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Artificial iris implants were originally developed for therapeutic purposes but have recently been used for cosmetic alteration of the eye colour. A 21-year-old woman presented with bilateral eye redness, visual loss, raised intraocular pressure, corneal oedema and hyphaema following implantation of artificial irises in Tunisia. Combined medical and surgical management led to improvements, but reduced vision and photophobia persisted. Cosmetic iris implantation can lead to persistently sight-threatening eye complications, and we strongly advise against its use.

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BACKGROUND: Diabetes mellitus has reached epidemic proportions and requires new strategies for treatment. Unfortunately, the efficacy of treatment regimens on maintaining/re-gaining functional beta cell mass can, at the present, only be determined indirectly. Direct monitoring of beta cell mass is complicated by the anatomy of the endocrine pancreas, which consists of thousands to a million of discrete micro-organs, i.e. islets of Langerhans, which are scattered throughout the pancreas. SCOPE OF REVIEW: Here, we review the progress made over the last years using the anterior chamber of the eye as a transplantation site for functional imaging of pancreatic islet cells in the living organism. Islets engrafted on the iris are vascularized and innervated and the cornea, serving as a natural body-window, allows for microscopic, non-invasive, longitudinal evaluation of islet/beta cell function and survival with single-cell resolution in health and disease. MAJOR CONCLUSIONS: Data provided by us and others demonstrate the high versatility of this imaging platform. The use of 'reporter islets' engrafted in the eye, reporting on the status of in situ endogenous islets in the pancreas of the same animal, allows the identification of key-events in the development and progression of diabetes. This will not only serve as a versatile research tool but will also lay the foundation for a personalized medicine approach and will serve as a screening platform for new drugs and/or treatment protocols. 'Metabolic' islet transplantation, in which islets engrafted in the eye replace the endogenous beta cells, will allow for the establishment of islet-specific transgenic models and 'humanized' mouse models as well as serving as the basis for a new clinical transplantation site for the cure of diabetes.

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BACKGROUND: A large iris defect or extensive iridodialysis can be an intractable cause of visual disturbance, photophobia, glare, monocular diplopia, or cosmetic deformity. The implantation of an artificial iris substitute could be an effective option, but this can cause a reduction in endothelial cell density. We succeeded in the anatomical restoration of iris tissue that was totally dialyzed out of the eye, and was preserved in cold balanced salt solution for 8 h. Engrafted iris tissue was maintained within the aqueous humor. CASE PRESENTATION: A 71-year-old man was referred to our clinic for management of an iatrogenic total iridodialysis. The totally dialyzed iris tissue was immediately preserved in sterile cold balanced salt solution and packed in a sterile biopsy bottle that was surrounded with ice cubes. Under general anesthesia, a pars plana vitrectomy was performed to remove the remaining lens cortex and vitreous fiber anterior to the equator. A sulcus-positioned intraocular lens (IOL) was repositioned and fixed by ab externo scleral sutures. Preserved iris tissue was inserted and ironed using both iris spatula and ocular viscoelastic devices. Five-point ab interno scleral sutures were made 1.0 mm posterior to the limbus. CONCLUSIONS: The engrafted iris was successfully maintained for 6 months and did not undergo any atrophic change or depigmentation, which may be caused by primary implantation failure due to a blocked blood supply.

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There are numerous scenarios in which replacing the diseased RPE monolayer is an attractive but as yet unrealised goal. The proof of concept that vision can be improved by placing a healthy neuroretina onto a different, healthy, underlying RPE layer is demonstrated in patch graft transplantations. The surgical procedure to relocate the neuroretina is both complex and is hampered by postoperative complications and as such newer replacement procedures are also being investigated including stem cell replacement therapies. Past studies have largely focused on using cell suspensions and have had disappointing outcomes largely due to the lack of control over cellular differentiation, incomplete attachment onto Bruch's membrane and subsequent integration into the existing RPE monolayer. The choice of which cells to transplant is still under investigation and is complicated by factors such as the ease of collection of an adequate sample, rejection following implantation, the age of the cells and ethical issues. In all these situations, however, understanding the mechanisms of cellular differentiation are likely to be prerequisite to future successes.The current research into replacing the RPE monolayer is briefly discussed with reference to our experiences comparing IPE and RPE cells in an in vitro environment.

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PURPOSE: Transplantation of pigment epithelial cells is a promising treatment modality to repair retinal damage in age-related macular degeneration. For this purpose, it is necessary to establish cell culture techniques that allow acquisition of proper functional and morphological characteristics by the cells to be transplanted. METHODS: Primary retinal pigment epithelial (RPE) and iris pigment epithelial (IPE) cells grown to confluence on collagen membranes were examined for morphology, adhesion, proliferation, apoptosis, as well as viability after ex vivo transplantation. RESULTS: Pigment epithelial cells adhere, proliferate, form monolayers, acquire differentiated properties, and remain viable during transplantation to the subretinal space. CONCLUSIONS: Pigment epithelial cells cultured on collagen membranes acquire differentiated characteristics and are amenable to be transplanted as cell monolayers.

