Real-Time Quantitation of Transport Across Vascular-Tissue Interfaces in Organ-On-Chip Models Using In Situ Mass Spectrometry

使用原位质谱法实时定量器官芯片模型中跨血管组织界面的运输

• 批准号: 10394501
• 负责人: Carrie German
• 金额: $ 31.42万
• 依托单位: CFD RESEARCH CORPORATION
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10394501
• 关键词: 3-Dimensional; Acetaminophen; Address; Albumins; Amiodarone; Animal Model; Animal Testing; Animals; Applied Research; Architecture; Award; Basic Science; Biological Assay; Biological Markers; Blood Vessels; Cell Death; Cell Survival; Cells; Cellular Assay; ChIP-on-chip; Chemicals; Coculture Techniques; Collaborations; Consumption; Development; Devices; Doxorubicin; Drug Delivery Systems; Drug Interactions; Drug Kinetics; Drug toxicity; End Point Assay; Endpoint Determination; Engineering; Ethics; Family; Feedback; Geometry; Hepatocyte; Image; In Situ; In Vitro; Kidney; Laboratories; Liquid substance; Liver; Location; Lung; Mass Spectrum Analysis; Measures; Membrane; Methods; Microfluidic Microchips; Microfluidics; Modeling; Nature; Nutrient; Optics; Organ; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacotherapy; Phase; Physiological; Process; Protocols documentation; Reporter; Research; Research Personnel; Resolution; Role; Safety; Sampling; Scientist; Side; Site; Specific qualifier value; Surface; System; Technology; Test Result; Testing; Therapeutic; Time; Tissue Extracts; Tissues; Toxic effect; Toxicity Tests; Toxicology; Universities; Vascular Endothelial Cell; Waste Products; base; biomaterial compatibility; chromatin immunoprecipitation; design; drug candidate; drug development; improved; in vitro testing; in vivo; instrumentation; multidisciplinary; novel; organ on a chip; phase 1 study; predictive modeling; real time monitoring; response; three dimensional cell culture

Abstract Current in vitro platforms are poor predictors of the in vivo safety, efficacy and pharmacokinetics of therapeutics, owing to a significant difference in the test conditions compared to physiological conditions. Therefore, drug toxicity testing is routinely performed using animal models. However, animal testing is expensive and time consuming. In addition, ethical concerns about the use of animals are increasingly calling for reduction/replacement of animal tests. To overcome these challenges, physiologically relevant organ-on-chip assays have been developed. These assays mimic the dynamic interactions encountered during drug delivery and recapitulates physiological flow rates, vascular architecture and the 3D nature of tissue (liver, lung, kidney, etc.), thereby providing improved quantitative and predictive capabilities to guide the development of drugs via accurate toxicity analysis. However, one of the critical components lacking from current organ-on-chip assays is the real-time analysis of drug concentration at specified locations within the assay to determine drug toxicity at defined tissue sites. To address this need, we propose to integrate our microfluidics-based, organ-on-chip systems with on-chip mass spectrometry analysis to measure drug concentrations across a vascularized liver construct. The Phase I effort will focus on integration the microfluidic device with a novel mass spectrometry (MS) assay. This method enables online temporal and spatial chemical characterization of chemical constituents within microfluidic devices by MS for the first time. The ChemSitu approach enables the means to continuously sample and chemically characterize small volumes of liquid directly from a microfluidic device at any point along the construct in near real-time and without negatively altering the state of the microfluidic system. A multi-disciplinary team of scientists and engineers with expertise in microfluidics-based cell assays and instrumentation development has been assembled for successful completion of this project. By providing an accurate, quantitative and predictive model of and quantitation of physiological interactions, the developed platform promises to establish a new paradigm for in vitro assessment of the physiological response to therapeutics.

抽象的 目前的体外平台无法很好地预测治疗药物的体内安全性、有效性和药代动力学， 由于测试条​​件与生理条件相比存在显着差异。因此，药 毒性测试通常使用动物模型进行。然而，动物试验既昂贵又耗时 消耗。此外，对使用动物的道德担忧越来越多地要求 减少/替代动物试验。为了克服这些挑战，生理相关的器官芯片 已开发出检测方法。这些测定模拟药物输送过程中遇到的动态相互作用 并概括了生理流速、血管结构和组织（肝、肺、肾、 等），从而提供改进的定量和预测能力来指导药物开发 准确的毒性分析。然而，当前器官芯片检测中缺乏的关键组件之一是 实时分析测定中指定位置的药物浓度，以确定药物毒性 明确的组织部位。 为了满足这一需求，我们建议将基于微流体的器官芯片系统与片上质量集成 光谱分析测量血管化肝脏结构中的药物浓度。第一阶段的努力 将重点关注微流体装置与新型质谱（MS）检测的集成。该方法使 通过 MS 对微流体装置内的化学成分进行在线时空化学表征 首次。 ChemSitu 方法可实现连续采样和化学表征 沿着结构的任何一点直接从微流体装置中近乎实时地输送少量液体 不会负面改变微流体系统的状态。由科学家和多学科专家组成的团队 具有基于微流体的细胞分析和仪器开发专业知识的工程师 为顺利完成该项目而组装。通过提供准确、定量和预测的模型 生理相互作用的分析和定量，开发的平台有望建立一个新的范例 用于体外评估对治疗的生理反应。