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Purpose: The complications with cytotoxic perfluorooctane (PFO) batches reported in 2015 were attributed to reactive underfluorinated impurities whose chemical identity and behavior still need to be clarified., Material and Methods: We analyzed original packaged samples of Ala ® octa batches involved in several reported cases of retinal toxicity. (A) The impurity profile was determined. (B) pH and fluoride ion content were measured. (C) Extraction with olive oil was performed to investigate differences in lipophilia among perfluorinated liquid (PFCL) as a measure for penetration of lipophilic cell membranes followed by measurements (A) and (B)., Results: (A) The detected impurities can be divided into: (1) reactive underfluorinated compounds and their degradation products including hydrogen fluoride (HF), (2) nonreactive underfluorinated compounds, (3) surface active compounds, (4) nonreactive fluorinated compounds, and (5) leachables from primary packaging components. The highest acute toxic potential is associated with the impurities of group (1). (B) HF was detected as a degradation product of reactive underfluorinated impurities by relying on the pH values and fluoride ion content of the water extracts. (C) Lipophilic impurities dissolved in PFO migrate into lipophilic extraction medium. In particular, HF is rapidly transferred in this way., Conclusions: HF as degradation product of unstable or reactive underfluorinated contaminants seems of particular importance triggering the acute toxicity of affected PFO. Contamination related toxicity and unwanted side effects can only be reliably excluded via analytical controlled multistage, high-purification processes., Translational Relevance: In Ala ® octa batches different impurities show retinal toxicity. HF seems of particular importance of the acute toxicity of PFO.

Purpose: Reactive and underfluorinated impurities are acknowledged as a source of cytotoxicity of perfluorocarbon liquids (PFCLs) used as blood substitutes. To determine whether this is also a relevant factor in retinal toxicity, we analyzed eight PFO batches associated with adverse ocular events., Methods: (A) The amount of reactive and underflurinated impurities was analyzed by fluoride-selective potentiometry and expressed as H-value. (B) Cytotoxicity of these batches was determined by an ISO 10993-5-compliant extractive test and compared to published data generated with a direct-contact method. (C) A toxic PFO batch (061014) was purified to remove reactive and underfluorinated impurities. (A) and (B) -measurements were repeated after that. (D) The dose dependence of the H-value and cytotoxicity was determined in a dilution experiment., Results: (A) The batches revealed H-values ranging from 1.400 ppm to 4.500 ppm. (B) All batches induced cell growth inhibition; seven must be classified as cytotoxic. Findings from ISO-conform extractive and direct-contact methods showed no difference. (C) After all reactive and underfluorinated impurities in batch 061014 were removed, the H-value dropped to <10 ppm and cytotoxicity disappeared. (D) Cytotoxicity increases gradually as the H-value rises., Conclusions: The clinical relevance of the H-value as a safety parameter for PFO endotamponades could be proven. The H-value is a measure for reactive and underfluorinated impurities that cause toxicity of PFCLs and should be incorporated in each endotamponade specification with a limit of 10 ppm to prove the effectiveness of the ultra-purification required and ensure a safe product. Despite the fact that an (ISO)-standard literally is a "standard" only, which cannot cover all imaginable possibilities, the incorporation of the H-value determination into the relevant ISO standard has been initiated. If a thorough risk assessment results in risks that cannot be detected and/or managed by the effective standard, additional investigations have to be performed.

