Ex vivo evaluation of retinal cytotoxicity after the use of multiple medical devices in pars plana vitrectomy in porcine eyes.

This study aimed to evaluate viability of retinal cells after the use of multiple intraoperative devices, namely a vitreal dye (triamcinolone acetonide,TA), a ERM/ILM dye (solution of trypan blue 0.15% and brilliant blue 0.025%), and two intraocular tamponades, namely perfluoro-n-octane, (PFO) and silicone oil (SO 1000 cSt), with minimal and maximal removal of their residues, during a simulated pars plana vitrectomy (PPV) in porcine eyes ex-vivo. The in vitro cytotoxicity of each of these compounds was verified on ARPE-19 cells by direct tests according to the ISO 10993-5 (2009). Pars plana vitrectomy was performed on 25 enucleated porcine eyes divided in five groups according to the following conditions: Group A) No surgery control: eye bulbs were kept at room temperature for 40 min; Group B) Sham surgery: PPV with the sole use of BSS for 40 min; Group C) Cytotoxic control: PPV with BSS infusion (20 min) followed by intravitreal injection of 1H-PFO (contact time: 20 min); Group D) Surgery with residues: PPV with BSS infusion and sequential intravitreal injection of TA, ERM/ILM dye, PFO and SO, with minimal removal of each compound after a specified contact-time (overall duration: 40 min); Group E) Surgery with minimal residues: PPV performed as in group D, but with maximal removal of each compound (overall duration: 40 min). All the experimental procedures were performed at room temperature. Immediately after surgery, the retina was extracted from each eye bulb and samples of 3-mm diameter were prepared. Retinal viability was determined for each sample by 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyltetrazolium bromide assay. A cell viability <70% was considered the cytotoxicity threshold. Kruskal-Wallis test was used to evaluate the differences in retinal viability between groups. No cytotoxicity was detected in retinal samples in groups A, B and E. Samples from eye bulbs that had undergone surgery with minimal removal of residues (group D) and cytotoxic controls (group C) showed high retinal cytotoxicity. The tested conditions indicated that the combined use of TA, ERM/ILM dye, PFO and SO during PPV does not affect retinal cells viability if all the devices are properly removed, whereas the cytotoxicity detected in group D may suggest that the presence and accumulation of the residues of the compounds used intraoperatively could negatively impact retinal viability due to a cumulative and/or synergistic cytotoxic effect between them, supporting the crucial role of an optimal removal of the intraoperative medical devices to ensure a safe vitrectomy to the patient.

Chronic mild and acute severe glaucomatous neurodegeneration derived from silicone oil-induced ocular hypertension.

Recently, we established silicone oil-induced ocular hypertension (SOHU) mouse model with significant glaucomatous neurodegeneration. Here we characterize two additional variations of this model that simulate two distinct glaucoma types. The first is a chronic model produced by high frequency (HF) pupillary dilation after SO-induced pupillary block, which shows sustained moderate IOP elevation and corresponding slow, mild glaucomatous neurodegeneration. We also demonstrate that although SO removal quickly returns IOP to normal, the glaucomatous neurodegeneration continues to advance to a similar degree as in the HF group without SO removal. The second, an acute model created by no pupillary dilation (ND), shows a greatly elevated IOP and severe inner retina degeneration at an early time point. Therefore, by a straightforward dilation scheme, we extend our original SOHU model to recapitulate phenotypes of two major glaucoma forms, which will be invaluable for selecting neuroprotectants and elucidating their molecular mechanisms.

Silicone Oil Particles in Prefilled Syringes With Human Monoclonal Antibody, Representative of Real-World Drug Products, Did Not Increase Immunogenicity in In Vivo and In Vitro Model Systems.

Silicone oil is a lubricant for prefilled syringes (PFS), a common primary container for biotherapeutics. Silicone oil particles (SiOP) shed from PFS are a concern for patients due to their potential for increased immunogenicity and therefore also of regulatory concern. To address the safety concern in a context of manufacturing and distribution of drug product (DP), SiOP was increased (up to ∼25,000 particles/mL) in PFS filled with mAb1, a fully human antibody drug, by simulated handling of DP mimicked by drop shock. These samples are characterized in a companion report (Jiao N et al. J Pharm Sci. 2020). The risk of immunogenicity was then assessed using in vitro and in vivo immune model systems. The impact of a common DP excipient, polysorbate 80, on both the formation and biological consequences of SiOP was also tested. SiOP was found associated with (1) minimal cytokine secretion from human peripheral blood mononuclear cells, (2) no response in cell lines that report NF-κB/AP-1 signaling, and (3) no antidrug antibodies or significant cytokine production in transgenic Xeno-het mice, whether or not mAb1 or polysorbate 80 was present. These results suggest that SiOP in mAb1, representative of real-world DP in PFS, poses no increased risk of immunogenicity.

