Rabbit Ocular Reactivity to Bacterial Endotoxin Contained in Aqueous Solution and Ophthalmic Viscosurgical Devices

Buchen, Shelley Y.; Calogero, Don; Hilmantel, Gene; Eydelman, Malvina B.

doi:10.1016/j.ophtha.2012.04.006

Cited by 17 publications

(14 citation statements)

References 18 publications

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“…However, other groups have reported inflammatory response following intracameral injection of OVDs containing ‡0.02 EU/eye levels of endotoxin. 4,5 In the current study, local ocular effects of ITV endotoxin were assessed using slit-lamp biomicroscopy, indirect ophthalmoscopy, laser flare meter measurement, and histopathology over the course of 43 days, and we found the NOEL for ITV endotoxin to be 0.01 EU/eye, suggesting that the vitreal cavity is more sensitive to the effects of endotoxin than the anterior segment and aqueous chamber. This may be related to the more rapid turnover of aqueous humor than the slow turnover of vitreous humor as mentioned above, which likely leads to a longer residence time of endotoxin within the eye.…”

Section: Discussionmentioning

confidence: 65%

“…Several studies have demonstrated that the eye is uniquely sensitive to the effects of endotoxin contamination. 4,5 However, much of this work has focused on anterior segment and intracameral routes of administration of endotoxin-laden formulations or OVDs. Contamination following ITV injection of therapeutic agents is of concern due to the recent increase of intravitreal therapies.…”

Section: Discussionmentioning

confidence: 99%

“…The eye has been shown to be very sensitive to the effects of intracameral endotoxin and endotoxin-contaminated ophthalmic viscosurgical devices (OVDs). [3][4][5] The inflammatory effects of endotoxin are well described, and it is often used to produce experimental animal models of uveitis following ITV in mice, 6 rabbits, [7][8][9][10][11] pigs, 12 and monkeys. 13 Clinically, cases of acute postoperative sterile uveitis or toxic anterior segment syndrome have been linked to endotoxin contamination of ophthalmic devices.…”

mentioning

confidence: 99%

“…The purpose of this 43-day study was to define the response to intravitreal purified reference endotoxin levels of 0.01 to 0.75 endotoxin unit/eye (EU/eye) in Dutch Belted rabbits, including the definition of a no-observable effect level (NOEL) and the time course of the response in both the anterior and posterior segments of the eye. As mentioned above, adverse ocular effects following intracameral endotoxin and endotoxin-contaminated OVDs in rabbits have been described previously, [3][4][5] and generally was used as the basis for dose range selection in the current study.…”

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confidence: 99%

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Determination of a No-Observable Effect Level for Endotoxin Following a Single Intravitreal Administration to Dutch Belted Rabbits

Bantseev¹,

Miller

Bentley

et al. 2017

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. The purpose of this study was to characterize the inflammatory response and determine a no-observable effect level (NOEL) in rabbit eyes after endotoxin intravitreal (ITV) injection.METHODS. Fifty-three naïve male Dutch Belted rabbits were treated with a single 50-lL ITV injection ranging from 0.01 to 0.75 endotoxin units/eye (EU/eye) and monitored for up to 42 days post treatment. Ophthalmic examination included slit-lamp biomicroscopy and indirect ophthalmoscopy. Laser flare photometry was performed in a subset of animals. On days 2, 8, 16, and 43, a subset of animals was necropsied and eyes processed for histopathological evaluation.RESULTS. Intravitreal injection of endotoxin at ‡0.05 EU/eye resulted in a dose-related anterior segment inflammation response. No aqueous flare or cell response was noted in the 0.01 EU/ eye dose group. A more delayed posterior segment response characterized by vitreal cell response was observed beginning on day 5, peaking on day 9, and decreasing starting on day 16 that persisted at trace to a level of 1þ on day 43. Microscopy findings of infiltrates of minimal mixed inflammatory cells in the vitreous and subconjunctiva and proteinaceous fluid in the anterior chamber and/or vitreous were observed in eyes given ‡0.1 EU/eye. CONCLUSIONS.We defined the NOEL for ITV endotoxin to be 0.01 EU/eye, suggesting that the vitreal cavity is more sensitive to the effects of endotoxin than the anterior segment and aqueous chamber. These data highlight the importance of assessing endotoxin level in intravitreal formulations, as levels as low as 0.05 EU/eye may confound the safety evaluations of intravitreal therapeutics in rabbits.

