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

用于药物发现的人体芯片系统的自动化和验证

• 批准号: 10021038
• 负责人: James J Hickman
• 金额: $ 140.45万
• 依托单位: HESPEROS, LLC
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-04 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10021038
• 关键词: Academia; Acute; Administrator; Adoption; Advanced Manufacturing Technology; Affect; Animals; Automation; Biological; Biological Markers; Biological Models; Blood - brain barrier anatomy; Cardiac; Cardiovascular system; Cell Culture Techniques; Cell Survival; Cells; Chemicals; Chronic; Clinical; Clinical Data; Clinical Trials; Collaborations; Complement Inactivators; Computer Models; Consumption; Contracts; Cosmetics; Data; Databases; Devices; Disease; Drug Costs; Drug toxicity; Evaluation; Failure; Food; Food Additives; Formulation; Gastrointestinal tract structure; Generations; Government; Grant; Health; Heart; Human; In Vitro; Individual; Industry; Lead; Liquid substance; Liver; Measurement; Measures; Mechanics; Methods; Microelectrodes; Microfluidics; Modeling; Modification; Monitor; Motion; Musculoskeletal; Myasthenia Gravis; Nervous system structure; Neuromuscular Junction; Neurons; Organ; Output; Parents; Performance; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Phase; Physiological; Physiology; Preclinical Drug Evaluation; Preclinical Testing; Procedures; Process; Production; Progress Reports; Pump; Research; Safety; Secure; Serum; Services; Signal Transduction; Signaling Molecule; Skeletal Muscle; Small Business Innovation Research Grant; Stress; System; Techniques; Technology; Telemetry; Testing; Time; Tissue Model; Toxic effect; Toxicity Tests; United States National Institutes of Health; Validation; Work; base; body on a chip; body system; cantilever; clinical application; cooking; cost; cost effective; design; drug candidate; drug development; drug discovery; drug efficacy; drug metabolism; drug testing; efficacy evaluation; efficacy testing; hemodynamics; improved; improved functioning; interest; microphysiology system; next generation; non-invasive monitor; novel; nutrient metabolism; operation; organ on a chip; pre-clinical; preclinical evaluation; preclinical study; predicting response; predictive modeling; programs; public health relevance; real time monitoring; residence; response; safety testing; sample collection; simulation; standard measure; validation studies

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.

项目总结/摘要 我们对Hesperos的总体战略是利用微生理系统与功能性系统相结合， 建立能够分析化学品和候选药物毒性和功效的平台 在临床前测试中。这是一家基于服务的公司，正在开发低成本的体外系统， 含有一种新的“无泵”微生理学平台和无血清培养基配方。无泵 使用摇摆运动来泵送细胞培养基的集成系统降低了系统的复杂性和成本。 流体回路设计并简化装置的设置和操作。该系统采用微电极 集成在芯片上的阵列和悬臂系统， 读数这些功能读数大大减少了细胞健康监测的生物标志物数量 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、脉管系统、血脑屏障、胃肠道和神经肌肉 连接（NMJ）。这些器官模块的各种组合可以集成到单个平台上， 检查由于药物代谢物或细胞信号分子的交换而引起的器官之间的相互作用 产生的反应。Hesperos已经与7家公司合作，使用这些多器官系统， 药物临床前评价或化学品毒性试验。Hesperos获得了NCATS的第二阶段资助 应用先进的制造技术以增加产量并降低装置的成本。 我们已经取得了重大进展，在我们的第二阶段赠款的点，莉莉波特博士（NCATS SBIR 管理员）和Dan Tagle博士（NCATS SBIR计划的计划经理）已经批准并 鼓励赫斯珀罗斯提交第二阶段B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，我们提出了许多修改， 降低制造成本并提高性能和可靠性。为了验证该系统，我们 将与阿斯利康，罗氏制药研究（心脏/肝脏/血液动力学模型，以测试心脏 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， 可用的临床数据。这些研究将为FDA的验证和认证提供基础。 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 并且应当将使用成本降低到显著低于动物研究， 预测人类系统的反应。Aim 2将利用Hesperos的系统来验证这3个平台 FDA认证。虽然该系统仍然具有重要的价值，制药（或食品或化妆品 如果没有FDA的批准，FDA的批准将大大加快这项技术的采用。