Heavy silicone oil and intraocular inflammation.

In the past two decades, many advances have been made in vitrectomy instrumentation, surgical techniques, and the use of different tamponade agents. These agents serve close retinal breaks, confine eventual retinal redetachment, and prevent proliferative vitreoretinopathy (PVR). Long-acting gases and silicone oil are effective internal tamponade agents; however, because their specific gravity is lower than that of the vitreous fluid, they may provide adequate support for the superior retina but lack efficacy for the inferior retina, especially when the fill is subtotal. Thus, a specific role may exist for an internal tamponade agent with a higher specific gravity, such as heavy silicone oils (HSOs), Densiron 68, Oxane HD, HWS 45-300, HWS 46-3000, and HeavySil. Some clinical evidence seems to presume that heavy tamponades are more prone to intraocular inflammation than standard silicone if they remain in the eye for several months. In this review, we discuss the fundamental clinical and biochemical/molecular mechanisms involved in the inflammatory response after the use of heavy tamponade: toxicity due to impurities or instability of the agent, direct toxicity and immunogenicity, oil emulsification, and mechanical injury due to gravity. The physical and chemical properties of various HSOs and their efficacy and safety profiles are also described.

Safety assessment of silylates and surface-modified siloxysilicates.

The Cosmetic Ingredient Review (CIR) Expert Panel assessed the safety of silica silylate, silica dimethyl silylate, trimethylsiloxysilicate, and trifluoropropyldimethyl/trimethylsiloxysilicate as used in cosmetics. These silylates and surface-modified siloxysilicates function in cosmetics as antifoaming agents, anticaking agents, bulking agents, binders, skin-conditioning agents--emollient, skin-conditioning agents-occlusive, slip modifiers, suspension agents--nonsurfactant, and viscosity increasing agents--nonaqueous. The Expert Panel reviewed the available animal and clinical data as well as information from a previous CIR safety assessment of amorphous silica. The CIR Expert Panel concluded that silica silylate, silica dimethyl silylate, trimethylsiloxysilicate, and trifluoropropyldimethyl/trimethylsiloxysilicate are safe as used when formulated and delivered in the final product not to be irritating or sensitizing to the respiratory tract.

DFPE, partially fluorinated ether: a novel approach for experimental intravitreal tamponade.

PURPOSE: To evaluate decafluoro-di-n-pentyl ether (DFPE) as a vitreous tamponade by examining ocular tolerance in rabbits' eyes. METHODS: Thirteen rabbits were divided into 4 groups after mechanical vitrectomy and were followed up to 12 months. The tamponade remained in the eye for 6 months in group 1 (DFPE) and Group 3 (DFPE and silicone oil) and for 12 months in group 2 (DFPE). Group 4 served as control. RESULTS: In groups 1, 2, and 3, dispersion of the fluid appeared 2 weeks postoperatively. Posterior subcapsular cataracts appeared in rabbits' eyes with large fills of DFPE (>50%). Histologic findings in groups 1 and 2 showed no detectable change in outer nuclear layer thickness. Except for some vacuolations, the inner retina was well preserved in all injected rabbits' eyes. On the electroretinography of injected rabbits' eyes, there was no effect on the a wave amplitude and b wave implicit time, but the b wave amplitude was elevated with statistical significance (P < 0.001) at 1, 3, and 6 months postoperatively but with no statistical significance (P > 0.05) after that period when compared with group 4 and unoperated fellow rabbits' eyes of each group. CONCLUSION: Decafluoro-di-n-pentyl ether demonstrated minimum adverse effects in retinal rabbits; further studies are needed before clinical use as short-term tamponade.

A new rat model of glaucoma induced by intracameral injection of silicone oil and electrocoagulation of limbal vessels.