Background: Perfluorocarbon liquids (PFCL) cause retinal damage when used as long-term ocular endotamponades. Whether these changes are related to the mechanical or to the chemical properties of PFCL is unclear. The purpose of this study was to evaluate pressure spikes or shearing forces during endotamponade with PFCL and standardised eye movements., Material and Methods: Part 1: In an eye model the resulting pressure forces of 6 PFCL were measured at four different sites during standardised eye movements. Part 2: Shearing forces were determined in a plexiglass eye model and the resulting tangential forces at the PFCL-retina interface were calculated. Part 3: Rabbit eyes were vitrectomised and filled with light and heavy fluorocarbons for 6 weeks. Subsequently, the retina were examined histologically and by immunohistochemistry., Results: With increasing filling of the eye model, the maximum of the pressure peaks moved from the inferior wall of the eye model to the lateral eye walls. For perfluorodecalin (PFD) the highest pressure peak was 407 Pa with a 75 % filling of the vitreous cavity. The lowest pressure peak was 314 Pa with a 50 % filling of hexafluoropropene oxide. Shearing forces for standardised accelerations were dependent on viscosity and ranged between 0.87 mN/m(2) (perfluorohexyloctane) and 8055 mN/m(2) (hexafluoropropene oxide). Part 3: Histological and immunohistochemical analyses did not reveal pressure-related damage or any difference between the effects of the different tamponades in vivo., Conclusion: In comparison with physiological dynamic and static pressure peaks, the measured mechanical forces induced by intraocular PFCL tamponades are low. Specific gravity and mechanical damage by intraocular PFCL as a cause of retinal damage seem unlikely. Animal studies underline these findings.

Purpose: To report and study the phenomenon of abnormal silicone oil adherent to the retina at the time of removal in a number of patients., Materials and Methods: Chart review was performed to identify possible patient or procedural factors that could predispose to sticky silicone oil formation. Gas chromatography-mass spectroscopy and nuclear magnetic resonance spectroscopy analyses were performed on sticky silicone oil samples, on perfluorocarbon liquid and on silicone oil samples straight from the vial., Results: Sticky silicone oil remnants were seen on the retina in 28 out of 234 silicone oil removal procedures between January 2001 and November 2002. Forceful removal was complicated in two patients by a choroidal hemorrhage and in one patient by a retinal tear. The use of perfluoro-octane (PFO; C(8)F(18)) rather than perfluorodecalin (C(10)F(18)) was related to the phenomenon (P < 0.001). Gas chromatography-mass spectroscopy analysis revealed a significant presence of PFO in samples of sticky silicone oil, and traces of partially fluorinated carbon liquid were found in the sticky oil as well as in the PFO samples., Conclusions: The use of PFO may have been a predisposing factor for the occurrence of sticky silicone oil. While the presence of silicone oil remnants on the retina did not cause lasting side effect, forceful attempts at removal can lead to complications.

Background: To investigate the reasons for difficulties removing silicone oil from the vitreous cavity due to putative adherence to the retina., Methods: Gas chromatography-coupled mass spectroscopy of the headspace (GC/MS/HS) and gel permeation chromatography (GPC) were used to detect volatile compounds in silicone oil samples explanted from patients, qualitatively as well as quantitatively. Surface and interfacial tensions of the explanted samples were measured using the pendent-drop technique. To simulate the removal of silicone oil from the vitreous cavity, the contact between silicone oil and differently treated surfaces and various aspiration techniques were tested in vitro., Results: The median concentration of perfluorodecalin in seven "sticky" samples was 2.4 times higher than in 14 non-sticky samples. In the sticky samples, the median surface tension of the aqueous phase was lower. The difficulty of aspirating silicone oil could be reproduced in vitro by reducing the surface tension of the aqueous environment of the silicone oil., Conclusion: The observed stickiness of silicone oil seems to be a matter of reduced surface tension of the surrounding aqueous material and/or contamination of silicone oil with perfluorocarbon liquid, which creates interruption of the material flow, giving the impression of adherence of the silicone oil to the retina.

