, which lies within the inner retina. The high-oxygen demands of the retina, and the relatively sparse nature of the retinal vasculature, are thought to contribute to the particular vulnerability of the retina to vascular disease. A large proportion of retinal blindness is associated with diseases having a vascular component, and disrupted oxygen supply to the retina is likely to be a critical factor. Much attention has therefore been directed at determining the intraretinal oxygen environment in healthy and diseased eyes. Measurements of oxygen levels within the retina have largely been restricted to animal studies in which oxygen sensitive microelectrodes can be used to obtain high-resolution measurements of oxygen tension as a function of retinal depth. Such measurements can immediately identify which retinal layers are supplied with oxygen from the different vascular elements. Additionally, in the outer retinal layers, which do not have any intrinsic oxygen sources, the oxygen distribution can be analysed mathematically to quantify the oxygen consumption rate of specific retinal layers. This has revealed a remarkable heterogeneity of oxygen requirements of different components of the outer retina, with the inner segments of the photoreceptors being the dominant oxygen consumers. Since the presence of the retinal vasculature precludes such a simple quantitative analysis of local oxygen consumption within the inner retina, our understanding of the oxygen needs of the inner retinal components is much less complete. Although several lines of evidence suggest that in the more commonly studied species such as cat, pig, and rat, the oxygen demands of the inner retina as a whole is broadly comparable to that of the outer retina, exactly which cell layers within the inner retina have the most stringent oxygen demands is not known. This may be a critical issue if the cell types most at risk from disrupted oxygen supply are to be identified. This paper reviews our current understanding of the oxygen requirements of the inner and outer retina and presents new data and mathematical models which identify three dominant oxygen-consuming layers in the rat retina. These are the inner segments of the photoreceptors, the outer plexiform layer, and the deeper region of the inner plexiform layer. We also address the intriguing question of how the oxygen requirements of the inner retina are met in those species which naturally have a poorly vascularised, or even totally avascular retina. We present measurements of the intraretinal oxygen distribution in two species of laboratory animal possessing such retinas, the rabbit and the guinea pig. The rabbit has a predominantly avascular retina, with only a narrow band of retinal vasculature, and the guinea pig retina is completely avascular. Both these animals demonstrate species adaptations in which the oxygen requirement of their inner retinas are extremely low when compared to that of their outer retinas. This finding both uncovers a remarkable ability of the inner retina in avascular species to function in a low-oxygen environment, and also highlights the dangers of extrapolating findings from avascular retinas to infer metabolic requirements of vascularised retinas. Different species also demonstrate a marked diversity in the manner in which intraretinal oxygen distribution is influenced by increases in systemic oxygen level. In the vascularised rat retina, the inner retinal oxygen increase is muted by a combination of increased oxygen consumption and a reduction of net oxygen delivery from the retinal circulation. The avascular retina of the guinea pig demonstrated a novel and powerful regulatory mechanism that prevents any dramatic rise in choroidal oxygen levels and keeps retinal oxygen levels within the normal physiological range. In contrast, in the avascular regions of the rabbit retina the choroidal oxygen level passively follows the increase in systemic oxygenation, and there is a dramatic rise in oxygen level in all retinal layers. The presence or absence of oxygen-regulating mechanisms may well reflect important survival strategies for the retina which are not yet understood. Intraretinal oxygen measurements in rat models of retinal disease are also presented. We describe how oxygen distribution across the rat retina is influenced by manipulation of systemic blood pressure. We examine the effect of acute and chronic occlusion of the retinal vasculature, and explore the feasibility of meeting the oxygen needs of the ischemic retina from the choroid. (ABSTRACT TRUNCATED)
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            Retinal oxygen: fundamental and clinical aspects.

            We reviewed research on retinal oxygen (O2) distribution and use, focusing on O2 microelectrode studies in animals with circulatory patterns similar to those of humans. The inner and outer halves of the retina are different domains in terms of O2. Understanding their properties can suggest mechanisms of and therapies for retinal diseases. Inner retinal PO2 averages about 20 mm Hg. Effective O2 autoregulation of the retinal circulation ensures that inner retinal PO2 is relatively uninfluenced by systemic hypoxia and hyperoxia and increased intraocular pressure in healthy animals. Failures of the retinal circulation lead to tissue hypoxia that underlies the vasoproliferation in diabetic retinopathy and retinopathy of prematurity. Choroidal blood flow is not regulated metabolically, so systemic hypoxia and elevated intraocular pressure lead to decreases in choroidal PO2 and photoreceptor O2 consumption. The same lack of regulation allows choroidal PO2 to increase dramatically during hyperoxia, offering the potential for O2 to be used therapeutically in retinal vascular occlusive diseases and retinal detachment.
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              Oxyphor R2 and G2: phosphors for measuring oxygen by oxygen-dependent quenching of phosphorescence.

              Oxygen-dependent quenching of phosphorescence is a useful and essentially noninvasive optical method for measuring oxygen in vivo and in vitro. Calibration of the phosphors is absolute, and once phosphors have been calibrated in one laboratory the same constants can be used by anyone else as long as the measurement is done under the same conditions. Two new phosphors, one based on Pd-meso-tetra-(4-carboxyphenyl)porphyrin and the other on Pd-meso-tetra-(4-carboxyphenyl)tetrabenzoporphyrin, are very well suited to in vivo oxygen measurements. Both phosphors are Generation 2 polyglutamic Pd-porphyrin-dendrimers, bearing 16 carboxylate groups on the outer layer. These phosphors are designated Oxyphor R2 and Oxyphor G2, respectively. Both are highly soluble in biological fluids such as blood plasma and their ability to penetrate biological membranes is very low. The maxima in the absorption spectra are at 415 and 524 nm for Oxyphor R2 and 440 and 632 nm for Oxyphor G2, while emissions are near 700 and 800 nm, respectively. The calibration constants of the phosphors are essentially independent of pH in the physiological range (6.4 to 7.8). In vivo application is demonstrated by using Oxyphor G2 to noninvasively determine the oxygen distribution in a subcutaneous tumor growing in rats.
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                Author and article information

                Contributors
                mshahidi@usc.edu
                Journal
                Sci Rep
                Sci Rep
                Scientific Reports
                Nature Publishing Group UK (London )
                2045-2322
                6 September 2017
                6 September 2017
                2017
                : 7
                Affiliations
                [1 ]ISNI 0000 0001 2175 0319, GRID grid.185648.6, Department of Bioengineering, , University of Illinois at Chicago, ; Chicago, IL 60607 USA
                [2 ]ISNI 0000 0001 2175 0319, GRID grid.185648.6, Department of Ophthalmology and Visual Science, , University of Illinois at Chicago, ; Chicago, IL 60612 USA
                [3 ]ISNI 0000 0001 2156 6853, GRID grid.42505.36, Department of Ophthalmology, , University of Southern California, ; Los Angeles, CA 90033 USA
                Article
                10955
                10.1038/s41598-017-10955-1
                5587610
                28878307
                © The Author(s) 2017

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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