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PURPOSE: To report the practicability and efficacy of autologous iris pigment epithelium (IPE) translocation in exudative age-related macular degeneration (ARMD) over 1 year. METHODS: The consecutive interventional case series included 56 patients with exudative ARMD. During vitrectomy the submacular neovascular membrane (CNV) was removed and IPE cells, harvested from a peripheral iridectomy, were injected into the submacular space. Included were patients with subfoveal occult CNV (11 eyes), classic CNV (10 eyes), mixed CNV (17 eyes), CNV with a pigment epithelial detachment (13 eyes) or CNV with a hemorrhage (5 eyes). Outcome measures were visual acuity, foveal fixation, size of CNV and rate of recurrence based on fluorescence angiographic imaging. RESULTS: All patients underwent successful surgical removal of the CNV with consecutive subretinal IPE injection. Visual acuity was better than 20/100 in 19 patients preoperatively and in 18 patients postoperatively. A visual acuity of 20/100 or less was found in 37 patients preoperatively and in 38 patients postoperatively. Mean preoperative visual acuity (1.0+/-0.3 logMAR units) did not change significantly after 1 year (1.0+/-0.3 logMAR units). Ten eyes (18%) developed a recurrence. Fixation within the surgically denuded area could be demonstrated in 25 eyes (45%). CONCLUSIONS: Autologous IPE translocation for ARMD over one year can preserve foveal function on a low level, but cannot improve visual acuity. IPE translocation is technically feasible with a low rate of complications. Continued research seems justified to improve functional outcome.

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Recent studies have suggested that factors in the target tissue influence the degree of plasticity and regeneration following aging and/or specific insults. We have investigated whether young or aged targets differ in their noradrenergic innervation from fetal locus coeruleus (LC) neurons, and also if a specific growth factor, glial cell line-derived neurotrophic factor (GDNF) can affect this innervation pattern. Tissue pieces of fetal brainstem and young (3 months) or old (18 months) iris tissue were transplanted simultaneously into the anterior chamber of the eye of adult hosts. We found that aged iris transplants became innervated to a significantly lesser degree by the cografted LC neurons than young iris transplants. Fetal hippocampal tissue was then grafted to adult hosts, and a fetal brainstem graft containing LC neurons was placed adjacent to the first graft, either at 3 or 21 months post-grafting. Thus, old/young chimeras of the noradrenergic coeruleo-hippocampal pathway were created. Aged hippocampal grafts received a much less dense innervation from co-grafted LC neurons than young hippocampal grafts. Tyrosine hydroxylase-positive-immunoreactive innervation was only found in the outskirts of aged grafts, while the young hippocampal grafts contained an even innervation pattern. The innervation density of hippocampal grafts was significantly enhanced by GDNF treatment. These findings demonstrate that target-derived factors may regulate neuronal plasticity, and that the age of the target is more important for innervation properties than the age of the neuron innervating a particular target.

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BACKGROUND: Subretina transplantation of epithelium may be a therapeutic option for surgical treatment of age-related macular degeration (AMD). Various experimental data have demonstrated that homologous transplantation of retinal pigment epithelium (RPE) can prevent photoreceptor deterioration. However, most investigators experienced immunogenic graft rejection when using homologous pigmented cells for grafting. Autologous cells were soon considered as an alternative for subretinal grafting. Particularly iris pigment epithelium (IPE) appeared suitable to replace homologous RPE for it embryogenetic similarity and its simple availability. Recent studies have shown, that IPE is capable of taking over functions of RPE in maintaining retinal metabolism. the purpose of this study was to evaluate if autologous IPE cells would survive when being transplanted subretinally. In addition, immunogenic reponses to the presence of "foreign" iris pigment cells needed to be excluded. MATERIALS AND METHODS: Iris tissue was obtained by peripheral iridectomy in the anesthetized pig. Sheets of pigment iris epithelium were separated from the specimens and transferred into tissue culture. After the cells had been grown to confluency, cell suspensions were injected into the subretinal space of the donor animal's fellow eye. After 4 weeks, the grafted eye was enucleated and examined histologically.. RESULTS: The histological exam revealed that the graft cells had survived in the subretinal space. No evidence of immunogenic rejection was observed. CONCLUSION: Autologous IPE-cells can survive in the host's sub-retinal space without creating inflammatory reactions. Transplanted IPE appears to interact with photoreceptor outer segments.

