Translational Center of Tissue Chip Technologies for quantitative characterization of Microphysiological Systems

用于微生理系统定量表征的组织芯片技术转化中心

• 批准号: 9275102
• 负责人: Murat Cirit
• 金额: $ 269.32万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-28 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9275102
• 关键词: Academia; Adopted; Adoption; Affect; Agreement; Animal Model; Binding; Bioinformatics; Biological; Biological Assay; Biology; Biometry; Cell Culture Techniques; Clinical; Clinical Trials; Collaborations; Complex; Computational Biology; Cues; Culture Media; Data; Data Analyses; Databases; Decision Making; Development; Devices; Diclofenac; Disclosure; Disease; Documentation; Dose; Drug Kinetics; Engineering; Ensure; Environment; Equilibrium; Equipment; Estradiol; Experimental Designs; Government Agencies; Human; In Vitro; Industry; Laboratories; Lead; Marketing; Methods; Midazolam; Modeling; Outcome; Outsourcing; Parents; Pharmaceutical Preparations; Pharmacology; Physiological; Physiology; Preclinical Testing; Process; Propranolol; Protocols documentation; Regimen; Reporting; Reproducibility; Research; Research Infrastructure; Research Personnel; Route; Running; Sampling; Scientist; Site; Staging; Stimulus; System; Systems Development; Technology; Technology Transfer; Testing; Therapeutic; Therapeutic Effect; Time; Tissue Engineering; Tissue Microarray; Toxic effect; Toxicity Tests; Toxicology; Toxin; Training; Translations; Ultracentrifugation; Validation; Verapamil; base; data acquisition; data sharing; design; drug candidate; drug development; drug standard; experience; high throughput screening; human tissue; in vivo; in vivo Model; industry partner; insight; instrumentation; lipophilicity; multidisciplinary; neurovascular; preclinical efficacy; preclinical study; preclinical toxicity; research and development; research study; response; transcriptomics

A large percentage of drug candidates fail at the clinical trial stage due to a lack of efficacy and unacceptable toxicity, primarily because the in vitro cell culture models and in vivo animal models commonly used in preclinical studies provide limited information about how a drug will affect human physiology. The need for more physiologically relevant in vitro systems for preclinical efficacy and toxicity testing has led to a major effort to develop “Microphysiological Systems (MPS)” based on engineered human tissue constructs. The MPS development process requires an initial assessment of viability and functionality, followed by an examination of the MPS response to various stimuli, including drugs, toxins, and disease-related cues. These extensive development efforts take place mainly in the developer's lab, and the reproducibility of the MPS results are rarely assessed by an independent research group or transferred to industry partners for use in drug development. Although there is a need for more physiologically-relevant preclinical testing technologies, the transition of MPS technologies from academia to industry remains challenging. Successful transfer and deployment of MPS technologies requires quantitative characterization and validation of the systems, preferably by an independent and unbiased external testing facility. We propose to fill this gap between academic research and development and industrial application of MPS technologies with our proposed Translational Center for Tissue Chip Technologies, which will provide unbiased testing and validation of MPS technologies as reflected in the current RFA. Our proposed Translational Center for Tissue Chip Technologies will take a holistic and mechanistic approach—based on quantitative systems pharmacology (QSP)—that combines quantitative experimental biology, computational biology, and biostatistics to achieve unbiased characterization of these complex systems and translation of experimental insights to clinical outcomes. Our translational systems pharmacology team at MIT includes tissue engineers, experimentalists, and computational biologists and will serve as the core of the proposed testing center. This multidisciplinary team is highly experienced in MPS technology testing and will be responsible for model-guided experimental design, experimental execution, data acquisition in collaboration with partner sites, data analysis, and reporting. The administrative organization and supporting infrastructure of our proposed testing center, as well as our systematic approach and workflows, will lead to transparent and unbiased MPS testing that will not only help researchers as they further develop and optimize their MPS technologies, but also ensure adoption of well-characterized and independently validated MPS platforms by industry to use in drug development and toxicology testing and government agencies to use in the regulatory decision-making process.

很大一部分候选药物由于缺乏疗效而在临床试验阶段失败 不可接受的毒性，主要是因为体外细胞培养模型和体内动物模型通常 临床前研究中使用的药物提供的有关药物如何影响人体生理学的信息有限。 对于更具生理相关性的体外系统进行临床前功效和毒性测试已导致重大 致力于开发基于工程人体组织结构的“微生理系统（MPS）”。 开发过程需要对可行性和功能进行初步评估，然后进行检查 MPS 对各种刺激的反应，包括药物、毒素和疾病相关线索。 开发主要在开发人员的实验室中进行，MPS 结果的再现性为 很少由独立研究小组评估或转移给行业合作伙伴用于药物 发展。 尽管需要更多与生理相关的临床前测试技术，但 MPS 技术从学术界到工业界的成功转移和部署仍然具有挑战性。 技术需要对系统进行定量表征和验证，最好由独立的机构进行 我们建议填补学术研究和开发之间的空白。 以及我们提议的组织芯片转化中心的 MPS 技术的工业应用 技术，将为 MPS 技术提供公正的测试和验证，如 当前的 RFA。 我们提议的组织芯片技术转化中心将采取整体和机械的方法 方法——基于定量系统药理学（QSP）——结合了定量实验 生物学、计算生物学和生物统计学，以实现这些复合物的公正表征 系统以及将实验见解转化为临床结果。 麻省理工学院的团队包括组织工程师、实验学家和计算生物学家，并将作为 这个多学科团队在 MPS 技术方面经验丰富。 测试并负责模型引导的实验设计、实验执行、数据采集 与合作伙伴网站、数据分析和报告合作。 我们拟议的测试中心的基础设施以及我们的系统方法和工作流程将导致 透明且公正的 MPS 测试不仅可以帮助研究人员进一步开发和优化 他们的 MPS 技术，但也确保采用经过充分表征和独立验证的 MPS 行业用于药物开发和毒理学测试的平台以及政府机构用于 监管决策过程。