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

在美国，接触性皮炎被认为是患者寻求皮肤科医生咨询的第三大常见原因，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都会遇到的化学物质，比如药物、个人护理和化妆品的成分，或者在职业环境中（比如食品、溶剂、塑料和化学工业的工人）。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和监管问题。目前，不同行业使用的化学品超过30,000种，而这些行业没有基于人类的安全数据，平均每年有200-300种新化学品进入市场。目前的动物试验提供了丰富的信息，但需要很长时间才能完成，价格昂贵，最重要的是与人类的生理相关性差，同时往往导致大量的动物牺牲。因此，迫切需要建立新的仿生人体体外实验模型，以成功取代和改进现有的动物实验。本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，用于化学物质致敏潜力的高通量测试。研究人员和其他研究人员已经开发了几种用于临床应用的人体皮肤组织工程模型，但这些系统不具备检测皮肤致敏剂所需的免疫能力，也不具备高通量应用的潜力，也不容易集成到其他关键的效应免疫细胞（如T细胞）中。在本提案中，我们将结合我们在微制造，免疫生物学，皮肤组织工程和微尺度组织构建方面的专业知识，开发一种可扩展且具有“自我报告”能力的免疫能力皮肤和淋巴结的小型化模型。该提案建立在申请人之间正在进行的开发具有免疫能力的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人体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一些主要限制，而且可以在药物测试和发现，毒理学和解决影响皮肤的免疫疾病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.