The gut is a digestive organ that absorbs nutrients but also plays a vital role in immune response and defense against external compounds.The complex interaction between the gut microbiota and other organs including t...The gut is a digestive organ that absorbs nutrients but also plays a vital role in immune response and defense against external compounds.The complex interaction between the gut microbiota and other organs including the immune system of the host has been known in various contexts,yielding the notion of‘axes’between the gut and other organs.While the presence of various gut-organ axes has been reported,the lack of adequate in vitro model systems for studying this interaction has restricted a deeper insight into these phenomena.Recently developed microphysiological systems(MPS),also known as organ-on-a-chip,allow researchers to study complex interactions between diverse organs,and here we provide a review of how recently developed gut-on-a-chip systems are used for building models of various diseases that were difficult to study.展开更多
Spheroids and organoids have attracted significant attention as innovative models for disease modeling and drug screening.By employing diverse types of spheroids or organoids,it is feasible to establish microphysiolog...Spheroids and organoids have attracted significant attention as innovative models for disease modeling and drug screening.By employing diverse types of spheroids or organoids,it is feasible to establish microphysiological systems that enhance the precision of disease modeling and offer more dependable and comprehensive drug screening.High-throughput microphysiological systems that support optional,parallel testing of multiple drugs have promising applications in personalized medical treatment and drug research.However,establishing such a system is highly challenging and requires a multidisciplinary approach.This study introduces a dynamic Microphysiological System Chip Platform(MSCP)with multiple functional microstructures that encompass the mentioned advantages.We developed a high-throughput lung cancer spheroids model and an intestine-liverheart-lung cancer microphysiological system for conducting parallel testing on four anti-lung cancer drugs,demonstrating the feasibility of the MSCP.This microphysiological system combines microscale and macroscale biomimetics to enable a comprehensive assessment of drug efficacy and side effects.Moreover,the microphysiological system enables evaluation of the real pharmacological effect of drug molecules reaching the target lesion after absorption by normal organs through fluid-based physiological communication.The MSCP could serves as a valuable platform for microphysiological system research,making significant contributions to disease modeling,drug development,and personalized medical treatment.展开更多
The U.S.Food and Drug Administration(FDA)'s program documents regarding the animal-free approach for the efficacy,pharmacokinetics,and safety evaluation of new drug preclinical studies have been rolled out gradual...The U.S.Food and Drug Administration(FDA)'s program documents regarding the animal-free approach for the efficacy,pharmacokinetics,and safety evaluation of new drug preclinical studies have been rolled out gradually.This process has taken the FDA seven years.Starting from the reduction of funding for animal of data from organ-on-a-chip solely for pharmacodynamic studies[[1],[2],[3]],to the explicit proposal of the animal-free approach for pharmacodynamic studies in the FDA Modernization Act in Reference[4],and to the indication in 2025 that safety studies should also prioritize safety research data from in vitro microphysiological systems[5],this demonstrates the FDAs determination to gradually achieve the animal-free approach and also signals a profound paradigm shift in the field of drug research and development.This policy direction not only addresses the requirements of ethics and technological advancement but may also reshape the entire new drug development industrial chain.展开更多
pioids are commonly used for treating chronic pain.However,with continued use,they may induce tolerance and/or hyperalgesia,which limits therapeutic efficacy.The human mechanisms of opioid-induced tolerance and hypera...pioids are commonly used for treating chronic pain.However,with continued use,they may induce tolerance and/or hyperalgesia,which limits therapeutic efficacy.The human mechanisms of opioid-induced tolerance and hyperalgesia are significantly understudied,in part,because current models cannot fully recapitulate human pathology.Here,we engineered novel human spinal microphysiological systems(MPSs)integrated with plug-and-play neural activity sensing for modeling human nociception and opioid-induced tolerance.Each spinal MPS consists of a flattened human spinal cord organoid derived from human stem cells and a 3D printed organoid holder device for plug-and-play neural activity measurement.We found that the flattened organoid design of MPSs not only reduces hypoxia and necrosis in the organoids,but also promotes their neuron maturation,neural activity,and functional development.We further demonstrated that prolonged opioid exposure resulted in neurochemical correlates of opioid tolerance and hyperalgesia,as measured by altered neural activity,and downregulation ofμ-opioid receptor expression of human spinal MPSs.The MPSs are scalable,cost-effective,easy-to-use,and compatible with commonly-used well-plates,thus allowing plug-and-play measurements of neural activity.We believe the MPSs hold a promising translational potential for studying human pain etiology,screening new treatments,and validating novel therapeutics for human pain medicine.展开更多
