Validation of a Human In Vitro Vaginal Irritation Test

描述（由申请人提供）：女性生殖道暴露于杀精子剂、药物、杀微生物剂、女性卫生用品和其他阴道护理产品（VCP）中所含的各种化学制剂可能导致炎症或组织损伤，从而危及女性健康。VCP对阴道上皮的扰动也会增加获得性传播感染（包括HIV-1）的风险。目前的阴道刺激/毒性测试主要使用耗时且昂贵的动物模型进行。此外，最常用的兔阴道毒性模型的结果并不总是与人体反应相关。迄今为止，还没有经过验证的人体外阴道刺激方法。本研究项目将开发这样的测试方法。第一阶段研究将预先验证MatTek的器官型阴道-宫颈外（VEC）组织模型，用于识别现有或新开发的VCP的潜在危害。体外试验将包括组织活力、结构损伤、屏障功能和细胞因子释放测量。将使用一组明确定义的模型试验材料在急性家兔阴道刺激试验中进行平行实验。体内和体外数据的相关性将导致开发敏感和可靠的体外阴道刺激试验方法。在第II阶段，将在多中心GLP研究中对试验方法进行正式确认。用于评估化学品/制剂的刺激潜力的预先验证的体外阴道器官型组织模型将在涉及阴道护理产品、杀微生物剂、杀精子剂和其他女性卫生和局部药物产品的行业中具有深远的应用。评价刺激水平对于尽量减少暴露于局部应用产品的女性的危害非常重要。所提出的基于人体组织的测定将提供一种灵敏且特异的时间有效的方法，以降低的成本筛选大量化学品/制剂。

DESCRIPTION (provided by applicant): Exposure of female reproductive tract to the various chemical agents contained within spermicides, medicaments, microbicides, feminine hygiene and other vaginal care products (VCP) can cause inflammation or tissue damage and thus endanger the health of women. Perturbation of the vaginal epithelium by VCP can also increase the risk of acquiring sexually transmitted infections including HIV-1. Current vaginal irritation/toxicity tests are primarily performed using animal models which are time consuming and costly. Furthermore, results from the most commonly used rabbit vaginal toxicity model do not always correlate with human responses. To date, no validated, human in vitro vaginal irritation method exists. This research project will develop such a test method. Phase I research will prevalidate MatTek's organotypic vaginal-ectocervical (VEC) tissue model for use in identifying potential hazard of existing or newly developed VCP. In vitro assays will include tissue viability, structural damage, barrier function, and cytokine release measurements. Parallel experiments will be performed in an acute rabbit vaginal irritation assay using a well defined set of model test materials. Correlation of the in vivo and in vitro data will result in the development of a sensitive and reliable in vitro vaginal irritation test method. During Phase II, the test method will undergo formal validation in a multi-center, GLP study. A prevalidated in vitro vaginal organotypic tissue model for assessing the irritation potential of chemicals/ formulations will have far reaching application in industries involved in vaginal care products, microbicides, spermicides, and other feminine hygiene and topical pharmaceutical products. Evaluation of irritancy levels is important to minimize hazards in women exposed to topically applied products. The proposed human tissue based assay will provide a sensitive and specific time-efficient method to screen a large number of chemicals/formulations at a reduced cost.