Understanding dynamic immune responses within a fluidic 3D skin equivalent model

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The skin is a complex, multicellular tissue comprised of epithelial cells, fibroblasts, blood vessels, nerves, and dendritic cells. Dynamic communication between circulating immune cells and tissue-resident skin cells orchestrates the response to infection, as well as tissue repair and regeneration. While existing organotypic skin models replicate the basic bi-layered structure of the epithelium and mesenchyme, modelling the complex and dynamic interaction with the immune system has proven extremely challenging. The proposed PhD project therefore aims to develop a 3D human skin model with fluidic delivery of circulating immune cells and investigate the dynamic responses to chemical irritants and bacterial products.The overall aim of this interdisciplinary PhD studentship is to gain new insight into human-specific inflammatory responses within the skin through the development of a novel immune-responsive organotypic model. The project will construct and validate a two-compartment model consisting of a 3D organotypic skin construct and an immune compartment joined by perfused cell culture medium. The specific objectives include:1. Establish a 3D organotypic model of human skin within a commercially available fluidic platform (Kirkstall Ltd, QV600).2. Characterise immune infiltration and the response of resident skin cells (keratinocytes and fibroblasts) when neutrophils, monocytes or macrophages are perfused through the system.3. Analyse the dynamic responses (migration, proliferation, and differentiation) of immune and resident skin cells to chemical irritants and purified bacterial products applied to the skin surface.4. Investigate the molecular mediators involved in skin-immune system cross-talk within this platform by profiling cytokine release (Luminex) and functional inhibition with RNAi and small molecules.The successful completion of this project will establish a next-generation model of human skin with immune-responsive capability. This platform will be a powerful tool for understanding human-specific skin biology and the testing and development of new compounds and therapeutics. This interdisciplinary studentship will provide advanced training in skin biology, 3D culture models, bioengineering, and immunology. PhD supervision and training will be managed by academics with expertise in each of these fields, and the student will benefit from state-of-the-art facilities within the Blizard. In addition, the student will carry out a 3 month industrial placement at Kirkstall Ltd, a UK-based SME developing fluidic culture systems for a range of different tissue models. Here, the student will gain additional experience in fluidic systems and their applications for different tissue and disease models. The student will further develop transferable skills in product development, commercialisation, communication, and marketing.