WAT-on-a-chip - Development of a micofluidic, microphysiologic in vitro adipose tissue model for high-throughput drug screening based on hiPSC-derived adipocytes.

药物发现和开发受到高失败率的阻碍，这些失败率归因于对非人类动物模型的依赖，以及在安全性和有效性测试期间使用的非生理条件。这一低效过程中的一个根本问题是，非人类动物模型不能充分代表人类生物学，更重要的是，它们不能充分概括人类疾病状态。随着患者特异性人类诱导多能干细胞(IPS)的发现，组织工程界现在可以在体外开发疾病特异性模型组织和器官，用于高含量的药物筛选和患者特异性药物。该项目的主要目标是在芯片上创建白色脂肪组织(WAT)模型系统。WAT被选为模型系统是因为它可以通过多种方式在药物传递和疗效方面发挥重要作用，包括被动药物储存、其他组织靶向药物的副作用和脂肪靶向药物的疗效。这种芯片上的Wat将基于一个微流控平台，它模拟了人类脂肪组织中最微量元素的尺寸和细胞排列。这种微流体设计将允许通过连续流动对介质灌流进行出色的控制，这也允许在将任何可溶性药物输送到脂肪组织模型时进行类似的控制。此外，该平台将允许对组织模型进行连续监测、采样和探测。该项目的次要目标包括(I)将葡萄糖传感器集成到平台中，以便能够实时监测血糖水平，指示组织的功能和药物反应，以及(Ii)在开发的平台内将人iPS细胞分化为功能脂肪细胞。最终的平台预计将是非常通用的，适用于脂肪组织的基础研究和用于治疗、诊断和应用的药物筛选。

Drug discovery and development is hampered by high failure rates attributed to the reliance on non-human animal models and non-physiological conditions employed during safety and efficacy testing. A fundamental problem in this inefficient process is that non-human animal models cannot sufficiently represent human biology, and more importantly, they cannot adequately recapitulate human disease states. With the discovery of patient-specific human induced pluripotent stem (iPS) cells, the tissue engineering community is now in position to develop in vitro disease-specific model tissues and organs to be used for high content drug screening and patient specific medicine. The principal goal of this project is to create a white adipose tissue (WAT) model system on a chip. WAT as a model system was chosen since it can play a major role for both drug delivery and efficacy in a variety of ways, including passive drug storage, side-effects of other tissue targeting drugs, and the efficacy of adipose targeted drugs. The WAT-on-a-chip will be based on a microfluidic platform that mimics the dimensions and cellular arrangement of minimal elements of human adipose tissue. This microfluidic design will allow excellent control over media perfusion via continuous flow, which also allows similar control in delivering any soluble drug to the adipose tissue model. Furthermore, the platform will allow for continuous monitoring, sampling, and probing of the tissue model. Secondary goals of this project include (i) the integration of a glucose sensor into the platform to enable live monitoring of glucose level, indicating functionality and drug-response of the tissue, and (ii) differentiation of human iPS cells to functional adipocytes within the developed platform. The final platform is envisioned to be extremely versatile and to be applicable for both fundamental studies of adipose tissue and the screening of drugs for therapeutic diagnostic and applications.