Microphysiological systems(MPS)created with human-derived cells and biomaterial scaffolds offer a potential in vitro alternative to in vivo animal models.The adoption of three-dimensional MPS models has economic,ethic...Microphysiological systems(MPS)created with human-derived cells and biomaterial scaffolds offer a potential in vitro alternative to in vivo animal models.The adoption of three-dimensional MPS models has economic,ethical,regulatory,and scientific implications for the fields of regenerative medicine,metabolism/obesity,oncology,and pharmaceutical drug discovery.Key opinion leaders acknowledge that MPS tools are uniquely positioned to aid in the objective to reduce,refine,and eventually replace animal experimentation while improving the accuracy of the finding’s clinical translation.Adipose tissue has proven to be an accessible and available source of human-derived stromal vascular fraction(SVF)cells,a heterogeneous population available at point of care,and adipose-derived stromal/stem cells,a relatively homogeneous population requiring plastic adherence and culture expansion of the SVF cells.The adipose-derived stromal/stem cells or SVF cells,in combination with human tissue or synthetic biomaterial scaffolds,can be maintained for extended culture periods as three-dimensional MPS models under angiogenic,stromal,adipogenic,or osteogenic conditions.This review highlights recent literature relating to the versatile use of adipose-derived cells as fundamental components of three-dimensional MPS models for discovery research and development.In this context,it compares the merits and limitations of the adipose-derived stromal/stem cells relative to SVF cell models and considers the likely directions that this emerging field of scientific discovery will take in the near future.展开更多
Physiological supporting systems,such as the vascular network and excretion system,are crucial for the effective functioning of organs.This study demonstrates that when a body-on-a-chip microdevice is coupled with min...Physiological supporting systems,such as the vascular network and excretion system,are crucial for the effective functioning of organs.This study demonstrates that when a body-on-a-chip microdevice is coupled with miniaturized physiological support systems,it can create a multi-organ microphysiological system capable of more accurately mimicking the physiological complexity of a body,thereby offering potential for preclinical drug testing.To exemplify this concept,we have developed a model system comprising 18 types of microtissues interconnected by a vascular network that replicates the in vivo blood distribution among the organs.Furthermore,this system includes an excretory system with a micro-stirrer that ensures elimination efficiency akin to in vivo conditions.Our findings indicate that this system can:(1)survive and function for almost two months;(2)achieve two-compartment pharmacokinetics of a drug;(3)investigate the dynamic relationship between the tissue distribution and toxicity of a drug;(4)establish the multimorbidity model and evaluate the effectiveness of polypharmacy,challenging tasks with traditional animal models;(5)reduce animal usage in drug evaluations.Notably,features from points(2)to(4)are capabilities not achievable by other in vitro models.The strategy proposed in this study can also be applied to the development of multi-organ microphysiological systems that mimic the physiological complexity of human organs or the entire body.展开更多
Organs-on-chips are microphysiological systems designed to replicate key functions of human organs,thereby accelerating innovation in life sciences,such as disease modeling,drug development,and precision medicine.Howe...Organs-on-chips are microphysiological systems designed to replicate key functions of human organs,thereby accelerating innovation in life sciences,such as disease modeling,drug development,and precision medicine.However,the lack of standardized defnitions,structural designs,cell sources,model constructions,and functional validations has posed challenges to their widespread translational applications.On April 29,2024,the Chinese Society of Biotechnology introduced"Organs-on-chips:Liver",China’s frst group standard for human liver-on-a-chip technology.This pioneering standard provides comprehensive guidelines,including scope,terminology,defnitions,technical requirements,detection methods,and quality control measures for developing liver models on chips.The introduction of this standard is set to facilitate the establishment of institutional protocols,promote widespread adoption,and drive the international standardization of liver-on-a-chip technologies.展开更多
Organs-on-chips are microphysiological systems that allow to replicate the key functions of human organs and accel-erate the innovation in life sciences including disease modeling,drug development,and precision medici...Organs-on-chips are microphysiological systems that allow to replicate the key functions of human organs and accel-erate the innovation in life sciences including disease modeling,drug development,and precision medicine.How-ever,due to the lack of standards in their definition,structural design,cell source,model construction,and functional validation,a wide range of translational application of organs-on-chips remains a challenging.“Organs-on-chips:Intestine”is the first group standard on human intestine-on-a-chip in China,jointly agreed and released by the experts from the Chinese Society of Biotechnology on 29th April 2024.This standard specifies the scope,terminology,definitions,technical requirements,detection methods,and quality control in building the human intestinal model on a chip.The publication of this group standard will guide the institutional establishment,acceptance and execution of proper practical protocols and accelerate the international standardization of intestine-on-a-chip for translational applications.展开更多
