Barrier function is the natural role of the skin. The lipid matrix present in the outermost layer of the skin, the stratum corneum is important for this function. Barrier impairment and altered... Show moreBarrier function is the natural role of the skin. The lipid matrix present in the outermost layer of the skin, the stratum corneum is important for this function. Barrier impairment and altered lipid composition are observed in several inflammatory skin diseases including atopic dermatitis and psoriasis. However, the relationship between the lipid properties and barrier function is not comprehended.In this project, a lipid model was prepared from synthetic lipids that closely resemble the stratum corneum lipid composition and organization. Subsequently, diseased skin models were developed to mimic various abnormalities in lipid composition observed in atopic dermatitis patients’ skin. Biophysical methods were used to monitor the changes in lipid organization in these models. Diffusion studies and trans-epidermal water loss measurements were performed to monitor the barrier function. This allowed the determination of the changes in lipid properties that were most instrumental in reducing the lipid barrier.This thesis further describes the use of simple skin lipid model membranes incorporating fewer components to provide a detailed insight into the relationship between lipid composition, lipid organization, and the skin barrier. The information gained in this project offers the opportunity to develop a new generation of formulations to treat these patients. Show less
In this thesis, a new approach for rational drug development in inflammatory skin disease was described by focusing on three important cornerstones: I) developing skin inflammation models for early... Show moreIn this thesis, a new approach for rational drug development in inflammatory skin disease was described by focusing on three important cornerstones: I) developing skin inflammation models for early phase proof-of-pharmacology, II) integrating objective clinical endpoints and III) profiling disease in a multimodal fashion to more thoroughly evaluate drug effects. The results of this thesis show that integration of this approach in a clinical development program can directly influence the next steps in clinical development of the drug candidate. While each new drug needs a tailored approach, these general aspects need to be considered when designing dermatological drug development programs. This will lead to a more rational, efficient and less expensive way of dermatological drug development. Show less
