Development of a web-based platform implementing novel Predictor of Skin Sensitization for Medical Devices (PreSS/MD)

项目摘要 医疗器械已被证明含有有毒化学物质，可能会浸出并导致急性接触 皮肤反复暴露或长时间接触这些毒素后，可导致皮炎（ACD）。ACD被认为是 占所有职业病的10-15%，也是报告的第二大职业危害。鉴于其 尽管ACD的发病率很高，但它也是一个巨大的公共卫生负担，每年的总成本高达10亿美元， 包括医疗费用、工人赔偿和因工作场所缺勤而损失的工作时间。为此， 美国食品和药物管理局已强制要求所有医疗器械必须进行评估， 使用体内动物试验（包括豚鼠最大剂量试验（GPMT））进行皮肤致敏。 尽管GPMT试验提供了关于潜在毒素的皮肤致敏作用的有价值的数据，但这些测定法是不可靠的。 耗时且昂贵。此外，机构间鉴定协调委员会 替代方法（ICCVAM）最近发布了一份战略路线图，呼吁开发 减少化学和医疗制剂的动物试验的替代方法。因此，有一个明确的需要， 实现医疗器械安全性评估的现代化，以减少动物试验并缩短监管审查时间， 这将最终更快地将更安全的设备推向市场。为了满足这一未满足的需求， 我们的FDA第一阶段SBIR项目的目的是：（i）为 GPMT测定法整合在人、小鼠和体外测定法中获得的数据;和（ii）整合这些数据。 该软件产品称为PreSS/MD（医疗器械皮肤致敏预测器）。 本研究的具体目标包括：1）收集，策划和整合最大的公开可用的 GMPT数据集; 2）为GMPT数据创建和验证新的计算模型; 3）开发 PreSS/MD网络服务器，允许用户预测医疗器械的皮肤致敏潜力。我们 还将开发一个混合物模型，包括在不同浓度下联合测试的化合物，使用 我们以前开发的方法。最后，我们将实现新的方法来帮助我们的用户 PreSS/MD平台根据负责皮肤的关键化学特征解释开发的模型 致敏此外，我们将采用生物医学知识图来阐明不良结局途径 （AOPs）用于皮肤致敏剂。第一阶段项目的成功实施将产生以下成果： PreSS/MD作为评价医疗器械皮肤致敏潜力的集中资源。我们预计 这种软件即服务的Web服务器平台对于寻求 医疗器械的监管批准。

PROJECT SUMMARY Medical devices have been documented to contain toxic chemicals that can leach and cause acute contact dermatitis (ACD) after repeated exposure or prolonged contact of the skin to these toxins. ACD is credited for 10-15% of all occupational illnesses and is also the second highest reported occupational hazard. Given its prevalence, ACD is also a great public health burden with combined yearly costs of up to $1 billion, which spans including medical costs, worker’s compensation and lost working time due to workplace absence. To this end, the U.S. Food and Drug Administration has mandated that all medical devices must be evaluated for possible skin sensitization using in vivo animal assays, which includes the Guinea pig maximization test (GPMT). Although GPMT tests provide valuable data on the skin sensitization effects of potential toxins, these assays are time-consuming and expensive. Moreover, the Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM) recently published a Strategic Roadmap, calling for the development of alternative approaches to reduce animal testing of chemical and medical agents. Thus, there is a stated need to modernize safety evaluation of medical devices to reduce animal testing and shorten the regulatory review time, which would ultimately bring safer devices to the market faster. To address this unmet need, the key objectives of our FDA Phase I SBIR project are to (i) produce rigorously validated computational models for the GPMT assay integrating data obtained in human, mouse, and in vitro assays; and (ii) integrate these models into a software product termed PreSS/MD (Predictor of Skin Sensitization for Medical Devices). Our specific aims for this study include: 1) collecting, curating, and integrating the largest publicly available dataset for GMPT; 2) creating and validating novel computational models for GMPT data; 3) developing the PreSS/MD web server to allow users to make predictions of skin sensitization potential in medical devices. We will also develop a model for mixtures, including compounds tested jointly in different concentrations, using an approach that we developed previously. Finally, we will implement novel approaches to help users of our PreSS/MD platform interpret the developed models in terms of key chemical features responsible for skin sensitization. In addition, we will employ biomedical knowledge graphs to elucidate Adverse Outcome Pathways (AOPs) for skin sensitizers. Successful execution of this Phase I project will yield in the development of PreSS/MD as a centralized resource to evaluate the skin sensitization potential for medical devices. We expect this software-as-a-service web server platform will be of great value for companies and sponsors seeking regulatory approval of medical devices.