The Cell Biology of PVR

PVR is the most common cause of failure following attempted retinal reattachment repair in primary cases, as well as complex forms of retinal detachment. The precise initiating events remain poorly understood, but it is known that the disease is characterized by cell-mediated tractional forces exerted on both preretinal and subretinal membranes, as well as more diffusely to the vitreous gel itself [9,14,15]. These contractile forces lead to stiffening and elevation of the retina, leakage through retinal breaks, and retinal re-detachment typically between 4 weeks and 8 weeks following attempted repair. The condition is more commonly encountered in eyes with large or multiple breaks and is more frequently seen in males and in patients with a history of trauma, hemorrhage, choroidal detachment, or giant retinal tear [5,10]. The membranes associated with this condition are composed of a variety of cell types, principally pigment epithelial, glial and myofibroblastic elements, either interspersed within the gel producing compaction of the collagen (hypocellular gel contraction) [15] or defined hy-percellular membranes on either the anterior or posterior surface of the retina [14]. Two of the earliest findings in eyes that go on to develop PVR are breakdown of the blood-ocular barriers with increased amounts of intravitreal protein and free-floating dispersed cells, principally retinal pigment epithelium (RPE). The cells appear to enter the growth cycle and actively proliferate in response to chemotactic and mitogenic stimuli and, subsequently, undergo an orderly sequence of steps, including attachment, contraction, and secretion of newly formed extracellular matrix (ECM) [14-21].

Initially, attempts to treat this condition by scleral buckling techniques alone were largely unsuccessful, as were the earliest techniques using vitrectomy without supplemental long-acting tamponades [6, 7, 14]. These initially unsuccessful surgical approaches served as the principal stimulus for a search for anti-proliferative agents that might improve success rates. Early studies were performed using triamcinolone acetonide, daunomycin, and fluorouracil in the early 1980s prior to the widespread availability of long-acting gases and silicone oil [8,22-26].

The introduction of long-acting gases, particularly perfluoro-propane, and the re-emergence of silicone oil (polydimethylsilox-ane) were major steps in the improvement in surgical success rates. The definitive silicone oil study confirmed that while silicone oil was superior to sulfur hexafluoride in providing visual acuity improvement and retinal reattachment in PVR, a companion study further amplified the relative equivalence of perfluoropropane to silicone oil in achieving retinal reattachment [27]. Approximately 64-73% of patients in the latter study achieved complete posterior retinal attachment and 43-45% achieved functional visual acuity of greater than 5/200 compared with success rates less than half that prior to the utilization of both of these long-acting tamponade techniques [28]. Paradoxically, with the improvement in anatomic reattachment associated with the long-acting tamponades of per-fluoropropane and silicone oil, both the medical need and the likelihood of demonstrating a statistically significant treatment benefit by incremental pharmacological methods were reduced, although studies actively continued throughout the 1980s and early 1990s to develop new pharmacological therapies. In addition to reducing the driving force for development of new drugs due to improved surgical success rates, the use of long-acting tamponades, including silicone oils and long-acting gases, also created unique problems related to bio-availability because of the presence of either a gas-filled eye or an eye filled with an hydrophobic agent [29]. Additionally, subsequent to the publication of the results of the silicone oil study, another pharmaceutical compound used as a temporary intraoperative tamponade, perfluoro-n-octane, as well as other liquid perfluorochemicals came into common use. The use of these compounds further improved the success rates for complex forms of retinal detachment repair in conjunction with long-acting tamponade even without the use of other pharmacological anti-proliferative agents with success rates reported in the range of 78% [30].

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