BACKGROUND: A satisfied glaucoma model is absent now. The aim of this study was to evaluate the effect of a combination of intracameral injection of silicone oil and electrocoagulation of corneal limbal vessels and episcleral veins in the rats to establish glaucoma model. METHODS: Operation was performed in each of the left eyes of 90 adult male rats. Right eyes were used as controls. Measurement of intraocular pressure (IOP) was performed with an applanation tonometer (Tono-Pen). Retinal ganglion cells (RGCs) were retrogradely labeled by applying FluoroGold onto the bilateral superior colliculus. RESULTS: During the follow-up (24 weeks), the IOP of the study eyes was significantly higher (P < 0.05) than the control eyes (at final examination, IOP of control eyes was (13.4 ± 1.0) mmHg and IOP of study eyes was (16.1 ± 1.8) mmHg). Correspondingly, at 24 weeks after operation, the RGCs density of the study eyes (2286.11 ± 290.45/mm(2)) was significantly lower than the control eyes (2626.46 ± 164.85/mm(2), P < 0.01). In the operated eyes, histological examination showed excavation of optic disc and increased neuroglial cells in the optic nerve, reduced thickness of retina and diminution of retinal ganglion cells, and atrophy of ciliary body and iris. Notably, the anterior chamber angle of the operated eye remained open. CONCLUSIONS: A combination of intracameral injection of silicone oil and electrocoagulation of corneal limbal vessels and episcleral veins may establish a reliable glaucoma model for further research.

Siliconomas / Siliconomas

INTRODUÇÃO: O silicone líquido industrial tem sido introduzido no organismo humano de forma clandestina, com a finalidade de corrigir defeitos, depressões, irregularidades e para aumentar volumes, tanto em mulheres como em homens ou transgêneros. Com tal uso, podem ocorrer várias complicações, tais como infecções, necroses teciduais e, mais tardiamente, a migração do produto, pelo sistema linfático, venoso ou mesmo pela força da gravidade. MÉTODO: Foram avaliados 11 pacientes portadores de siliconomas, pertencentes ao ambulatório do Serviço de Cirurgia Plástica do Hospital Universitário da UFJF e da Clínica Plastic Center, em Juiz de Fora, MG, no período de janeiro de 2005 a dezembro de 2010. Desses, 7 eram do gênero masculino e quatro do gênero feminino, sendo que desse total, 3 eram transgêneros. Todos os pacientes referiam com clareza o material injetado em seus organismos e todos fizeram o procedimento em ambiente não hospitalar e por indivíduos leigos. CONCLUSÃO: Este artigo tem como objetivo maior esclarecer as consequências danosas que esse produto pode causar no organismo, como cicatrizes de grandes proporções e sequelas estéticas e funcionais.

INTRODUCTION: The industrial liquid silicone has been introduced in the human body in a clandestine manner, with the purpose of correcting defects, depressions, irregularities and to increase volumes in women, men or transgenders. Several complications can occur, such as infection, tissue necrosis, and later migration of the product through the lymphatic system, venous system, or even by force of gravity. METHODS: Eleven patients with siliconomas, belonging to the ambulatory service of plastic surgery of Hospital Universitário da UFJF and Clinic Plastic Center in Juiz de Fora, MG, were evaluated from January 2005 to December 2010. Of these, 7 were male and 4 female, and there were 3 transvestites. All patients clearly referred the material injected into their bodies and have done all the procedure in a non-hospital environment and by lay individuals. CONCLUSION: This article's primary goal is to clarify the harmful consequences that this product may cause to the body such as scars and major aesthetic and functional sequelae.

[Advantages and disadvantages of heavy silicone oil]. / Vor- und Nachteile des schweren Silikonöls.

Heavy silicone oil does not have any evidence-based advantages or disadvantages over conventional silicone oil. It is up to the surgeon to choose the type of tamponade considered to be most suitable for the individual eye. Suitable indications for heavy silicone oil are, for example proliferative vitreoretinopathy (PVR) and risk of PVR in the lower retina. Persistent or complicated macular holes can often be closed with heavy oil but in exchange higher rates of emulsification and cataracts are to be expected. Heavy silicone oils should not remain in the eye for longer than approximately 2 months, therefore, severe ocular trauma and ocular hypotension are not suitable indications. Initial technical difficulties to remove sticky (rare) oil from the retina have now been overcome by using liquid perfluorocarbons.

Effects of perfluorocarbon liquids and silicone oil on human retinal pigment epithelial cells and retinal ganglion cells.

PURPOSE: To examine the effects of perfluorocarbon liquid (PFCL) and silicone oil (SO) on human retinal pigment epithelium (RPE) cells and retinal ganglion cells (RGCs) in vitro. METHODS: Human RPE cells (ARPE-19 cells), seeded on microporous inserts, were exposed to PFCL or SO and incubated for 3 or 7 days. Perfluorocarbon liquid was in contact with cells at the apical or baso-lateral side, not inhibiting cell feeding. Then, the quantification of cell proliferation and cell viability were evaluated by WST-1 assay. In the same way, RGCs were exposed for 1 hour or 3 days, and the number of viable RGCs was counted by using a fluorescence viability agent. RESULTS: Perfluorocarbon liquid affected the survival of ARPE-19 cells and RGCs when compared with the nontreated control group. ARPE-19 cells decreased significantly after being in contact with PFCL at the baso-lateral side for 7 days. However, PFCL contact at the apical side reduced the number of RGCs in a time-dependent manner. In case of SO, the viability of the ARPE-19 cells decreased significantly after being in contact with SO at the baso-lateral side for 7 days. However, SO did not reduce the number of RGCs after a 3-day exposure. CONCLUSION: Perfluorocarbon liquid is directly toxic to ARPE-19 cells when exposed to the cells for 7 days. On the contrary, it seems that RGCs are damaged in a time-dependent manner by the more mechanical rather than toxic effects of PFCL. Silicone oil seems to exert mechanical rather than toxic effects on ARPE-19 cells. When PFCL is used as a postoperative tamponade clinically, understanding the difference in the effects will lead to more effective and safer results.

