Heart-Lung Micromachine for Safety and Efficacy Testing

描述（由申请人提供）：减缓新的和更安全的医疗产品开发和监管批准的主要问题之一是缺乏实验体外模型系统，可以通过预测药物在人体内的功效、生物利用度和毒性来取代昂贵和耗时的动物研究。尽管在细胞培养模型的发展方面取得了相当大的进展，但这些方法未能重建整个活体器官的结构和机械特征以及对其功能至关重要的综合多器官系统生理学。该项目基于PI和Co-PI实验室的最新突破，这些突破使设计仿生微系统技术成为可能，该技术使用在三维微流体系统中培养的活人体细胞来复制呼吸肺和跳动心脏的复杂生理功能和机械微环境。该项目的长期目标是将这些“器官芯片”微型设备集成在一起，生产出一种“心肺微型机器”，可以对气雾剂药物、纳米疗法和其他综合心肺功能的医疗产品的疗效、生物利用度和安全性进行定量实时测量。这项建议的具体目标包括：1)展示呼吸肺芯片设备测量肺吸收、气雾剂药物和纳米疗法的功效和毒性的能力；2)展示跳动心脏微设备通过测量心脏细胞收缩性、电传导和组织炎症的变化来检测心脏毒性的能力；3)创建一种集成的心肺微系统技术，可以评估药物和纳米疗法通过气溶胶输送到肺部对体外心脏功能和毒性的影响。在这些研究中，我们将展示一种新的仿生微系统技术的原理证明，该技术可以在进入临床试验之前分析与治疗药物使用相关的功效和生物利用度，以及检测不良毒性。如果成功，这些器官芯片微型设备可以大大缩短时间，降低与雾化药物、纳米疗法和其他医疗产品开发相关的成本，并为未来的监管决策提供信息。

DESCRIPTION (provided by applicant): One of the major problems slowing development and regulatory approval of new and safer medical products is the lack of experimental in vitro model systems that can replace costly and time-consuming animal studies by predicting drug efficacy, bioavailability and toxicity in man. Although considerable advances have been made in the development of cell culture models, these methods fail to reconstitute structural and mechanical features of whole living organs and integrated multi-organ system physiology that are central to their function. This project is based on recent breakthroughs in the laboratories ofthe PI and Co-PI that make it possible to engineer biomimetic microsystems technologies that use living human cells cultured within three- dimensional microfluidic systems to replicate the complex physiological functions and mechanical microenvironment ofthe breathing lung and beating heart. The long-term goal of this project is to intejgrate these 'organ-on-chip' microdevices to produce a 'Heart-Lung Micromachine' that can provide quantitative real-time measures of the efficacy, bioavailability and safety of aerosol-based drugs, nanotherapeutics and other medical products on integrated lung and heart function. The specific aims of this proposal include: 1) to demonstrate the ability ofthe breathing lung-on-a-chip device to measure pulmonary absorption, efficacy and toxicity of aerosol-based drugs and nanotherapeutics, 2) to demonstrate the ability ofthe beating heart microdevlce to detect cardiotoxicity by measuring changes in cardiac cell contractility, electrical conduction, and tissue inflammation, and 3) to create an integrated heart-lung microsystem technology that can assess the effects of drugs and nanotherapeutics delivered to the lung by aerosol on cardiac function and toxicity in vitro. In these studies, we will demonstrate proof-of-principle for a new biomimetic microsystem technology that can analyze efficacy and bioavailability, as well as detect adverse toxicities, associated with use of therapeutic agents before entering clinical trials. If successful, these organ-on-chip microdevices could greatly shorten the timeline and reduce costs associated with development of aerosolized drugs, nanotherapies and other medical products, as well as inform regulatory decision-making in the future. PUBLIC HEALTH RELEVANCE: We propose to build a 'Heart-Lung Micromachine' composed of microfluidic channels lined by living cells as a screening platform that could replace animal assays currently used for development and regulatory review of drugs and nanotherapies. This biomimetic technology could greatly shorten the time required to bring drugs to patients, increase their safety, decrease their costs, and improve clinical outcome.