Advanced Human on a Chip Systems for Drug Discovery

 描述(由申请人提供)：我们公司的总体战略是利用微生理系统与功能读数相结合，建立能够在临床前测试期间对化学品和候选药物的毒性和有效性进行复杂分析的平台，最初的重点是预测性毒性。这是一家以服务为基础的公司，正在开发低成本的体外系统，其中包含一种新型的“无泵”微生理平台和无血清培养基配方。无泵集成系统使用摇摆运动来泵送蜂窝介质，降低了流体电路设计的复杂性和成本，并简化了设备的设置和操作。该系统采用集成在芯片上的微电极阵列和悬臂系统，以实现非侵入性的电子和机械读数。这些功能读数极大地减少了我们系统中监测细胞健康和功能的生物标记物的数量。我们已经构建了代表心脏、肌肉、神经和肝脏功能的生理系统，这些系统已经被制药和化妆品公司评估并用于希克曼实验室的测试。我们还拥有人类神经肌肉连接的功能性原型系统，以及一个由心脏、肝脏、神经元和骨骼肌室组成的集成四器官系统。这些设备目前正在进行验证研究，作为一种服务可供行业和政府使用，我们现在正在与主要制药公司谈判使用这些系统。然而，目前所有的系统都是手工制造和组装的，这一因素将继续阻碍这些系统的生产。在这项提案中，将利用和开发先进的制造技术，以提高制造和测试的速度，并将成本降低一个数量级。我们将与NIST合作开发这些先进的制造技术，并利用希克曼与Michael Tarlov博士在生物分子测量部门的团队的长期合作。这些系统将用已知的多器官相互作用的药物和针对单个器官的药物进行测试，结果将与人类的临床反应进行比较。特别是，我们将确定该系统是否能够预测对制药和化妆品行业感兴趣的化学品的半定量多器官反应。舒勒博士开创了“芯片上的身体”系统，这是一个现实的多器官平台，使用细胞培养来预测人类对药物和生物制剂的反应，并将创造出下一代设备。希克曼博士开发了具有功能的体外人体生理系统，并将它们集成到无血清介质配方中的微生理平台上。

 DESCRIPTION (provided by applicant): Our overall strategy for the company is to utilize microphysiological systems in combination with functional readouts to establish platforms capable of sophisticated analysis of chemicals and drug candidates for toxicity and efficacy during pre-clinical testing, with initial emphasis on predictive toxicity. This is a service based company that is developing low-cost in vitro systems containing a novel "pumpless" microphysiological platform and serum-free medium formulation. The pumpless integrated system, using a rocking motion to pump the cellular medium, reduces the complexity and cost of the fluidic circuit design and simplifies set-up and operation of the device. The system employs microelectrode arrays and cantilever systems that are integrated on chip to allow for noninvasive electronic and mechanical readouts. These functional readouts greatly reduce the number of biomarkers to be monitored for cell health and function in our systems. We have constructed physiological systems that represent cardiac, muscle, neuronal and liver function that are already being evaluated and utilized for testing in Hickman's lab by pharmaceutical and cosmetic companies. We also have functional, prototype system for human neuromuscular junction, and an integrated 4-organ system consisting of cardiac, liver, neuronal and skeletal muscle compartments. These devices are currently under validation studies and are available as a service for use by industry and government and we are negotiating with major pharmaceutical companies now to utilize these systems. However, all current systems are fabricated and assembled by hand and this factor will continue to hinder production of these systems. In this proposal, advanced manufacturing techniques will be utilized and developed to increase rates of fabrication and testing and lower cost by an order of magnitude. We will partner with NIST to develop these advanced manufacturing techniques and take advantage of Hickman's long association with Dr. Michael Tarlov's group in the Biomolecular Measurement Division. These systems will be tested with drugs that have known multi-organ interactions and ones that target single organs and the results will be compared to human clinical responses. In particular, we will determine whether the system would predict semi-quantitative multi-organ responses to chemicals of interest to the pharmaceutical and cosmetic industries. Dr. Shuler has pioneered the "Body-on-a-Chip" system, a realistic multi-organ platform using cell cultures to predict human response to drugs and biologics and will create a next-generation device. Dr. Hickman has developed functional in vitro human physiological systems and integrated them onto the microphysiological platform in serum-free medium formulations.