The conventional microwell-based platform for construction of organoid models exhibits limitations in precision oncology applications because of low-speed growth and high variability. Here, we established organoid mod...The conventional microwell-based platform for construction of organoid models exhibits limitations in precision oncology applications because of low-speed growth and high variability. Here, we established organoid models on a nested array chip for fast and reproducible drug testing using 50% matrigel. First, we constructed mouse small intestinal and colonic organoid models. Compared with the conventional microwell-based platform, the mouse organoids on the chip showed accelerated growth and improved reproducibility due to the nested design of the chip. The design of the chip provides miniaturized and uniform shaping of the matrigel that allows the organoid to grow in a concentrated and controlled manner. Next, a patient-derived organoid(PDO) model from colorectal cancer tissues was successfully generated and characterized on the chip. Finally, the PDO models on the chip, from three patients, were implemented for high-throughput drug screening using nine treatment regimens. The drug sensitivity testing on the PDO models showed good quality control with a coefficient of variation under 10% and a Z’ factor of more than 0.7. More importantly, the drug responses on the chip recapitulate the heterogeneous response of individual patients, as well as showing a potential correlation with clinical outcomes. Therefore,the organoid model coupled with the nested array chip platform provides a fast and reproducible means for predicting drug responses to accelerate precise oncology.展开更多
In pre-clinical phase of new drug development,it is particularly important to establish an in vitro model to mimic the metabolism situation of human body.The aim of the in vitro model is to reduce the usage of experim...In pre-clinical phase of new drug development,it is particularly important to establish an in vitro model to mimic the metabolism situation of human body.The aim of the in vitro model is to reduce the usage of experimental animals and to make a more accurate prediction of the drug metabolism in vivo.Microfluidic chip is an emerging technology to establish predictive models.By integrating subcellular fractions,hepatocytes or liver tissue in the microfluidic chips,more predictive in vitro metabolism models can be established for drug development.The microfluidic platform offers dynamic and controlled fluids,as well as sophisticated liver tissue assembly to remodel the physiological and pathological microenvironment of liver in the human body.This review updates the microfluidic-based liver drug metabolism models since 2011,and summarizes the development of different models based on different chip vectors(subcellular components,primary hepatocytes,and tissue sections).It serves as a guide for newcomers to this dynamic field.展开更多
Macrophage-mediated inflammation plays a pivotal role in cardiovascular disease pathogen-esis.However,current cell-based models lack a comprehensive understanding of crosstalk between mac-rophages and cardiomyocytes,h...Macrophage-mediated inflammation plays a pivotal role in cardiovascular disease pathogen-esis.However,current cell-based models lack a comprehensive understanding of crosstalk between mac-rophages and cardiomyocytes,hindering the discovery of effective therapeutic interventions.Here,a microfluidic model has been developed to facilitate the coculture of macrophages and cardiomyocytes,allowing for mapping key signaling pathways and screening potential therapeutic agents against inflammation-induced dynamic myocardial injury.Through metabolic profiling and bioinformatic enrich-ment analysis,the microchip model with dynamic cell-cell crosstalk reveals robust activation of inflam-matory and oxidative stress-associated metabolic pathways,closely resembling metabolic profiles of myocardial infarction in both humans and rodents.Furthermore,an integrative screening strategy has been established to screen bioactive natural products precisely,identifying ginsenoside Rb 1 and protoca-techualdehyde as promising cardioprotective candidates in vitro and in vivo.Taken together,the micro-fluidic coculture model advances mechanistic insight into macrophage-mediated cardio-immunology and may accelerate the discovery of therapeutics for myocardial injury.展开更多
