Heart-Lung Micromachine for Safety and Efficacy Testing

用于安全性和有效性测试的心肺微型机器

• 批准号: 8322783
• 负责人: DONALD E INGBER
• 金额: $ 105.87万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-27 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8322783
• 关键词: Aerosols; Animals; Biological Assay; Biological Availability; Biological Models; Biomimetics; Breathing; Cardiac; Cardiotoxicity; Cell Culture Techniques; Cells; Clinical; Clinical Trials; Complex; Decision Making; Development; Devices; Engineering; Future; Goals; Heart; Human; In Vitro; Inflammation; Laboratories; Life; Lung; Measures; Mechanics; Medical; Methods; Microfluidics; Modeling; Organ; Outcome; Patients; Pharmaceutical Preparations; Physiological; Physiology; Respiratory physiology; Safety; Screening procedure; System; Technology; Therapeutic Agents; Time; TimeLine; Tissues; Toxic effect; absorption; aerosolized; base; body system; cost; drug efficacy; efficacy testing; heart function; improved; in vitro Model; man; microsystems; nanotherapeutic; nanotherapy; public health relevance; reconstitution; safety testing

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.

描述（申请人提供）：减缓新的和更安全的医疗产品的开发和监管批准的主要问题之一是缺乏实验性体外模型系统，该系统可以通过预测人体内的药物功效、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开发方面取得了相当大的进展，这些方法不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实验室最近的突破，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体人类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，以生产一种“心肺微机器”，可以提供定量实时测量气溶胶药物，纳米治疗药物和其他医疗产品对肺和心脏功能的有效性，生物利用度和安全性。这项建议的具体目标包括：1）证明呼吸肺芯片装置测量基于气溶胶的药物和纳米治疗剂的肺吸收、功效和毒性的能力，2）证明跳动心脏微装置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，以及3）创建集成的心肺微系统技术，其可以评估通过气溶胶递送到肺的药物和纳米治疗剂对体外心脏功能和毒性的影响。在这些研究中，我们将证明一种新的仿生微系统技术的原理证明，该技术可以分析疗效和生物利用度，并检测与进入临床试验前使用治疗药物相关的不良毒性。如果成功的话，这些芯片上的器官微设备可以大大缩短时间轴，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。 公共卫生相关性：我们建议建立一个由活细胞排列的微流体通道组成的“心肺微机器”作为筛选平台，可以取代目前用于药物和纳米疗法开发和监管审查的动物试验。这种仿生技术可以大大缩短将药物带给患者所需的时间，提高其安全性，降低其成本，并改善临床结果。

项目成果

Micropatterning Alginate Substrates for in vitro Cardiovascular Muscle on a Chip.

• DOI: 10.1002/adfm.201203319
• 发表时间: 2013-08-12
• 期刊: Advanced functional materials
• 影响因子: 19
• 作者: Agarwal A;Farouz Y;Nesmith AP;Deravi LF;McCain ML;Parker KK
• 通讯作者: Parker KK

Microfluidic heart on a chip for higher throughput pharmacological studies.

• DOI: 10.1039/c3lc50350j
• 发表时间: 2013-09-21
• 期刊: Lab on a chip
• 影响因子: 6.1
• 作者: Agarwal A;Goss JA;Cho A;McCain ML;Parker KK
• 通讯作者: Parker KK

Clear castable polyurethane elastomer for fabrication of microfluidic devices.

清除可铸的聚氨酯弹性体，用于制造微流体设备。

• DOI: 10.1039/c3lc50558h
• 发表时间: 2013-10-07
• 期刊: Lab on a chip
• 影响因子: 6.1
• 作者: Domansky K;Leslie DC;McKinney J;Fraser JP;Sliz JD;Hamkins-Indik T;Hamilton GA;Bahinski A;Ingber DE
• 通讯作者: Ingber DE

A human disease model of drug toxicity-induced pulmonary edema in a lung-on-a-chip microdevice.

• DOI: 10.1126/scitranslmed.3004249
• 发表时间: 2012-11-07
• 期刊: Science translational medicine
• 影响因子: 17.1
• 作者: Huh D;Leslie DC;Matthews BD;Fraser JP;Jurek S;Hamilton GA;Thorneloe KS;McAlexander MA;Ingber DE
• 通讯作者: Ingber DE

A mini-microscope for in situ monitoring of cells.

• DOI: 10.1039/c2lc40345e
• 发表时间: 2012-10-21
• 期刊: Lab on a chip
• 影响因子: 6.1
• 作者: Kim SB;Koo KI;Bae H;Dokmeci MR;Hamilton GA;Bahinski A;Kim SM;Ingber DE;Khademhosseini A
• 通讯作者: Khademhosseini A