Cardiotoxicity Assays on an Integrated Platform of a Heart-on-a-Chip and an Optical Immunosensor

芯片心脏和光学免疫传感器集成平台的心脏毒性测定

• 批准号: 10265584
• 负责人: Mehmet Remzi Dokmeci
• 金额: $ 29.78万
• 依托单位: TERASAKI INSTITUTE FOR BIOMEDICAL INNOVATION
• 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 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10265584
• 关键词: 3-Dimensional; Address; Adopted; Animal Model; Animal Testing; Architecture; Behavior; Biochemical; Biological Assay; Biological Markers; Biomimetics; Bioreactors; Biosensing Techniques; Biosensor; Cardiac; Cardiac Myocytes; Cardiotoxicity; Chemicals; Clinical; Clinical Trials; Concentration measurement; Crystallization; Detection; Development; Drug Industry; Drug Interactions; Drug Kinetics; Drug toxicity; Economics; Electric Stimulation; Evaluation; Failure; Fluorescence; Future; Goals; Heart; Human; In Situ; Kinetics; Label; Lead; Legal patent; Measurement; Mechanical Stimulation; Methods; Microfluidic Microchips; Microfluidics; Modeling; Monitor; Natural regeneration; Optics; Organ; Organ Model; Organoids; Perfusion; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacotherapy; Physiological; Physiology; Process; Research; Sampling; Structure; Surface; System; Technology; Temperature; Testing; Time; Tissue Microarray; Tissue Model; Toxic effect; Toxicity Tests; Validation; base; bioprinting; combinatorial; cytotoxic; drug candidate; drug development; drug discovery; fluorophore; human tissue; induced pluripotent stem cell; innovation; interest; novel; optical sensor; organ on a chip; personalized medicine; personalized screening; photonics; precision medicine; response; screening; sensor; sensor technology; side effect

Abstract Toxicity assays based on human organs-on-a-chip platforms have become increasingly important for drug discovery and development, since they allow testing cytotoxic effects of pharmaceutical compounds on the physiologically relevant human tissue models before moving forward to expensive animal testing or clinical trials. Multiple physiological and biochemical parameters of the organ-on-a-chip models must be continually monitored in order to assess the responses of these models to drug treatments. Although fluorescence detection has been widely adopted for bioassays, it requires the addition of fluorophores to the samples, which may disturb cellular activities and more seriously, it is practically impossible for real-time fluorescence labeling of the biomarkers that are constantly secreted by the organ models during drug toxicity testing. Thus, fluorescence detection is not a viable option here - direct detection, or “label-free” detection, is required for monitoring the dynamic process of drug interactions with organoids to obtain detailed information on transient as well as delayed or cumulative drug effects. The overarching goal of the proposed research is thus to address these challenging issues of drug toxicity assays by using a human organ-on-a- chip model monitored with an automated, label-free, optical biosensor system that allows for real-time, long- term, sensitive, and kinetic analyses of human cardiac tissue models in response to various drugs in their microenvironments. To accomplish this goal, we propose a unique approach that is based on our patented label-free biosensor in conjunction with advanced organ-on-a-chip technologies. The open-microcavity configuration of our biosensor enables synergistic integration of the sensor chip with a heart-on-a-chip model through an automated microfluidic platform, which has the built-in capability to regenerate the sensor surface for continual kinetic studies over extended periods of time. The heart-on-a-chip model will be developed using an innovative 3D bioprinting approach that produces functional biomimetic cardiac organoids using cardiomyocytes derived from human induced pluripotent stem cells (iPSCs). A microfluidic perfusion bioreactor with the built-in capacity for simultaneous electrical and mechanical stimulations will be constructed to maintain long-term functionality of the organoids. On the other hand, the long-term stability of the proposed biosensor system will be significantly enhanced using negative thermal expansion materials for fabrication of the sensor chip. The cardiotoxicity of a panel of drugs will be evaluated in situ via quantification of the biomarkers secreted by the human cardiac model. The technology developed from this project will be highly transformative, which may be applied for other organs and lead to future personalized screening of drug toxicities, efficacy, and pharmacokinetics for precision medicine.

抽象的 基于人体器官芯片平台的毒性测定对于药物变得越来越重要 发现和开发，因为它们允许测试药物化合物对细胞的细胞毒性作用 在进行昂贵的动物测试或临床之前，先建立生理相关的人体组织模型 芯片器官模型的多种生理生化参数必须不断进行试验。 监测以评估这些模型对药物治疗的反应。 检测已广泛应用于生物测定，它需要向样品中添加荧光团， 这可能会干扰细胞活动，更严重的是，实时荧光实际上是不可能的 药物毒性测试过程中器官模型不断分泌的生物标志物的标记。 因此，荧光检测在这里不是一个可行的选择 - 直接检测或“无标记”检测是 监测药物与类器官相互作用的动态过程以获得详细信息 有关短暂以及延迟或累积药物效应的信息 拟议的总体目标。 因此，研究的目的是通过使用人体器官来解决药物毒性测定的这些挑战性问题。 芯片模型通过自动化、无标记、光学生物传感器系统进行监控，该系统允许实时、长期 对人体心脏组织模型对各种药物的反应进行术语、敏感性和动力学分析 微环境。 为了实现这一目标，我们提出了一种独特的方法，该方法基于我们获得专利的无标记生物传感器 与先进的片上器官技术相结合。 生物传感器能够通过以下方式将传感器芯片与片上心脏模型协同集成 自动化微流控平台，具有再生传感器表面的内置功能 将使用芯片开发心脏模型，进行长时间的连续动力学研究。 一种创新的 3D 生物打印方法，利用 源自人类诱导多能干细胞 (iPSC) 的心肌细胞微流体灌注。 具有同时进行电和机械刺激的内置能力的生物反应器将 另一方面，是为了维持类器官的长期功能。 所提出的生物传感器系统将使用负热膨胀材料得到显着增强 传感器芯片的制造将通过量化进行原位评估。 该项目开发的技术将是人类心脏模型分泌的生物标记物。 具有高度变革性，可应用于其他器官并导致未来的个性化筛查 精准医学的药物毒性、功效和药代动力学。