Benchmarking different brands of perfluorocarbon liquids.

PURPOSE: To compare the analytical quality characteristics of currently available CE-marked perfluorocarbon liquids (PFCL) applied intraoperatively during vitreoretinal surgery. METHODS: Twenty-one samples of 8 brands of perfluorooctane (PFO) and 25 samples of 13 brands of perfluorodecalin (PFD) were analysed. Gas chromatography coupled with mass spectroscopy (GC/MS) was used to determine the content of the main product. The amount of reactive and underfluorinated impurities was analysed and expressed as an H-value using fluoride selective potentiometry after a chemical transformation reaction to detect impurities that triggered both acute and latent toxic effects. UV-active substances were determined in order to draw conclusions on the integrity of primary packaging components. Moreover, we controlled for any 1H-PFO contamination in PFO, as it is known to modify PFO's surface characteristics. RESULTS: Significant differences in the tested products' purity profiles were detected. The PFO batches revealed H-values ranging from < 10 to 1230 ppm and 1H-PFO concentrations ranging from < 1 to 376 ppm. Leachable substances from packaging components cause UV absorption in the 0.1 to > 3 AU range. The PFD batches revealed H-values ranging from < 10 to 70 ppm and leachables from packaging components resulting in absorbances in the 0 AU to 3.2 AU range. CONCLUSION: The quality characteristics of the analysed PFCL vary significantly, not only among different brands but among batches from the same manufacturer as well. Manufacturers should communicate the purity of their products in an understandable and clear manner. This would require providing a complete certificate of analysis focussing especially on quality characteristics to enable vitreoretinal surgeons to differentiate between the effects from the PFCL itself and those from impurities.

Benchmarking different brands of silicone oils.

PURPOSE: To compare the analytical quality characteristics of currently available CE-marked silicone oils used as ocular endotamponades in vitreoretinal surgery. METHODS: Thirty-four samples of 12 brands were analysed. To assess the quality characteristics of silicone oils, we measured the oligosiloxane content and polydispersity, widely accepted as purity parameters. UV-active substances (> 220 nm) were analysed to draw conclusions about the integrity of primary packaging components. RESULTS: We identified significant differences in the impurity profiles of the products tested, which revealed oligosiloxane contents ranging from < 0.1 to 491 ppm, polydispersity ranging from 1.6 to 3.0 and UV-active substances (> 220 nm) ranging from 0.2 to 3.8 AU. CONCLUSION: The quality characteristics of the analysed silicone oils vary significantly not only among different brands but also among batches of the same manufacturer. Manufacturers should communicate the purity and quality characteristics of their products in an understandable and clear manner. This involves providing a complete certificate of analysis with special focus on quality characteristics, to enable the vitreoretinal surgeon to differentiate between the effects of the silicone oil itself and those of impurities.

Hydrofluoric Acid and Other Impurities in Toxic Perfluorooctane Batches.

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.

How to Ward Off Retinal Toxicity of Perfluorooctane and Other Perfluorocarbon Liquids?

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.

The phenomenon of "sticky" silicone oil.

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.

Influence of a new surface modification of intraocular lenses with fluoroalkylsilan on the adherence of endophthalmitis-causing bacteria in vitro.

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.

Interaction of different ocular endotamponades as a risk factor for silicone oil emulsification.

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.

Preparation and processing of vitreoretinal instrumentation and equipment as a risk factor for silicone oil emulsification.

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.

Determination of the solubility of perfluorocarbon liquids in silicone oil in vitro and in vivo.

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.