High-resolution optical imaging assessment of microbicide toxicity

评价杀微生物剂的安全性和有效性需要评估潜在的伤害 由宫颈阴道和直肠上皮中的杀微生物剂引起。的发展 成像技术和协议，可用于内窥镜，快速，定量 局部应用杀微生物剂后的组织损伤评估可能具有显著的 对杀微生物剂在动物模型和临床研究中的开发和测试的影响。 不幸的是，目前的成像技术，如白色光阴道镜检查或结肠镜检查，不能 提供上皮损伤的高分辨率图像，并且不能探测表面以下， 上皮损伤和炎症可能是明显的。然而，近年来， 已经开发了一种技术，其中现在可以执行 上皮组织与显微镜分辨率在体内。我们的总体目标是开发一种内窥镜 基于图像的方法，可用于1）评估可能由 杀微生物剂和2）将影像学研究结果与生殖器感染易感性相关联， 小鼠宫颈阴道和直肠感染HSV-2。我们将部署新兴的高分辨率 包括共焦荧光显微镜和光学相干的成像模式 断层扫描（OCT）来表征宫颈，阴道， 未处理的性幼稚小鼠以及用已知的 刺激性杀微生物剂这些结果将与使用井的感染易感性相关 HSV-2感染的特征性小鼠模型。这将使我们能够评估 共聚焦荧光和OCT成像的观察HSV-2的易感性的基础上， 杀微生物剂诱导的上皮变化，注意结果的再现性/一致性。 在这个项目的第一阶段，我们将展示高分辨率光学成像的能力， 定量评估宫颈阴道和直肠组织对已知杀微生物剂的反应， 测试预测杀微生物剂诱导的敏感性变化的生物终点的能力 宫颈阴道在第二阶段，提出的基于图像的直肠反应评估将 扩展到建立基于图像的标记物与直肠易感性之间的相关性 使用杀微生物剂后。此外，仪器和成像参数将 以使成像方案适合于宫颈阴道和直肠的成像 在大型动物模型和人类中的上皮反应。我们还计划使用发达的 成像协议，以评估新的杀微生物剂在小动物模型中的性能， 产品开发。

Evaluation of safety and efficacy of microbicides requires an assessment of potential injury caused by micobicides in the epithelium of cervicovaginal tract and rectum. The development of imaging technology and protocols that can be used for endoscopic, rapid, and quantitative assessment of tissue injury following topical application of microbicides could have significant impact on the development and testing of microbicides in animal models and clinical studies. Unfortunately, current imaging technology such as white light colposcopy or colonoscopy cannot provide high resolution images of epithelial injury and cannot probe below the surface where epithelial injury and inflammation may be evident. However, in recent years, new imaging technology has been developed where it is now possible to perform high resolution imaging of epithelial tissue with microscopic resolution in vivo. Our overall goal is to develop an endoscopic imagedbased approach that can be used to 1) assess the degree of injury that may be induced by microbicides and 2) correlate the results of imaging studies to susceptibility to genital infection in mice cervicovaginal tract and rectum caused by HSV-2. We will deploy emerging high resolution imaging modalities including confocal fluorescence microscopy and optical coherence tomography (OCT) to characterize the changes that occur in the architecture of cervical, vaginal, and rectal epithelium of untreated sexually na¿ve mice as well as mice treated with known irritative microbicides. These results will be correlated to susceptibility to infection using a well characterized mouse model of HSV-2 infection. This will allow us to assess the predictive value of confocal fluorescence and OCT imaging for observed HSV-2 susceptibility based on microbicide-induced epithelial changes with attention to reproducibility/consistency of findings. In phase I of this project we will demonstrate the capabilities of high resolution optical imaging to quantitatively assess the response of cervicovaginal and rectal tissue to known microbicides and test the ability to predict the biological end point of microbicide-induced changes in susceptibility in cervicovaginal tract. In phase II, the proposed imagedbased assessment of rectal response will be extended to establish correlation between image-based markers and rectal susceptibility following application of microbicides. Furthermore, instrumentation and imaging parameters will be optimized to make the imaging protocol suitable for imaging of cervicovaginal and rectal epithelial response in large animal models and humans. We also plan to use the developed imaging protocol to assess the performance of novel microbicides in small animal models as new products are developed.