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In newt lens regeneration, the dorsal iris has lens forming ability and the ventral iris has no such capability, whereas there is no difference in the morphological criteria. To investigate the real aspects of this characteristic lens regeneration in the newt at the cellular level, a useful model system was constructed by transplanting the dorsal and ventral reaggregate derived from singly dissociated pigmented epithelial cells of the iris into the blastema of the forelimb in the newt. The lens was formed from the dorsal reaggregate with high efficiency, but not from the ventral one. No lens formation was observed in the implantation of the reaggregate into the tissue of the intact limbs. In detailed examination of the process of lens formation from the reaggregate, it was shown that tubular formation was the first step in the rearrangement of cells within the reaggregate. This was followed by depigmentation, vesicle formation with active cell growth, and the final step was lens fiber formation by transdifferentiation of epithelial cells composing the lens vesicle. The process was almost the same as in situ lens regeneration except the reconstitution of the two-layered epithelial structure was embodied as flattened tubular formation in the first step. The present study made it possible for the first time to examine lens forming ability in the reaggregate mixed with dorsal and ventral cells, because the formation of a reaggregate was started from singly dissociated cells of the dorsal and ventral cells of the iris. Mixed reaggregate experiments indicated that the existence of the dorsal cells in a cluster within the reaggregate is important in lens formation, and ventral cells showed an inhibitory effect on the formation. The present study demonstrated that the limb system thus constructed was effective for the analysis of lens formation at the cellular level and made it possible to examine the role of dorsal and ventral cells in lens regeneration.

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39 eyes in 20 patients with high hyperopia ranging from +3.00 to +7.00, high myopia ranging from -6.00 to -20.00 with accompanying astigmatism from -1.00 to -5.00, were implanted with the anterior chamber phakic intraocular lens from Ophthalmic Innovations International, Inc. Resulting visual acuities, avoidance of complications, special considerations for heavy iris pigmentation and general outcomes are discussed.(AU)

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PURPOSE: The correct orientation of retinal pigment epithelium (RPE) cells is necessary for the integrity and proper function of the retina. For transplantation of RPE/iris pigment epithelium (IPE) grafts to the subretinal space in age-related macular degeneration, this cellular orientation is most effectively provided by a membranous support. The goal of this study was to establish an autologous or homologous membrane as a substratum for the growth of RPE/IPE. METHODS: Porcine and bovine RPE and IPE were placed in primary culture on a dissected sheet (5 x 5 mm) of autologous porcine and bovine Descemet's membrane in slide chambers and grown to confluence. RESULTS: RPE and IPE cells cultured on Descemet's membrane form an intact monolayer. Light and electron microscopy showed the formation of both an intact monolayer and microvilli in both cell types. CONCLUSION: Since the slow host-graft rejection appears to play an important role in the failure of RPE transplantation in the subretinal space, it is critical to be able to transplant autologous materials. The techniques presented here establish a novel means to culture RPE or IPE cells on autologous Descemet's membrane where they form a "cell monolayer patch," consisting of a fragment of Descemet's membrane with cultured RPE or IPE, which can be easily manipulated and transplanted, using an established glass pipette method.

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Age-related macular degeneration is one of the most serious diseases in elderly people because of its disasterous visual outcome and its prevalence. Even if the submacular and choroidal neovascular membranes could be surgically excised, severe damage or evacuation of retinal pigment epithelium is inevitable in the operated area. Pigmentary dystrophy is also a devastating hereditary eye disease with severe visual disturbance. Up to now, there have been no effective treatments for either of them. We conducted basic experiments on retinal pigment epithelium (RPE) culture, transplantation of the cells to the subretinal space of animals, especially, the Royal College of Surgeon's (RCS) rat, a model of hereditary retinal degeneration, and observed their effects in preventing photoreceptor cell death. 1) We reviewed recent reports of RPE function in relation to cytokine production and autocrine/paracrine function of these ligands. Some cytokines with strong mitogenic effects as nerve trophic/growth factors were able to rescue photoreceptor cell death in dystrophic, ischemic, and light-damaged retinas in the rats. We transplanted allograft pigmented RPE from Long Evans rats or xenograft, human and bovine RPE into the subretinal space of RCS rats, and could observe the retardation of the photoreceptor cell death. 2) As a source of human transplantable RPE in clinical practice, we could use patients' own RPE cells as autografts or those from aborted human fetus eyes as allografts. At present, we cannot use RPE cells from different species as xenografts. We tried to obtain enough RPE cells for culture in vitro from patients with large or giant retinal tears, but were unsuccessful. Cells were easily obtained from fetus eyes, and could be cultured and transplanted as fresh, primary, or multiple passage cells. We also tried cryopreservation of these cells for up to 3 months. Enzymatic expression of tyrosinase, tyrosinase related protein I and II and some other enzymes was examined by proliferating chain reaction to detect possible transformation during the procedure. The cell characteristics were well preserved. In the future, if these RPE cells could be safely kept and available in deep-frozen condition, we could use them clinically at the appropriate time and in appropriate numbers for patients as an "RPE bank" just like an "eye bank" for corneal transplantation. 3) Immunological reaction is very important if we consider this technique for clinical application. Up to now, in experimental animals, no immunological reaction has been reported even for xenograft human RPE in rats, in funduscope and histological examination, because the intraocular space is an immunologically privileged site. But transplantation of human RPE cells with a collagen sheet into the anterior chamber in rabbits caused a definite reaction detected by suppression of the electroretinogram and macrophage infiltration into the subretinal space, not only in the operated eye but also in the contralateral non-operated eye. These results suggest that we must be cautious in clinical use of heterogeneous RPE transplantation. The expression of MHC class II cells was observed in the course of photoreceptor cell degeneration in the RCS rats but it was suppressed if they were rescued by the transplantation of human cultured RPE in these animals. 4) For clinical application of this technique, autografts are naturally much better than the xeno grafts or allografts. We tried to use iris pigment epithelium (IPE) for transplantation because it consists of pigmented cells of neural origin and enough could be obtained with ease by peripheral iridectomy. We also tried transfection of a vector (pCNX2) or vector-inserted cDNA of rat bFGF into the rat IPE and transplanted into the subretinal space of RCS rats. These transfected cells expressed strong mRNA of bFGF. The photoreceptors were well preserved and immunological reaction could not be detected by funduscopical or histological examinat