Introduction: Dynasilan is a fluoroalkylsilan that is able to interact with surface active centres on intraocular lenses (IOL), offering a new way for surface modification of different IOL materials. The purpose of this in vitro study was to investigate the influence of this new surface modification on the adherence of two typical endophthalmitis causing bacteria (Staphylococcus epidermidis, Propionibacterium acnes)., Materials and Methods: In a pilot experiment, the effect of Dynasilan coating on the adherence of S. epidermidis was tested on glass slides. Forty-two Dynasilan-modified and 42 unmodified IOL (14 PMMA, 14 silicone and 14 hydrogel) were incubated at 37 degrees C in brain heart infusion broth (10(8) CFU/ml) with either S. epidermidis for 24 h or with P. acnes for 1 h. Subsequently, the adherent bacteria were resuspended using ultrasonification at 35 kHz for 3x45 s. After dilution series and incubation at 37 degrees C on Petri dishes for 24 h and 3 days, respectively, the colonies were counted., Results: In the pilot experiment, a markedly lower number of adherent S. epidermidis was observed on Dynasilan-modified glass slides. Of all IOL materials incubated with S. epidermidis, those modified with Dynasilan showed a lower mean number of adherent bacteria (mean 1.37x10(7); SD 2.37x10(7)) than those untreated (2.43x10(7); SD 3.04x10(7)). IOLs incubated with P. acnes showed a significantly lower mean number of adherent bacteria of 2.51x10(4) (SD 2.71x10(4)) on Dynasilan-modified IOLs versus 6.27x10(4) (SD 7.70x10(4)) on untreated IOLs., Conclusion: The presented in vitro results indicate that Dynasilan surface modification is able to reduce the adherence of S. epidermidis and P. acnes on all IOL materials tested. Further studies regarding the stability of this modification and its biocompatibility must be performed.

Purpose: To investigate the influence of other substances used intraoperatively in vitreoretinal surgery on the emulsification of silicone oil in patients' eyes., Methods: Gas chromatography coupled mass spectroscopy of the headspace (GC/MS/HS) was used to detect volatile compounds in silicone oil samples explanted from patients qualitatively as well as quantitatively. Surface and interfacial tensions of the explanted samples were measured using the pendent drop technique., Results: Some samples of nonemulsified explanted silicone oil were not different in their content of volatile substances measured by GC-MS/HS. In all explanted samples of emulsified silicone oil volatile substances could be detected, which do not exist or are at the detection limit in native silicone oil for ophthalmic use. The majority of contaminants are heavy liquids, cleaning substances, and oligosiloxanes., Conclusion: The contact of silicone oil with all types of substances should be reduced to a minimum. Reuse of tubing sets must be avoided. If a direct exchange between heavy liquids and silicone oil seems necessary, turbulence at the interfaces must be avoided and the contact time between these two endotamponades must be kept as short as possible. If these precautions are obeyed, the risk of emulsification of silicone oil used as an ocular endotamponade can be significantly reduced, down to the influence of individual patients' conditions.

Purpose: To investigate possible sources for the induction of silicone oil emulsification in patients' eyes., Methods: The contaminants on a ready-to-use standard set of vitreoretinal instruments cleaned and sterilized in an eye clinic were determined. The determination of detergents was carried out according to a standardized procedure, which uses ultrapurified water to rinse the equipment in question, followed by a measurement of the conductivity. Silicone oil remnants were determined using Fourier transformed infrared spectroscopy., Results: Ionic components of detergents and remnants of silicone oil could be detected on instrumentation deemed sterile, clean, and ready-to-use., Conclusion: During routine cleaning and sterilization of vitreoretinal instruments and accessories, remnants of silicone oil and detergents can persist and trigger emulsification of silicone oil, which came into contact with these contaminated devices during instillation of the endotamponade.

Introduction: Dynasilan is a fluoroalkylsilan which is able to bind to surface active molecules of intraocular lenses (IOLs), thereby offering a new option for surface modification of silicone lenses. The purpose of this in vitro study was to investigate the influence of this new surface treatment on the adherence of two typical endophthalmitis-inducing bacteria ( Staphylococcus epidermidis, Propionibacterium acnes)., Materials and Methods: A total of 14 Dynasilan-treated and 14 untreated silicone lenses were incubated at 37 degrees C for 24 h in brain heart infusion broth (10(8) CFU/ml) either with Staphylococcus epidermidis or with Propionibacterium acnes for 1 h. Subsequently, the adherent bacteria were resuspended using ultrasonification at 35 kHz for 3 x 45 s. After a dilution series and incubation at 37 degrees C for 24 h or 3 days the colonies were counted., Results: On untreated IOLs incubated with Staphylococcus epidermidis the average number of bacteria was 3.6 x 10(7)/ml, and on treated IOLs the number of counted colonies was reduced to 1.09 x 10(7)/ml. Incubated with Propionibacterium acnes the average number of adherent bacteria on untreated IOLs was 4.75 x 10(4)/ml and on modified IOLs the number was reduced to 2.94 x 10(4)/ml., Conclusion: Dynasilan surface treatment may reduce the adherence of Staphylococcus epidermidis and Propionibacterium acnes on silicone intraocular lenses. Further studies regarding the stability of this treatment, its biocompatibility and influence on lens epithelial cell adhesion are in progress.

