Collaborative Research: GOALI: High-Impact Multiscale Physicochemical Advancements for the Prediction of Transient Dermal Absorption

这一目标ali项目将推进皮肤渗透科学，特别是预测人体接触化学剂时皮肤的短暂吸收，无论这些化学剂是有益的还是有害的。前一种情况包括外用药物和化妆品有益剂；后者包括农场工人遇到的雾化农药，城市居民遇到的空气污染物，以及工人在混凝土和金属加工等环境中遇到的微量化学物质。建模和仿真最近已成为美国FDA仿制药审批流程的一个组成部分，可以降低成本并加快这些产品的审批速度。包括美国NIOSH在内的全球监管机构越来越多地将建模作为其皮肤风险评估过程的一部分。该项目将解决两个困扰皮肤瞬时吸收预测的棘手问题：(1)化学物质与皮肤蛋白质（尤其是角蛋白）缓慢可逆的结合使许多常见化学物质（包括局部类固醇）的摄取和释放谱复杂化；(2)沉积在皮肤表面或毛囊内的固体颗粒的逐渐溶解影响凝胶和软膏中药物的吸收以及皮肤对空气污染物中浸出的重金属的吸收。该项目的结果将纳入一个公开的、基于电子表格的皮肤渗透程序，以及一个由GOALI工业合作伙伴宝洁公司维护的最先进的皮肤吸收模拟代码。部分研究将被纳入辛辛那提大学化妆品科学领域的本科和研究生培训。该教育计划还专门针对本科生女性和代表性不足的少数民族学生的本科研究经历。该项目需要：(1)在严格的理论框架支持下，对外皮肤屏障细胞（角质层细胞）中角蛋白结合速率常数进行实验测量和广泛参数化；(2)开发和实现能够代表皮肤上沉淀固体吸收的界面质量传输关系。知识价值在于识别和解决当前对皮肤吸收的理解中的重要战略空白，这些空白阻碍了涉及多相和多尺度运输的这两个领域的进展。该项目的一个核心要素是基于严格粗粒化的两个阶段的多尺度建模-从超微结构（细胞内）到微观（细胞间）到宏观（组织）尺度-在解决渗透分子与角质层角蛋白缓慢可逆结合的过程中，这极大地影响了运输速率。该项目将从理论上严格和实用的角度定义皮肤屏障的储层容量，这将为准确预测瞬时皮肤吸收结果的广谱能力开辟道路。对溶解限制吸收的详细处理将最终解决表面上相似的分子所观察到的显著不同的吸收率，这些吸收率长期以来一直困扰着制药和消费品开发工作以及与化学品接触有关的风险评估。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

This GOALI project will advance the science of skin penetration and, in particular, the prediction of transient dermal absorption for human exposure to chemical agents, whether they are beneficial or hazardous. The former case includes topical drugs and cosmetic benefit agents; the latter includes aerosolized pesticides encountered by farm workers, airborne pollutants encountered by residents in city environments, and trace chemicals encountered by workers in settings such as concrete and metal working. Modeling and simulation has recently become a component of the US FDA’s approval process for generic drug products, which reduces cost and accelerates approval of these products. Global regulatory agencies including US NIOSH have increasingly included modeling as part of their dermal risk assessment process. This project will address two vexing issues plaguing predictions of transient skin absorption: (1) slowly reversible binding of chemicals to skin proteins (especially keratin) complicates the uptake and release profiles of many commonly-encountered chemicals including topical steroids; and (2) gradual dissolution of solid particles deposited on the skin surface or within hair follicles affects absorption of drugs from gels and ointments and dermal absorption of heavy metals leached from airborne pollutants. Results from the project will be incorporated into a publicly available, spreadsheet-based skin penetration program and also a state-of-the-art simulation code for dermal absorption maintained by the GOALI industrial partner, Procter & Gamble. Parts of the research will be incorporated into undergraduate and graduate training in the cosmetic science area at the University of Cincinnati. The educational plan also specifically targets undergraduate research experiences for undergraduate women and underrepresented minority students.This project entails: (1) experimental measurement and broad parameterization of rate constants for keratin binding in the outer skin barrier cells (corneocytes) supported by a rigorous theoretical framework; and (2) development and implementation of interfacial mass transport relationships capable of representing absorption of precipitated solids on the skin. Intellectual merit lies in the identification and resolution of important strategic gaps in the current understanding of dermal absorption, which block progress in these two areas involving multiphase and multiscale transport. A central element of the project is multiscale modeling based on two stages of rigorous coarse graining - from ultrastructural (intracellular) to microscopic (intercellular) to macroscopic (tissue) scales - in resolving slow reversible binding of permeating molecules to stratum corneum keratin, which dramatically affects transport rates. The project will define the reservoir capacity of the skin barrier in theoretically rigorous and pragmatically useful terms, which will open the way to a broad-spectrum ability to accurately predict transient dermal absorption outcomes. The detailed treatment of dissolution-limited absorption will finally resolve dramatically different absorption rates observed for ostensibly similar molecules that have long baffled pharmaceutical and consumer product development efforts and risk assessments related to chemical exposures.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.