Prevalidation trial for a novel in vitro eye irritation test using the reconstructed human cornea-like epithelial model, MCTT HCE™

Yang, Hyeri; Kim, Da Eun; Jang, Won Hee; An, Shi; Cho, Sun A.; Jung, Mi Sook; Lee, Ji Eun; Yeo, Kyung Wook; Koh, Sang Bum; Jeong, Tae Cheon; Kang, Mi Jeong; Chun, Young Jin; Lee, Su Hyon; Lim, Kyung Min; Bae, Seung Jin

doi:10.1016/j.tiv.2016.11.010

Cited by 20 publications

(8 citation statements)

References 28 publications

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“…Although various 3D RhCE models are widely used as in vitro alternative tests for eye irritation, these methods are critically dependent on tissue viability for distinguishing irritants from non-irritants [12][13][14][15][16], which has several limitations, including low specificity and a high false-positive rate of test results [14,17,18]. In this situation, gene expression screening for ocular irritation potential can enhance the prediction rate of a prediction model based on cell viability [23].…”

Section: Discussionmentioning

confidence: 99%

“…Despite the importance as a criterion for eye irritation potential assessment in the RhCE model, assessment methods that rely solely on tissue viability still have limitations of low specificity associated with the high false-positive rate depending on the characteristics of the materials, especially for moderate to weak eye irritants [14,17,18]. Therefore, to improve the specificity and accuracy of in vitro test performance, a new additional biomarker for eye irritation should be discovered to enhance the predictive capability for eye irritation before the viability test.…”

Section: Introductionmentioning

confidence: 99%

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Egr1 Gene Expression as a Potential Biomarker for In Vitro Prediction of Ocular Toxicity

et al. 2021

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Animal models are used for preclinical toxicity studies, and the need for in vitro alternative methods has been strongly raised. Our study aims to elucidate the potential mechanism of change in EGR1 expression under situations of toxic injury and to develop an Egr1 promoter–luciferase gene reporter assay for an in vitro alternative method for toxicity prediction in drug discovery. We first found an increase in early growth response-1 (EGR1) mRNA/protein expressions in the liver and kidney of cisplatin-treated injured rats. Additionally, the EGR1 protein level was also elevated under situations of ocular injury after sodium lauryl sulfate (SLS) eye drops. These in vivo observations on injury-related EGR1 induction were confirmed by in vitro studies, where human corneal epithelial cells were treated with representative irritants (SLS and benzalkonium chloride) and 17 chemicals having different UN GHS irritant categories. Additionally, our results suggest the involvement of ERK, JNK, p38 MAPK pathways in EGR1 elevation in response to gamma-butyrolactone-induced injury. As EGR1 is considered to be a pivotal factor in proliferation and regeneration, siRNA-mediated knockdown of Egr1 promoted cytotoxic potential through a delay of injury-related recovery. More importantly, the elevation of promoter activities was observed by various irritants in cells transfected with Egr1 promoter-reporter vector. In conclusion, Egr1 can be a potential biomarker in a promoter-reporter system to improve the accuracy of in vitro predictions for ocular irritation.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Egr1 Gene Expression as a Potential Biomarker for In Vitro Prediction of Ocular Toxicity

et al. 2021

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“…The water-soluble formazan forming dye, WST-1, is used to determine tissue viability for hazard classification. A threshold of tissue viability of 35% for liquids and 65% for solids was chosen to discriminate between irritants (GHS Cat 1/2) and non-irritants (GHS No Cat) (Yang et al 2017;Lim et al 2019). The MCTT HCE EIT catch-up validation database containing 30 reference chemicals met the VMG criteria for reproducibility and predictive capacity, as required by the Performance Standards of this Guideline (OECD 2019a).…”

Section: Hazard Assessment-current Status Of 3d In Vitro Eye Irritation Tests (Eit) and Regulatory Acceptancementioning

confidence: 99%

In vitro reconstructed 3D corneal tissue models for ocular toxicology and ophthalmic drug development

