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IN VITRO SKIN EQUIVALENT MODELS FOR TOXICITY TESTING.
Hayden, P.J., Ayehunie, S., Jackson, G.R., Kupfer-Lamore, S., Last, T.J., Klausner, M., Kubilus, J.
MatTek Corporation, Ashland, MA, U.S.A.
Published in Alternative Toxicological Methods. Editors H. Salem, S.A. Katz. CRC Press LLC, Boca Raton, FL, USA, 229-247 (2003).
Keywords: Air-liquid interface (ALI), Apoptosis , Basal cell layer, Birbeck granules, Carcinogenicity , Corrosivity , Drug metabolism, Drug screening applications, ELISA, ET-50, Electrotransport drug delivery technology, Epiderm RNA isolation protocol, Epiderm-200 , Epiderm-224 , Epiderm-296 , Epiderm-FT, Gene microarray technology, Gingival epithelium, Granular cell layer, High-throughput, ICCVAM, Immunoderm , Irritation , Langerhans cells, Lot-to-lot reproducibility, MTT assay, Mechanistic studies, Melanoderm , Melanogenesis, Metabolism, Necrosis , Ocular corneal epithelium, Percutaneous absorption, Permeation , Photoaging , Phototoxicity , Safety and efficacy, Sensitization , Skin cancer, Skin equivalent, Spinous cell layer, Stratum corneum, Toxicity testing, Tracheal/bronchial, UV radiation, Vaginal epithelium, Validation
Endpoints: Cell viability, Cytokine release, ET-50, Gene expression, Irritation score, MTT Assay, melanine
Materials Tested: Cosmetic products and ingredients, Topical therapeutics
Summary: Prior to human use of new cosmetic or therapeutic products, in vivo animal tests are often conducted in order to screen for safety and efficacy. However, modern product development processes are rendering animal testing increasingly expensive and impractical. Furthermore, the tenets of ethical animal testing call for practice of the three R's of refinement, reduction and replacement of animal tests. Therefore, a growing need exists for rapid and reliable in vitro methods for safety screening of new cosmetic formulations and lead candidates for topical therapeutics. This need is especially acute for cosmetic producers, who must produce safe and efficacious products, but whose consumers increasingly will not tolerate animal testing. For drugs and cosmetics intended for topical application to the skin, safety issues include irritation, sensitization, toxicity and carcinogenicity. A further issue for topical products is their potential interaction with UV radiation to produce photoinduced irritation, sensitization, toxicity, or carcinogenicity.
Common methods of in vitro safety testing include the use of human cells grown in submerged monolayer cell cultures. However, the use of submerged monolayer cultures is not well suited for testing of many ingredients or finished products intended for topical application, For example, submerged cultures restrict the testing to materials that can be dissolved in aqueous media. Thus, many oil-soluble ingredients or finished products such as creams, lotions, or powders cannot be adequately tested in submerged culture systems. Furthermore, submerged culture systems of skin cells do not possess differentiated functions and barrier properties of stratified skin tissues and thus do not accurately reflect the in vivo physiology of the skin.
Three-dimensional organotypic skin models, which overcome many of the short-comings of safety testing in submerged monolayer skin cell cultures, are commercially available (MatTek Corp., Ashland, MA). These models are cultured at the air-liquid interface (ALI) and are more suitable for safety and efficacy testing of topical products. Among the safety issues that organotypic skin models can address are tissue damage (i.e., cell death by necrosis or apoptosis), irritation, and DNA damage caused by topical treatment of ultraviolet radiation. This paper will describe a variety of commercially available ALI cultures and present a survey of applications of these models for topical pharmaceutical and cosmetic product safety assessment.
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