A miniaturized model of human skin and lymph node for drug discovery and testing Contact dermatitis in the United States is thought to be the third most common reason for patients to seek consultation with a dermatologist and accounting for nearly 95% of all reported occupational skin diseases. The main culprits are chemicals that we encounter on a daily basis as ingredients of drugs, personal care and cosmetic products or in an occupational context (e.g. workers in food, solvent, plastic and chemical industries). Therefore, predicting allergenic potential of chemicals and drug leads is an important safety and regulatory concern. There are currently in excess of 30,000 chemicals used by different industries where no human based safety data exist and an average of 200-300 new chemicals are introduced to the market annually. The current animal tests are informative, but take a long time to perform, are expensive and most importantly have poor physiological relevance to humans and at the same time tend to result in a large number of sacrificed animals. Hence, there is an urgent need to establish novel biomimetic human based in vitro testing models which could successfully replace and improve current animal testing. The goal of this proposal is to engineer a miniaturized and integrated model of human skin and lymph node for high throughput testing of allergenic potential of chemicals. Several tissue engineered models of human skin have been developed both by the investigators and others for clinical applications, yet these systems do not have the immune competency required for sensing skin sensitizers or potential for high throughput applications nor can be easily integrated into other crucial effector immune cells like T cells. In this proposal, we will combine our expertise in microfabrication, immunobiology, skin tissue engineering and microscale tissue constructs to develop a miniaturized model of immunocompetent skin and lymph node which is scalable and has 'self-reporting'capabilities. This proposal builds on ongoing collaborations between applicants on developing immunocompetent biomimetic tissue models. This platform will not only overcome a number of major limitations in using biologically relevant and scalable human based in vitro models for testing skin sensitization potential of chemicals and drug compounds, but could have wider applications in drug testing and discovery, toxicology and addressing fundamental questions in the biology of immune diseases affecting skin.
Through this work, we will develop a miniaturized and integrated model of human skin and lymph node which is amenable to high throughput screening and can be used as a platform for drug discovery and safety testing. We will first fabricate perforated microwells to enable culturing skin model at air-liquid interface. We will the engineer an immunocompetent model of epidermis consist of keratinocytes and dermal fibroblasts interspersed with dendritic cells within perforated microwells. Fibroblasts and dendritic cells will be encapsulated in a hydrogel, and keratinocytes will be seeded on top of this hydrogel layer allowing full differentiation of Keratinocytes at air-liquid interface. The cell ladn hydrogel will also contain T cells allowing cross-talk between activated dendritic cells and T cell simulating events in human lymph node. We will then conduct high throughput studies of chemicals with the engineered 'skin-lymph node'model and also implement a read- out system for monitoring the behavior of cells inside the microwells. We will also engineer a multi-parameter readout system using a combination of immobilized microarray of antibodies and fluorescence based assays to monitor cellular responses to chemicals in real-time and in situ. The new model will then be validated against data from in vivo animal models and parallel experiments using immunocompetent human skin explants.
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