Kaluzhny

Klausner

2021

In Vitro Cell.Dev.Biol.-Animal

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Testing of all manufactured products and their ingredients for eye irritation is a regulatory requirement. In the last two decades, the development of alternatives to the in vivo Draize eye irritation test method has substantially advanced due to the improvements in primary cell isolation, cell culture techniques, and media, which have led to improved in vitro corneal tissue models and test methods. Most in vitro models for ocular toxicology attempt to reproduce the corneal epithelial tissue which consists of 4-5 layers of non-keratinized corneal epithelial cells that form tight junctions, thereby limiting the penetration of chemicals, xenobiotics, and pharmaceuticals. Also, significant efforts have been directed toward the development of more complex threedimensional (3D) equivalents to study wound healing, drug permeation, and bioavailability. This review focuses on in vitro reconstructed 3D corneal tissue models and their utilization in ocular toxicology as well as their application to pharmacology and ophthalmic research. Current human 3D corneal epithelial cell culture models have replaced in vivo animal eye irritation tests for many applications, and substantial validation efforts are in progress to verify and approve alternative eye irritation tests for widespread use. The validation of drug absorption models and further development of models and test methods for many ophthalmic and ocular disease applications is required.

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“…Several studies have sought to evaluate the predictability of eye irritation through a comparative analysis between the existing Draize test method using rabbits and a human corneal model. The RhCE models could distinguish between irritants and non-irritants with high accuracy [ 13 , 14 , 15 , 16 ].…”

Section: Introductionmentioning

confidence: 99%

Preliminary Study on an Alternative Test Method with MCTT HCETM for Ocular Irritation Test of Ophthalmic Medical Devices

Kim

Seo

Kim

et al. 2023

Toxics

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The sustained growth of the market for ophthalmic medical devices has increased the demand for alternatives to animal testing for the evaluation of eye irritation. The International Organization for Standardization has acknowledged the need to develop novel in vitro tests to replace animal testing. Here, we evaluated the applicability of an alternative method based on a human corneal model to test the safety of ophthalmic medical devices. 2-Hydroxyethyl methacrylate (HEMA) and Polymethyl methacrylate (PMMA), which are used to fabricate contact lenses, were used as base materials. These materials were blended with eye irritant and non-irritant chemicals specified in the OECD Test Guideline (TG) 492 and Globally Harmonized System (GHS) classification. Then, three GLP-certified laboratories performed three replicates using the developed method using 3D reconstructed human cornea epithelium, MCTT HCETM. OECD TG 492 describes the procedure used to evaluate the eye hazard potential of the test chemical based on its ability to induce cytotoxicity in a reconstructed human cornea-like epithelium (RhCE) tissue. Results: The within-laboratory reproducibility (WLR) and between-laboratory reproducibility (BLR) were both 100%. When a polar extraction solvent was used, the sensitivity, specificity, and accuracy were all 100% in each laboratory. When a non-polar extraction solvent was used, the sensitivity was 80%, the specificity was 100%, and the accuracy was 90%. The proposed method exhibited excellent reproducibility and predictive capacity within and between laboratories. Therefore, the proposed method using the MCTT HCETM model could be used to evaluate eye irritation caused by ophthalmic medical devices.

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Prevalidation trial for a novel in vitro eye irritation test using the reconstructed human cornea-like epithelial model, MCTT HCE™

Cited by 20 publications

References 28 publications

Egr1 Gene Expression as a Potential Biomarker for In Vitro Prediction of Ocular Toxicity

Egr1 Gene Expression as a Potential Biomarker for In Vitro Prediction of Ocular Toxicity

In vitro reconstructed 3D corneal tissue models for ocular toxicology and ophthalmic drug development

Preliminary Study on an Alternative Test Method with MCTT HCETM for Ocular Irritation Test of Ophthalmic Medical Devices

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