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: 10249004
• 负责人: Mehmet Remzi Dokmeci
• 金额: $ 31.45万
• 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 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10249004
• 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 基于芯片上人类器官的毒性测定对于药物而言越来越重要 发现和开发，因为允许药物化合物对细胞毒性作用的测试对 在进行昂贵的动物测试或临床之前，与生理学相关的人体组织模型 试验。 受到监测以评估模型对药物治疗的响应。 检测已被广泛用于生物测定，它需要向样品中添加荧光照射器， 可能会干扰细胞活动，更严重的是，实时荧光几乎不可能 在药物tomocity测试期间由器官模型分泌的生物标志物的标记。 因此，荧光检测在这里不是Viole选项 - 直接检测或“无标记”检测是 监测药物相互作用与类器官的动态过程所需的需要 有关瞬态和累积药物效应的信息。 因此，研究补充说，通过使用人类对a- 用自动化监控的芯片模型 人类心脏组织模型对各种药物的术语，敏感和动力学分析 微环境。 为了实现这一目标，我们提出了一种独特的方法，该方法基于我们的无专利标签生物传感器 与高级芯片技术的结合。 生物传感器可以通过一个通过一个心脏的芯片模型来使传感器芯片协同整合 自动化微流体平台，具有内置能力，可以再生传感器表面 长时间的持续动力学研究将使用心脏挑战。 Ennovative 3D生物打印方法，使用使用功能性仿生心脏器官 源自人类诱导的多能干细胞（IPSC）的心肌细胞 具有体积和机械刺激能力的生物反应器将是 另一方面，构建为维持器官的长期功能。 支撑生物传感器系统将使用负面的材料显着增强 传感器芯片的制造。 人类心脏模型分泌的生物标志物。 高度变革性，可以应用于其他器官，并导致未来的个性化筛选 药物毒性，功效和药代动力学用于精密医学。