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

点击翻译按钮获取中文摘要

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.