Automation and validation of human on a chip systems for drug discovery

项目摘要/摘要 我们对Hesperos的总体战略是利用微生理系统与功能 建立能够对化学品和候选药物进行毒性和有效性分析的平台 在临床前测试期间。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 包含一种新型的“无泵”微生理平台和无血清培养基配方。没有泵的人 集成系统，使用摇摆运动来泵送蜂窝介质，降低了复杂性和成本 流体电路设计，简化了设备的设置和操作。该系统采用微电极 集成在芯片上的阵列和悬臂系统，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监测细胞健康的生物标志物的数量 并在我们的系统中发挥作用。我们已经构建了代表人类心脏的生理系统， 骨骼肌、神经元、肝脏、血管、血脑屏障、胃肠道和神经肌肉 结点(NMJ)。这些器官模块的各种组合可以集成到单个平台上以 检查由于药物代谢物或细胞信号分子的互换而引起的器官之间的相互作用 对毒品的反应产生的。Hesperos已经与7家使用这些多器官系统的公司合作 药物的临床前评价或化学品的毒性试验。Hesperos收到了NCATS的第二阶段拨款 应用先进制造技术，提高生产能力，降低设备成本。 我们在第二阶段拨款方面取得了重大进展，Lili Porter博士(NCATS SBIR 管理员)和Dan Tagle博士(NCATS SBIR计划的计划经理)已批准并 鼓励Hesperos提交第二阶段申请。将这项技术提升到一个可以 对于临床前研究中的常规应用，我们提出了一些修改建议，以进一步 降低制造成本，提高性能和可靠性。为了验证该系统，我们 将与罗氏制药研究公司的阿斯利康(一种心脏/肝脏/血流动力学模型)合作，测试心脏 安全性)和Bioverativ(使用NMJ系统验证重症肌无力模型)。我们将确定是否 这些系统可以预测对这些药物的半定性多器官反应，并与人类 可获得的临床数据。这些研究将为FDA的验证和资格鉴定提供基础。 目标1将使4器官系统的使用更容易纳入制药公司的工作流程 并应将使用成本降低到显著低于动物研究，并提供 对人体系统反应的预测。AIM 2将利用Hesperos的系统来验证这3个平台 申请FDA资格。虽然该系统对制药(或食品或化妆品)仍具有重要价值 公司)，如果没有FDA的批准，FDA的批准将极大地加速这项技术的采用。

Project Summary/Abstract Our overall strategy for Hesperos is to utilize microphysiological systems in combination with functional readouts to establish platforms capable of analysis of chemicals and drug candidates for toxicity and efficacy during pre-clinical testing. 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 human cardiac, skeletal muscle, neuronal, liver, vasculature, blood brain barrier, gastrointestinal tract and neuromuscular junctions (NMJs). Various combinations of these organ modules can be integrated onto a single platform to examine interactions among organs due to interchange of drug metabolites or cell signaling molecules produced in response to drugs. Hesperos has worked with 7 firms using these multi-organ systems for preclinical evaluation of drugs or toxicity tests on chemicals. Hesperos received a Phase II grant from NCATS to apply advanced manufacturing technology to increase throughput and decrease the cost of the device. We have made major advances in our Phase II grant to the point where Dr. Lili Porter (NCATS SBIR Administrator) and Dr. Dan Tagle (Program Manager of NCATS SBIR Program) have approved and encouraged Hesperos to submit a Phase IIB application. To move this technology to a level where it can be cost effective for routine applications in preclinical studies we propose a number of modifications to further reduce manufacturing cost and improve performance and reliability. In an attempt to validate the system, we will partner with AstraZeneca, Roche Pharma Research (a heart/liver/hemodynamic model to test for cardiac safety) and Bioverativ (to validate a Myasthenia Gravis model using an NMJ system). We will determine if these systems can predict semi-qualitative multi-organ responses to those drugs and compare to human clinical data where available. These studies will provide a basis for validation and qualification with the FDA. Aim 1 will make the use of the 4-organ system easier to incorporate into the workflow at pharmaceutical firms and should reduce the cost of use to significantly less than animal studies and provide the advantage of prediction of response in a human system. Aim 2 will utilize Hesperos’s systems to validate these 3 platforms for FDA qualification. While the systems still have significant value to pharmaceutical (or food or cosmetic companies) without FDA approval, FDA approval would greatly accelerate adoption of this technology.