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

基本信息

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
项目类别：
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

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

展开

项目摘要

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，因为它们允许测试药物化合物的细胞毒性作用在进行生理相关的人体组织模型之前，请先进行昂贵的动物测试或临床试验。 A-A-CHIP模型的多个物理和生化参数必须连续监测以评估这些模型对药物治疗的反应。虽然荧光检测已被广泛用于生物测定，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在药物毒性测试期间不断被器官模型分泌的生物标志物的标记。在这里，荧光检测不是一个可行的选择 - 直接检测或“无标签”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变以及延迟或累积药物作用的信息。拟议的总体目标因此，研究是通过使用人类的An-a-来解决药物毒性测定的这些挑战问题使用自动，无标签的光学生物传感器系统监控的芯片模型，该系统允许实时，长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先进的芯片技术结合。我们的开放式微腔配置生物传感器可以通过一个通过一个心动的芯片模型来实现传感器芯片的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连续动力学研究。将使用心脏直接芯片模型开发一种创新的3D生物打印方法，该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。微流体灌注具有简单电力和机械刺激的内置能力的生物反应器将是构建以维持类器官的长期功能。另一方面，长期稳定拟议的生物传感器系统将使用负面热膨胀材料显着增强传感器芯片的制造。一组药物的心脏毒性将通过定量原位评估人类心脏模型分泌的生物标志物。该项目开发的技术将是高度变革性，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。