HLS-Development of a cardiac ischemia model in an organ-on-a-chip platform

HLS-在器官芯片平台中开发心脏缺血模型

• 批准号: 10579914
• 负责人: James J Hickman
• 金额: $ 85.48万
• 依托单位: HESPEROS, LLC
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10579914
• 关键词: Acute; Affect; Award; Back; Biological Markers; Biological Models; Biological Products; Biomedical Engineering; Blood Vessels; Cardiac; Cardiac Myocytes; Cell Culture Techniques; Cells; Cellular biology; Characteristics; Chemicals; Chronic; Coculture Techniques; Competence; Contracts; Cosmetics; Development; Devices; Drug Compounding; Drug Costs; Drug toxicity; Electrocardiogram; Electronics; Electrophysiology (science); Evaluation; Event; Exhibits; Generations; Goals; Grant; Health; Heart failure; Housing; Human; In Situ; In Vitro; Investigation; Ischemia; Legal patent; Letters; Liver; Measurement; Measures; Mechanics; Membrane Potentials; Microelectrodes; Microfluidics; Modeling; Monitor; Motion; Muscle; Muscle Contraction; Muscle function; Myocardial Infarction; Myocardial Ischemia; Neurons; Organ; Output; Pattern; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Phase; Phenotype; Philosophy; Physiological; Physiology; Preclinical Testing; Process; Production; Proteins; Protocols documentation; Publishing; Pump; Recovery; Reperfusion Injury; Reperfusion Therapy; Rest; Serum; Services; Small Business Innovation Research Grant; Smooth Muscle; Smooth Muscle Myocytes; Stress; Surface; System; Systems Integration; Techniques; Testing; Therapeutic; Time; Tissues; Toxic effect; Validation; Vascular Endothelial Cell; Vascular Smooth Muscle; body on a chip; body system; cantilever; cardioprotection; clinical development; commercialization; constriction; cost; design; drug candidate; drug development; drug discovery; drug testing; experience; experimental study; heart electrical activity; heart function; hemodynamics; human model; in vivo; induced pluripotent stem cell; induced pluripotent stem cell derived cardiomyocytes; instrumentation; manufacture; microphysiology system; non-invasive monitor; novel; operation; organ on a chip; patch clamp; pressure; prevent; prophylactic; response; restoration; screening; sensor; simulation; skills; small molecule

Project Summary Our overall strategy for Hesperos 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 and is developing low-cost in vitro systems utilizing a novel “pumpless” microphysiological platform described in US Patent 8,748,180B2. The commercialization potential of our system has been validated by the award of a Phase IIB SBIR to apply advanced manufacturing techniques to increase output and lower cost of production. The pumpless integrated system, using a rocking motion to pump the serum-free cellular medium, reduces the complexity and cost of the fluidic circuit design and simplifies set-up and operation of the device. Hickman has developed microelectrode arrays and cantilever systems that are integrated on chip for noninvasive electronic and mechanical readouts. We have detailed an in vitro cardiac system where the two main components of function, electrical conduction and muscle force, have been reproduced in vitro. The independent measurement of these two key variables allows a detailed description of a compound’s effect on overall cardiac function and is currently being used under contract by multiple companies. Because we can measure these functional outputs independently, we can also use these readouts to give ideas on mechanism of action of a compound. We have adapted this chip based system into a platform for testing cardiac ischemia and reperfusion as published in APL Bioengineering that demonstrated an investigational compound effectively reduced ischemia/reperfusion damage in vitro. The human iPSC cardiac cells used in this device were shown to reach some aspects of functional maturation as primarily evidenced by patch clamp electrophysiological measurements indicating resting membrane potentials of -85 mV or better. We will expand this system by integrating a hemodynamic module of vascular smooth muscle cells and microvascular endothelial cells with the microfluidic system and develop continuous monitoring instrumentation. This cardiac organ-on-a-chip platform will be validated by screening compounds that act either directly on the cardiac cells or affect hemodynamics, and will be used to screen investigational compounds from our pharma partners. A microphysiological system will be developed with continuous readouts for smooth muscle cell contraction, cardiac electrical and mechanical function, fitted with environmental sensors, and integrated with an environmental chamber for inducing ischemia. We will first optimize and validate environmental conditions and protocols for inducing and measuring cardiac ischemic damage, followed by validation with ischemia drugs with published in vivo and in vitro results. The uniqueness will be the combination of Hickman’s functional modules with Shuler’s “pumpless” system, as well as continuous measurement of both cardiac and hemodynamic effects. Our team contains all of the skill sets required to construct, evaluate and commercialize the integrated system and associated components to achieve the goals.

项目摘要 我们针对Hesperos的总体策略是将微生物生理系统与功能读数结合使用 建立能够对毒性和效率的化学物质和候选药物进行复杂分析的平台 在临床前测试期间，最初强调预测性毒性。这是一家基于服务的公司，是 使用新颖的“ Pumpless”微生理平台开发低成本的体外系统 专利8,748,180b2。我们系统的商业化潜力已通过一个阶段的奖励来验证 IIB SBIR应用高级制造技术来增加产出和降低生产成本。这 Pumpless集成系统，使用摇摆运动泵送无血清的细胞介质，减少 流体电路设计的复杂性和成本，简化了设备的设置和操作。希克曼有 开发的微电极阵列和悬臂系统，这些系统集成在非侵入性电子的芯片上 和机械读数。我们详细介绍了一个体外心脏系统，其中两个主要组成部分 功能，电导传导和肌肉力量已在体外再现。独立测量 在这两个关键变量中，可以详细描述化合物对整体心脏功能的影响 目前正在由多家公司根据合同使用。因为我们可以测量这些功能输出 独立地，我们还可以使用这些读数来就化合物的作用机理提出想法。我们有 将这种基于芯片的系统调整为测试心脏缺血和再灌注的平台 有效降低缺血/再灌注的研究化合物的生物工程技术 体外损害。该设备中使用的人IPSC心脏细胞已显示到达到的某些方面 功能成熟为主要成熟，这是由斑块夹电生理测量结果证明的 静止的膜电位为-85 mV或更高。我们将通过整合血流动力学来扩展该系统 带有微流体系统的血管平滑肌细胞和微血管内皮细胞的模块 开发连续监控仪器。这个心脏器官片平台将由 筛选直接作用于心脏细胞或影响血液动力学的化合物，将用于 我们的药物合作伙伴的筛选研究化合物。将开发一个微生物生理系统 连续读数，用于平滑肌肉细胞收缩，心脏电气和机械功能，适合 环境传感器，并与诱导缺血的环境室整合。我们将首先 优化和验证诱导和测量心脏缺血的环境条件和方案 损害，然后用缺血药物验证，并在体内发表和体外结果。独特性 Hickman的功能模块与Shuler的“ Pumpless”系统的结合以及继续 测量心脏和血流动力学作用。我们的团队包含所有需要的技能 构建，评估和商业化集成系统和相关组件以实现目标。