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Fragments of larval Xenopus laevis dorsal iris implanted together with the pituitary into the tail fin transdifferentiate into neural retina. On the contrary, in the control experiments the implanted tissues, dorsal iris alone, pituitary, or dorsal iris with liver fragments, do not undergo any retinal transformation.

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The iris of the adult rat contains one or several neurotrophic factors that enhance the survival of dissociated parasympathetic neurons (from the embryonic chick ciliary ganglion) in culture. To assay survival activity, iris homogenates were serially diluted with culture medium and the percentage of neurons surviving for 2 days in a collagen matrix in culture determined. The extract induced survival curves that were similar for denervated and normal irides. Similarly no differences in fibre outgrowth from cultured whole ciliary ganglia were found. The results suggest that the apparent level of parasympathetic growth factor(s) is not under strict control of the innervation of the iris.

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Trigeminal, substance P-containing nerves have been studied in the stretch-prepared rat iris with immunohistochemical techniques. The normal iris exhibited a slightly irregular plexus of individual fibres in the dilator, intermingled with thin, meandering axon bundles. The sphincter contained more circumferentially oriented fibres. Occasional free nerve endings were present in all parts of the iris; no obvious association with blood vessels was detected. All substance P-positive nerves in the iris disappeared after lesioning the trigeminal nerve. Irides of neonates showed scattered, smooth fibres in a sparse plexus, without visible axon bundles. Over the first two postnatal weeks, the density of innervation developed rapidly, reaching a transiently supranormal level and fluorescence intensity, compared to adulthood. From 3 weeks on, the pattern and density of substance P-containing fibres approached the normal adult appearance. In irides grafted to the anterior eye chamber, the intrinsic substance P nerves degenerated, disappearing completely after 5 days. Reinnervation from the host irides transpired over the next few weeks, approximating normal density after 3 weeks, and organotypic density and distribution from 4 weeks on. No obvious hyperinnervation was encountered after longer postoperative times (3 months). In the host iris, many substance P fibres disappear or exhibit low fluorescence intensity during the first postoperative week, recovering fully during the next 2 weeks. Over longer postoperative periods irregular, moderate hyperinnervation developed with increased numbers of axons in bundles. In conclusion, we show normal distribution and plasticity during ontogeny and maturity of substance P-containing iris nerves in the rat, with a sensitive immunohistochemical technique in iris whole mounts.

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Immunohistochemistry with antiserum raised against glial fibrillary acidic protein (GFAP) revealed a dense plexus of GFAP-positive fibers in normal rodent iris. These fibers were not stained with 2 monoclonal GFAP antibodies which readily stain astrocytes, suggesting that they contain a polypeptide closely related, but not identical, to CNS GFAP. The GFAP-positive iris fibers did not disappear after short-term intraocular grafting or culturing of irides; instead a conspicuous system of fluorescent, star-shaped cells appeared. In the retina Müller glia were intensely fluorescent using GFAP antiserum whereas positive staining was observed with GFAP monoclonals only after injury to the retina. These antibodies, however, readily stained astrocytes in the inner layers of the normal retina. Taken together, these findings support the idea of GFA proteins as a group of closely related but not identical polypeptides.

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