A miniaturized model of human skin and lymph node for drug discovery and testing

描述（由申请人提供）：在美国，用于药物发现和测试的人体皮肤和淋巴结的微型模型接触性皮炎被认为是患者寻求皮肤科医生咨询的第三大最常见原因，占所有报告的职业性皮肤病的近95%。主要的罪魁祸首是我们每天作为药物、个人护理和化妆品的成分或在职业环境中（例如食品、溶剂、塑料和化学工业的工人）遇到的化学品。因此，预测化学品和药物先导物的致敏潜力是一个重要的安全性和监管问题。目前有超过30，000种化学品被不同的行业使用，而这些行业没有基于人类的安全数据，平均每年有200-300种新化学品被引入市场。目前的动物试验是信息丰富的，但需要很长的时间来执行，是昂贵的，最重要的是具有差的生理相关性的人，同时往往会导致大量的牺牲动物。因此，迫切需要建立新型的仿生人体外测试模型，以成功地取代和改善现有的动物测试。该提案的目标是设计一个小型化和集成的人体皮肤和淋巴结模型，用于化学品过敏潜力的高通量测试。研究人员和其他人已经开发了几种人类皮肤的组织工程模型用于临床应用，但这些系统不具有感测皮肤敏化剂所需的免疫能力或高通量应用的潜力，也不能容易地整合到其他关键的效应免疫细胞如T细胞中。在这项提案中，我们将联合收割机结合我们在微加工，免疫生物学，皮肤组织工程和微尺度组织结构方面的专业知识，开发一种可扩展的免疫活性皮肤和淋巴结的小型化模型，并具有“自我报告”能力。该提案建立在申请人之间正在进行的关于开发免疫活性仿生组织模型的合作基础上。该平台不仅将克服在使用生物相关和可扩展的基于人的体外模型来测试化学品和药物化合物的皮肤致敏潜力方面的许多主要限制，而且可以在药物测试和发现、毒理学以及解决影响皮肤的免疫疾病的生物学中的基本问题方面具有更广泛的应用。

DESCRIPTION (provided by applicant): 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.