Cytotoxicity of silicone oil on cultivated human corneal endothelium.

BACKGROUND AND OBJECTIVE: To investigate the cytotoxic effects of silicone oil on the cultivated human corneal endothelial cells (CEs). METHODS: We cultured human CE and passed them in insert wells that allowed the apical side of CE monolayer in contact with the silicone oil. The tested silicone oils were of two different viscosities, 1,000 and 5,000 centistoke (CS). MTS proliferation bioassay and calcein-acetoxymethyl ester (CAM)-ethidium homodimer staining were performed to evaluate cell viability after CEs were co-cultured with silicone oils for 48 h. Apoptosis of CEs was evaluated by TdT-mediated dUTP nick-end labelling (TUNEL) stain. RESULTS: The MTS bioassay showed that contact of silicone oil inhibited CE proliferation. The higher viscosity (5,000 CS) silicone oil suppressed cell cycling significantly more than the lower viscosity (1,000 CS) silicone oil. CAM-ethidium homodimer staining revealed CE death, 9.1+/-0.1% (1,000 CS silicone oil) and 41.6+/-0.4% (5,000 CS), but apoptosis played only minor role in silicone oil toxicity, 1.7+/-0.1% (1,000 CS silicone oil) and 9.4+/-0.1% (5,000 CS). CONCLUSIONS: Silicone oil is cytotoxic to cultivated human CEs. Avoiding the forward migration of silicone oil to the anterior chamber and corneal CE contact is critical in preventing silicone oil-associated keratopathy. Silicone oil should be removed as early as possible once the goal of tamponade has been achieved.

Long-term exposure of the rabbit eye to silicone oil causes optic nerve atrophy.

A silicone oil endotamponade following vitrectomy has for decades been a standard method in human ophthalmology with a view to restoring a detached retina. However, severe functional deficiencies may remain after treatment. In adult rabbits, the injection of silicone oil into the eye-ball following vitrectomy resulted in a decrease of 89% in the number of myelinated optic nerve fibres after a survival time of 1 year (418,313+/-29,703 versus 45,620+/-23,905). Concomitantly, the cross-sectional area of the optic nerve was also reduced significantly (0.853+/-0.159 mm2 versus 0.355+/-0.107 mm2). The number of non-neuronal elements of the optic nerve remained virtually unchanged immediately behind the eye-ball and in the middle part of the nerve, whereas it increased significantly close to the optic chiasm (3040+/-433 versus 3888+/-403). Thus, destruction of the myelinated optic nerve fibres is likely to be responsible for the functional deficiencies observed after silicone oil implantation.

Hazard assessment of silicone oils (polydimethylsiloxanes, PDMS) used in antifouling-/foul-release-products in the marine environment.

Non-eroding silicone-based coatings can effectively reduce fouling of ship hulls and are an alternative to biocidal and heavy metal-based antifoulings. The products, whose formulations and make up are closely guarded proprietary knowledge, consist of a silicone resin matrix and may contain unbound silicone oils (1-10%). If these oils leach out, they can have impacts on marine environments: PDMS are persistent, adsorb to suspended particulate matter and may settle into sediment. If oil films build up on sediments, infiltration may inhibit pore water exchange. PDMS do not bioaccumulate in marine organisms and soluble fractions have low toxicity to aquatic and benthic organisms. At higher exposures, undissolved silicone oil films or droplets can cause physical-mechanic effects with trapping and suffocation of organisms. These 'new' effects are not covered by current assessment schemes. PDMS make the case that very low water solubility and bioavailability do not necessarily preclude damage to marine environments.

In vivo retinal tolerance of various heavy silicone oils.

