PI: Nitsche
Detailed mechanistic understanding of molecular absorption through the skin is critical to the evolving needs of transdermal and topical drug development, and risk assessment of chemical exposures. This project addresses the primary current scientific stumbling blocks for more reliable prediction of transient drug/chemical absorbed amounts and concentrations in skin tissue as well as systemic absorption, all involving multiphase transport processes at various scales. Specifically, it will: (i) produce a significantly advanced model of the stratum corneum (SC, outermost barrier) layer, including solute diffusion with reversible keratin binding within the corneocyte phase, diffusional anisotropy within the lipid phase, and more concrete representations of the SC porous pathway than are currently considered; (ii) extend a quantitative diffusion model of the viable epidermis below the SC to include intra- and extracellular protein binding; and (iii) develop a realistic model of hindered solute diffusion through the collagen/proteoglycan matrix of the underlying dermis. This strategically targeted set of theoretical and computational developments, informed by selected experimental data, will materially advance the ability to quantitatively predict skin-absorption parameters. Such parameters are directly relevant to a broad spectrum of industrial applications in pharmaceutical and consumer products, and are also critical to supplying the science needed to inform and satisfy evolving regulatory requirements for chemical risk. On the academic side the project is collaboration between the pharmaceutics group of the PI at the University of Cincinnati, and the microscopic transport groups of two PIs at the State University of New York at Buffalo and the University of Illinois at Chicago. The industrial co-PI for this GOALI project is at Procter & Gamble. With the technical input and experience of the industrial partner, the science generated will be incorporated into an accessible and transparent computational platform that can be understood by the product development, toxicology, and regulatory communities.
This project will advance the science of drug/chemical transport through skin, which is of substantial commercial value to industrial corporations (especially cosmetic and personal care companies such as the GOALI partner P&G) dedicated to preserving the public health while advancing business interests through new product development. The primary envisioned application of the technology is an improved, user-friendly computer tool for dermal risk assessment that is of particular importance in light of current and foreseeable restrictions on animal testing. This tool will be made available to the general public, other companies and government agencies by the disclosure mechanisms discussed within the proposal. Broader medical impacts include insights into the mechanism of contact sensitization and dermal drug activity. One of the central elements of the project is the theoretical, coarse-graining, method, whereby microscopic details of drug/chemical transport at the cellular level can be successfully incorporated into predictions of the overall outcome of, for example, a chemical exposure or the application of a drug patch. Parts of the analysis will answer such open theoretical questions as how to carry out coarse-graining in biological systems, where molecules frequently bind and unbind to the tissues through which they move. Broader carry over to other areas of biology are concretely mapped out in the project; these include (i) effects of binding on cellular communication through intercellular pores, and (ii) molecular motion in lipids, including applications to cryobiology. Specific aspects of this research will be spun off into undergraduate and graduate curricula in engineering, pharmaceutical sciences and public health. Finally, high school outreach and recruiting from underrepresented groups will leverage (i) a current NSF S-STEM grant supporting need-based scholarships in one of the co-PI?s departments, and (ii) professional engineers in the local AIChE section.