Purpose: To investigate the solubility of perfluorocarbon liquids (PFCL) in silicone oil., Methods: Forty-eight samples of silicone oil (1,300 mPas, n = 22; 5,000 mPas, n = 26) were analyzed for dissolved fluorocarbon molecules after surgical removal from patients who had initially undergone vitreoretinal surgery with (n = 41) and as control without (n = 7) the use of perfluorodecalin in headspace gas chromatography. In vitro, the solubility of three different PFCL-perfluorooctane (PFO), perfluorodecalin (PFD), and fluoromethylcyclohexane (FMCH)-in silicone oil of various viscosities was determined. The diffusion phenomena during a direct exchange were studied., Results: In 39 of 41 silicone oil samples removed from patients who had undergone vitreoretinal surgery with the use of PFD, small amounts of dissolved perfluorocarbons could be detected. The mean value in 5,000-mPas silicone oil was 939.0 x 10-4 m/% and in 1,300-mPas silicone oil was 322.75 x10(-4) m/%. No perfluorocarbon molecules were found in seven control patients. In vitro, the following maximum solubilities in 1,000-mPas silicone oil were measured at room temperature: PFO, 3.2 m/%; PFD, 5.1 m/%; and FMCH, 10.3 m/%. The maximum values measured in 5,000-mPas silicone oil were PFO, 3.3 m/%; PFD, 5.7 m/%; and FMCH, 8.5 m/%; and in 100-mPas silicone oil were PFO, 2.4 m/%, and PFD, 5.1 m/%., Conclusion: Perfluorocarbon liquids dissolve in silicone oil. This may lead to transient formation of "heavy silicone oil," but no stable heavy silicone oil can be created adding PFCL. Intraocularly, retained PFCL vanish in silicone oil and are removed during silicone oil removal.

Background: Partially fluorinated alkanes (FALKs) are a new class of substances which can be used in vitreoretinal surgery as an intraoperative tool and as a long-term tamponade. The aim of this in vitro study was (1) to investigate the solubility of FALKs in silicone oil during direct exchange, (2) to study their combined use and solubility in PFCLs, (3) to evaluate their lipophilic properties and (4) to investigate the possibility of preparing "heavy silicone oil"., Methods: (1) Four different FALKs (F6H6, F6H8, O44 and O62) were directly exchanged with silicone oil (5,000 mPas). The dissolved amount of fluorocarbons in the removed silicone oil was determined by gas chromatography and by gravimetry. Furthermore, the diffusion phenomena during the exchange process were studied. (2) The behaviour of FALKs in PFCLs was investigated and the solubility of the resulting mixtures in silicone oil was measured. (3) The solubility of FALKs and PFCLs in native olive oil was analysed. (4) Different FALKs were added to silicone oil and measurements of the resulting specific gravity and the viscosity were performed., Results: (1) FALKs dissolved in silicone oil up to the following values: F6H6=45 m%, F6H8=54 m%, 044=100 m%, O62=18 m%. (2) FALKs dissolved in PFCL, thereby changing the physicochemical properties of PFCL depending on the type of FALK and ratio used. (3) The lipophilic properties of FALKs and PFCLs could be characterized by their dissolution in native olive oil (F6H8=23.4 m%, 044=16.7 m%, F6H6=12.3 m%, 062=5.3 m%, PFD=1.1 m%, PFO=0.6 m%). (4) It was possible to prepare "heavy silicone oil" e.g. by adding 30 vol% F6H8, resulting in a specific gravity of 1.08 g/ml, or by adding 80 vol% 044, resulting in a specific gravity of 1.25 g/ml, but decreasing the viscosity of the mixtures dramatically., Conclusion: (1) If FALKs are used as an intraoperative tool, a direct exchange with silicone oil should be avoided owing to their capacity to dissolve in silicone oil, resulting in a mixture with unpredictable properties. (2) A combined use with PFCLs and silicone oil is possible, if the right ratio is chosen. (3) The solubility of FALKs in native olive oil may be an indicator for their tissue penetration and may render feasible their use as a long-term tamponade. (3) "Heavy silicone oil" preparation using FALKs is possible, but the mixture needs further evaluation in terms of emulsification, mobilization of oligosiloxanes, tissue penetration and long-term stability.

