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

很大比例的候选药物在临床试验阶段失败，原因是缺乏疗效和 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 用于临床前研究，提供有关药物将如何影响人体生理的有限信息。需要 对于更多与生理相关的体外系统进行临床前疗效和毒性测试已经导致了主要的 努力开发基于工程化人体组织结构的“微生理系统(MPS)”。下议院议员 开发过程需要对可行性和功能性进行初步评估，然后检查 MPS对各种刺激做出反应，包括药物、毒素和与疾病相关的线索。这些广泛的 开发工作主要在开发人员的实验室进行，MPS结果的重现性为 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 从学术界到工业界的MPS技术仍然具有挑战性。MPS调拨部署成功 技术要求对系统进行量化表征和验证，最好是由独立的 和不偏不倚的外部测试设施。我们建议填补学术研究和开发之间的差距 MPS技术与我们建议的组织芯片翻译中心的工业应用 技术，这将为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换中心将采取整体和机械式的 基于定量系统药理学(QSP)的方法--结合定量实验 生物学、计算生物学和生物统计学，以实现对这些复合体的公正描述 系统和将实验洞察力转化为临床结果。我们的翻译系统药理学 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，他们将担任 拟议中的测试中心的核心。这支多学科团队在MPS技术方面经验丰富 负责模型导引的实验设计、实验执行、数据采集 与合作伙伴网站协作、数据分析和报告。行政组织和支持 我们拟建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 透明和公正的MPS测试，不仅有助于研究人员进一步开发和优化 他们的MPS技术，但也确保采用特征良好和独立验证的MPS 由行业使用的平台用于药物开发和毒理学测试，以及政府机构用于 监管决策过程。

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.