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Section: Discussionmentioning

confidence: 65%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Determination of a No-Observable Effect Level for Endotoxin Following a Single Intravitreal Administration to Dutch Belted Rabbits

Bantseev¹,

Miller

Bentley

et al. 2017

Invest. Ophthalmol. Vis. Sci.

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“…Retinal tamponades are ophthalmic viscosurgical devices (OVD), which are viscous and viscoelastic intraocular fluids used during a variety of surgeries to create and maintain space in the anterior chamber to protect internal eye tissues. However, they may be contaminated with endotoxin as well [19,20]. Due to the serious risks associated with endotoxin, the U.S. Food and Drug Administration (FDA) has issued endotoxin testing recommendations for intraocular single-use ophthalmic devices for industry.…”

Section: Introductionmentioning

confidence: 99%

Rapid detection of bacterial endotoxins in ophthalmic viscosurgical device materials by direct analysis in real time mass spectrometry

Hitchins

Wickramasekara

2016

Analytica Chimica Acta

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Bacterial endotoxins are lipopolysaccharides bound to the bacterial cell wall and released when bacteria rupture or disintegrate. Possible contamination of endotoxin in ophthalmic devices can cause a painful eye inflammation or result in toxic anterior segment syndrome after cataract surgery. Measurement of bacterial endotoxin in medical device materials is difficult since endotoxin binds with polymer matrix and some of the materials are very viscous and non-water soluble, where traditional enzyme-based Limulus amebocyte lysate (LAL) assay cannot be applied. Here we propose a rapid and high throughput ambient ionization mass spectrometric (MS) method using direct analysis in real time (DART) for the evaluation of endotoxin contamination in medical device materials. Large and structurally complex endotoxin instantaneously breaks down into low-mass characteristic fragment ions using DART and is detected by MS in both positive and negative ion modes. This method enables the identification and separation of endotoxin from medical materials with a detection limit of 0.03 ng mL−1 endotoxins in aqueous solution. Ophthalmic viscosurgical device materials including sodium hyaluronate (NaHA), non-water soluble perfluoro-n-octane (PFO) and silicone oil (SO) were spiked with different known concentrations of endotoxin and analyzed by DART MS, where the presence of endotoxin was successfully detected and featured small mass fragment ions were generated for NaHA, PFO and SO as well. Current findings showed the feasibility of measuring endotoxin contamination in medical device materials using DART-MS, which can lead to a one-step analysis of endotoxins in different matrices, avoiding any potential contamination during sample pre-treatment steps.

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Microbiological Considerations for Ophthalmic Products: Sterility, Endotoxin Limits, and Preservatives

Hasegawa

Gulmezian-Sefer

Cheng

et al. 2021

Ophthalmic Product Development

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Rabbit Ocular Reactivity to Bacterial Endotoxin Contained in Aqueous Solution and Ophthalmic Viscosurgical Devices

Cited by 17 publications

References 18 publications

Determination of a No-Observable Effect Level for Endotoxin Following a Single Intravitreal Administration to Dutch Belted Rabbits

Determination of a No-Observable Effect Level for Endotoxin Following a Single Intravitreal Administration to Dutch Belted Rabbits

Rapid detection of bacterial endotoxins in ophthalmic viscosurgical device materials by direct analysis in real time mass spectrometry

Microbiological Considerations for Ophthalmic Products: Sterility, Endotoxin Limits, and Preservatives

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