Purpose: To describe a solvent that removes silicone oil adhesions on intraocular lenses (IOLs)., Method: The solvent O44 is a partially fluorinated alcane that dissolves silicone oil. Silicone oil adhesions on silicone and poly(methyl methacrylate) IOLs were treated with O44. The extent of silicone oil adhesions and the effectiveness of O44 were studied by gross microscopy., Results: The solvent O44 removed silicone oil adhesions from both IOL types., Conclusion: The substance O44 may be a successful intraoperative tool to remove silicone oil IOL adhesions, avoiding IOL explantation.

Aim: To examine the efficiency of O44, a partial fluorinated octane, as a solvent for silicone oil adhesions on intraocular lenses., Materials and Methods: After placing silicone- and PMMA-lenses in silicone oil, the adhesions were treated with O44. The extent of silicone oil adhesions and the effectiveness of O44 were studied by gross microscopy by scanning electrone microscopy (SEM) and combined energy dispersive spectrometry (EDX). Furthermore an explanted silicone lens with oil adhesions was treated with O44 and examined. To simulate the effect of adhesion proteins PMMA- and silicone lenses were placed in silicone oil and human plasma., Results: With EDX it was possible to prove that O44 is able to remove silicone oil adhesions from PMMA-lenses. The removal from an explanted silicone lens by O44 could be demonstrated by light microscopy. Silicone oil adhesions on intraocular lenses (IOL's) in vitro showed a different oil coverage than the IOL in vivo. Silicone lenses in vitro were often covered by a homogenous oil film and therefore the demonstration of the silicone adhesions and of the efficacy of O44 was difficult. The adhesions of IOL's placed additional in human plasma did not show any differences., Conclusions: O44 may be a successful intraoperative tool to remove silicone oil adhesions avoiding explantation of silicone oil contaminated IOL's. Silicone oil adhesions in vivo seem to be influenced by adhesive proteins.

Using perfluoromethylcyclopentane (FMCP; US patent no. 5,441,989, granted 1995) we have developed a new vitreous gas tamponade in a rabbit model that allows complete filling of the vitreous cavity without vitrectomy and without a significant increase in intraocular pressure. In humans this procedure would allow the blockage of inferior and posterior retinal holes without special positioning of the patient. Perfluoromethylcyclopentane (FMCP), a liquid perfluorocarbon with a boiling point slightly above body temperature, is injected in minute volumes into the vitreous cavity, where it vaporizes, thereby filling a gas volume approximately 500 times its liquid volume. FMCP was injected into the midvitreous in six rabbits (six eyes). After 2-3 days a complete gas tamponade was achieved in three eyes. Two eyes showed 75-90% filling, and one eye was filled only 50% with gas. Intraocular pressure was highest in the completely filled eyes, ranging from 26.6 to 38.8 mmHg. In all eyes the maximum expansion of the gas bubble lasted 2 weeks. One eye developed a retinal detachment. All eyes showed transient subcapsular cataracts. The results of this study showed that intravitreal injection of FMCP, a new perfluorocarbon liquid, results in a complete gas tamponade of the vitreous cavity which lasts 2 weeks without severe intraocular pressure rise and without vitrectomy. This procedure will be especially useful for eyes that have retinal detachment from inferior or posterior retinal holes. Injection of a conventional gas such as SF6 or C3F8 usually does not block retinal holes in inferior or posterior locations without tedious positioning and risk of (transient) glaucoma. Since the mechanism of transition of FMCP from liquid to gas in the vitreous is poorly understood, we are currently studying FMCP vaporization in an in vitro eye model.