PURPOSE: Heavy silicone oils are currently under investigation as a permanent tamponade in eyes with inferior PVR. This study was an investigation of Densiron 68 (Fluoron GmbH, Neu-Ulm, Germany) and several new heavy silicone oil admixtures on the basis of the perfluoroalkanes F4H5 (perfluorobutylpentane), F4H6 (perfluorobutylhexane), and F4H8 (perfluorobutyloctane) with respect to their long-term tolerance in a rabbit model. METHODS: Because of the better solubility of the F4Hn-species (n = 5-8) in comparison to F6H8, we used F4H5, F4H6, and F4H8 to generate highly viscous, heavy silicone oils (HSO). After vitrectomy and fluid-air exchange, the left eye of each of five rabbits per group was filled with HSO 68-1500 (Densiron 68), HSO 45-5000, HSO 45-3000, HSO 46-5000, HSO 46-3000, HSO 48-5000, or HSO 48-3000, or pure F4H5, F4H6, or F4H8. Detailed clinical investigation, ERG testing, and histologic evaluation were performed throughout a 3-month follow-up. RESULTS: Densiron 68 and HSOs based on F4H5, as well as the three control oils (silicone oil of 1000, 3000, and 5000 mPa . s) were well tolerated over 3 months. Histologically, the retina was unaffected. In contrast, intraocular inflammation, cataract formation, and retinal detachment and degeneration were noticed in all groups with HSOs based on F4H6 or F4H8. CONCLUSIONS: Biocompatibility of the new HSOs is dependent on the lipophilic behavior (R(F)/R(H) ratio) and furthermore on the molecular dimension of the used semifluorinated alkanes (SFAs). HSOs on the basis of F4H5 may have advantages over silicone oils, on the basis of F6H8, for use as a tamponade agent for the inferior retina in difficult retinal situations.

[A dynamic model of total chronic heart failure in rats].

A dynamic model ofbiventricular chronic heart failure (CHF) induced by fractional introduction of silicon oil into the pleural cavity in rats is proposed. Silicon oil led to enlargement of the heart, myocardial hypertrophy of both ventricles, considerable pulmonary and hepatic congestion due to circulatory failure, decreased stroke volume and cardiac output, increased peripheral vascular resistance, changes in the activity of sympathoadrenal system of the heart and blood. The severity of the induced CHF varied with the dose and number of silicon oil administrations.

A new, heavier-than-water silicone oil: a solution of perfluorohexyloctane in polydimethylsiloxane.

PURPOSE: To pre p a re and explore new solutions of semifluorinated alkane in silicone oil, which have a specific gravity slightly higher than silicone oil and vitreous fluid (referred to in the following as heavier-than-water silicone oils (HWSs), and to investigate, in vitro, whether HWSs can be used to plug retina holes, while allowing dehydration of the subretinal space. METHODS: HWS solutions were pre p a red with silicone oil 5000 and perfluorohexyloctane (F6H8). The stability was investigated under different conditions. The viscosity was determined by means of a capillary viscometer. The surface and interface tension were measured using the ring method. RESULTS: HWSs are insoluble in an aqueous medium. Densiron(R)68 (HWS 1.06) is a transparent homogeneous liquid which is slightly heavier (1.06 g/cm3) than water and has a refractive index close to that of vitreous liquid. Densiron68 (HWS 1.06) has a low viscosity (1480 mPas) and interface tension (40.82 mN/m), making it an effective tamponade in the surgical treatment of an inferior detached retina. In addition, the interfaces between Densiron68 and other perfluorocarbon liquids are clearly visible. However, the interface layer between Densiron68 and water is not clear. Finally, all HWSs are stable over the long term at ambient temperatures, as well as physically and thermally resistant. CONCLUSIONS. Due to its physiochemical properties, Densiron68 could meet the requirements for a heavier-than-water tamponade.

The effects of foul-release coatings on the settlement and behaviour of cyprid larvae of the barnacle Balanus amphitrite amphitrite Darwin.

Foul-release coatings are generally assumed to affect fouling of surfaces via interfering with adhesion of fouling organisms. However, the potential effects of these coatings on other aspects of the biology of fouling organisms such as behaviour have not in general been explored. The effects of wax-based foul-release coatings containing silicone oil on the settlement and behaviour of cyprid larvae of the barnacle Balanus amphitrite were studied. Settlement (as measured by metamorphosis) of cyprids was strongly inhibited on all coatings but particularly on those containing silicone oil at concentrations of 5% or more. The behaviour of cyprids was also altered on coatings containing > or = 5% silicone oil, with cyprids assuming an inverted position, preventing adhesion. This effect was reversible in part; when cyprids exposed to experimental coatings for 1 d were transferred to uncoated surfaces their behaviour returned to normal, except that metamorphosis did not occur. The results indicate that model foul-release coatings containing wax and silicone oil can affect settlement and behaviour, as well as adhesion.