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

项目摘要 我们对Hesperos的总体战略是将微生理系统与功能读数相结合 建立能够对化学品和候选药物进行复杂的毒性和有效性分析的平台 在临床前测试期间，最初的重点是预测性毒性。这是一家以服务为基础的公司 利用美国描述的新型“无泵”微生理平台开发低成本的体外系统 专利8748,180B2。我们的系统的商业化潜力已经通过一个阶段的授予得到了验证 IIB SBIR应用先进的制造技术来提高产量和降低生产成本。这个 无泵集成系统，使用摇摆运动来泵送无血清细胞培养液，减少了 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。希克曼有 开发了集成在芯片上的微电极阵列和悬臂系统，用于非侵入性电子产品 和机械读数。我们已经详细介绍了一个体外心脏系统，其中两个主要组件 功能，电传导和肌肉力量，已经在体外复制。独立测量 这两个关键变量可以详细描述化合物对整体心脏功能的影响 目前正被多家公司按合同使用。因为我们可以测量这些函数输出 独立地，我们也可以使用这些读数来给出关于化合物的作用机理的想法。我们有 将这个基于芯片的系统改造成APL上发表的心脏缺血和再灌注测试平台 生物工程证明了一种研究化合物有效地减少了缺血/再灌注 体外损伤。该设备中使用的人IPSC心肌细胞被证明达到了 主要由膜片钳电生理测量证明的功能成熟 静息膜电位为-85 mV或更好。我们将通过集成血液动力学来扩展这个系统 具有微流控系统的血管平滑肌细胞和微血管内皮细胞模块以及 发展连续监测仪器。这一心脏器官芯片平台将通过 筛选直接作用于心肌细胞或影响血流动力学的化合物，并将用于 筛选来自我们的制药合作伙伴的研究化合物。将开发一种微生理系统， 连续读数，用于测量心肌细胞收缩、心脏电和机械功能，配有 环境传感器，并与环境小室集成，用于诱导缺血。我们将首先 优化和验证诱发和测量心肌缺血的环境条件和方案 损伤，随后用已公布的体内和体外结果与缺血药物进行验证。独特性 将是希克曼的功能模块与舒勒的“无泵”系统的组合，以及连续 心脏和血流动力学效应的测量。我们的团队包含所需的所有技能集 构建、评估和商业化综合系统和相关组件，以实现这些目标。

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.