基金supported by grants from the National Natural Science Foundation of China (No.82174086)the Beijing Natural Science Foundation (No.7222273)+3 种基金the Beijing Xisike Clinical Oncology Research Foundation (Nos.Y-xsk2021-0004 and Y-XD202001-0172)the Youth Talents Promotion Project of China Association of Chinese Medicine (No.2020-QNRC2-08)the Clinical Medicine Plus X-Young Scholars Project of Peking University (No.BMU2021MX009)the Peking University People’s Hospital Research and Development Funds (No.RDY2020-18)。
文摘The conventional microwell-based platform for construction of organoid models exhibits limitations in precision oncology applications because of low-speed growth and high variability. Here, we established organoid models on a nested array chip for fast and reproducible drug testing using 50% matrigel. First, we constructed mouse small intestinal and colonic organoid models. Compared with the conventional microwell-based platform, the mouse organoids on the chip showed accelerated growth and improved reproducibility due to the nested design of the chip. The design of the chip provides miniaturized and uniform shaping of the matrigel that allows the organoid to grow in a concentrated and controlled manner. Next, a patient-derived organoid(PDO) model from colorectal cancer tissues was successfully generated and characterized on the chip. Finally, the PDO models on the chip, from three patients, were implemented for high-throughput drug screening using nine treatment regimens. The drug sensitivity testing on the PDO models showed good quality control with a coefficient of variation under 10% and a Z’ factor of more than 0.7. More importantly, the drug responses on the chip recapitulate the heterogeneous response of individual patients, as well as showing a potential correlation with clinical outcomes. Therefore,the organoid model coupled with the nested array chip platform provides a fast and reproducible means for predicting drug responses to accelerate precise oncology.
基金National Natural Science Foundation of China(Grant No.81573684 and 81530097)Beijing Municipal Science and Technology Project(Grant No.Z181100002218028)National Key Technology R&D Program “New Drug Innovation” of China(Grant No.2018ZX09711001-008-003)
文摘In pre-clinical phase of new drug development,it is particularly important to establish an in vitro model to mimic the metabolism situation of human body.The aim of the in vitro model is to reduce the usage of experimental animals and to make a more accurate prediction of the drug metabolism in vivo.Microfluidic chip is an emerging technology to establish predictive models.By integrating subcellular fractions,hepatocytes or liver tissue in the microfluidic chips,more predictive in vitro metabolism models can be established for drug development.The microfluidic platform offers dynamic and controlled fluids,as well as sophisticated liver tissue assembly to remodel the physiological and pathological microenvironment of liver in the human body.This review updates the microfluidic-based liver drug metabolism models since 2011,and summarizes the development of different models based on different chip vectors(subcellular components,primary hepatocytes,and tissue sections).It serves as a guide for newcomers to this dynamic field.
基金supported by the National Natural Science Foundation of China(U23A20514,82174086,82173949, 82100295)the National Key Research and Development Project(2023YFC3505000,China)+1 种基金the Key Research and Development Project of Shandong Province(2021CXGC010507,China)the Beijing Natural Science Foundation(7222273,China).
文摘Macrophage-mediated inflammation plays a pivotal role in cardiovascular disease pathogen-esis.However,current cell-based models lack a comprehensive understanding of crosstalk between mac-rophages and cardiomyocytes,hindering the discovery of effective therapeutic interventions.Here,a microfluidic model has been developed to facilitate the coculture of macrophages and cardiomyocytes,allowing for mapping key signaling pathways and screening potential therapeutic agents against inflammation-induced dynamic myocardial injury.Through metabolic profiling and bioinformatic enrich-ment analysis,the microchip model with dynamic cell-cell crosstalk reveals robust activation of inflam-matory and oxidative stress-associated metabolic pathways,closely resembling metabolic profiles of myocardial infarction in both humans and rodents.Furthermore,an integrative screening strategy has been established to screen bioactive natural products precisely,identifying ginsenoside Rb 1 and protoca-techualdehyde as promising cardioprotective candidates in vitro and in vivo.Taken together,the micro-fluidic coculture model advances mechanistic insight into macrophage-mediated cardio-immunology and may accelerate the discovery of therapeutics for myocardial injury.