Coronavirus disease 2019(COVID-19), caused by severe acute respiratory syndrome coronavirus 2(SARSCo V-2), has become a global pandemic. Clinical evidence suggests that the intestine is another high-risk organ for SAR...Coronavirus disease 2019(COVID-19), caused by severe acute respiratory syndrome coronavirus 2(SARSCo V-2), has become a global pandemic. Clinical evidence suggests that the intestine is another high-risk organ for SARS-Co V-2 infection besides the lungs. However, a model that can accurately reflect the response of the human intestine to the virus is still lacking. Here, we created an intestinal infection model on a chip that allows the recapitulation of human relevant intestinal pathophysiology induced by SARSCo V-2 at organ level. This microengineered gut-on-chip reconstitutes the key features of the intestinal epithelium-vascular endothelium barrier through the three-dimensional(3 D) co-culture of human intestinal epithelial, mucin-secreting, and vascular endothelial cells under physiological fluid flow. The intestinal epithelium showed permissiveness for viral infection and obvious morphological changes with injury of intestinal villi, dispersed distribution of mucus-secreting cells, and reduced expression of tight junction(E-cadherin), indicating the destruction of the intestinal barrier integrity caused by virus.Moreover, the vascular endothelium exhibited abnormal cell morphology, with disrupted adherent junctions. Transcriptional analysis revealed abnormal RNA and protein metabolism, as well as activated immune responses in both epithelial and endothelial cells after viral infection(e.g., upregulated cytokine genes), which may contribute to the injury of the intestinal barrier associated with gastrointestinal symptoms. This human organ system can partially mirror intestinal barrier injury and the human response to viral infection, which is not possible in existing in vitro culture models. It provides a unique and rapid platform to accelerate COVID-19 research and develop novel therapies.展开更多
New drug discovery is under growing pressure to satisfy the demand from a wide range of domains, especially from the pharmaceutical industry and healthcare services. Assessment of drug efficacy and safety prior to hum...New drug discovery is under growing pressure to satisfy the demand from a wide range of domains, especially from the pharmaceutical industry and healthcare services. Assessment of drug efficacy and safety prior to human clinical trials is a crucial part of drug development, which deserves greater emphasis to reduce the cost and time in drug discovery. Recent advances in microfabrication and tissue engineering have given rise to organ-on-a-chip, an in vitro model capable of recapitulating human organ functions in vivo and providing insight into disease pathophysiology, which offers a potential alternative to animal models for more efficient pre-clinical screening of drug candidates. In this review, we first give a snapshot of general considerations for organ-on-a-chip device design. Then, we comprehensively review the recent advances in organ-on-a-chip for drug screening. Finally, we summarize some key challenges of the progress in this field and discuss future prospects of organ-on-a-chip development. Overall,this review highlights the new avenue that organ-on-a-chip opens for drug development, therapeutic innovation, and precision medicine.展开更多
基金supported by Korea Technology and Information Promotion Agency(S3316767)National Research Foundation of Korea(2022R1A4A2000748 and 2022M3A9B6018217)+2 种基金Alchemist Project(KEIT 20018560,NTIS 1415184668)by of the Korea Evaluation Institute of Industrial TechnologyKorea Institute of Marine Science&Technology Promotion(KIMST,RS-2024-00402200)Hongik University Research Fund.
文摘The gut is a digestive organ that absorbs nutrients but also plays a vital role in immune response and defense against external compounds.The complex interaction between the gut microbiota and other organs including the immune system of the host has been known in various contexts,yielding the notion of‘axes’between the gut and other organs.While the presence of various gut-organ axes has been reported,the lack of adequate in vitro model systems for studying this interaction has restricted a deeper insight into these phenomena.Recently developed microphysiological systems(MPS),also known as organ-on-a-chip,allow researchers to study complex interactions between diverse organs,and here we provide a review of how recently developed gut-on-a-chip systems are used for building models of various diseases that were difficult to study.
基金funded by the National Key Research and Development Program of China(No.2021YFF1200803)National Natural Science Foundation of China(No.62120106004,61901412,62271443)and China Postdoctoral Science Foundation Funded Project(2022M712783).
文摘Spheroids and organoids have attracted significant attention as innovative models for disease modeling and drug screening.By employing diverse types of spheroids or organoids,it is feasible to establish microphysiological systems that enhance the precision of disease modeling and offer more dependable and comprehensive drug screening.High-throughput microphysiological systems that support optional,parallel testing of multiple drugs have promising applications in personalized medical treatment and drug research.However,establishing such a system is highly challenging and requires a multidisciplinary approach.This study introduces a dynamic Microphysiological System Chip Platform(MSCP)with multiple functional microstructures that encompass the mentioned advantages.We developed a high-throughput lung cancer spheroids model and an intestine-liverheart-lung cancer microphysiological system for conducting parallel testing on four anti-lung cancer drugs,demonstrating the feasibility of the MSCP.This microphysiological system combines microscale and macroscale biomimetics to enable a comprehensive assessment of drug efficacy and side effects.Moreover,the microphysiological system enables evaluation of the real pharmacological effect of drug molecules reaching the target lesion after absorption by normal organs through fluid-based physiological communication.The MSCP could serves as a valuable platform for microphysiological system research,making significant contributions to disease modeling,drug development,and personalized medical treatment.
文摘The U.S.Food and Drug Administration(FDA)'s program documents regarding the animal-free approach for the efficacy,pharmacokinetics,and safety evaluation of new drug preclinical studies have been rolled out gradually.This process has taken the FDA seven years.Starting from the reduction of funding for animal of data from organ-on-a-chip solely for pharmacodynamic studies[[1],[2],[3]],to the explicit proposal of the animal-free approach for pharmacodynamic studies in the FDA Modernization Act in Reference[4],and to the indication in 2025 that safety studies should also prioritize safety research data from in vitro microphysiological systems[5],this demonstrates the FDAs determination to gradually achieve the animal-free approach and also signals a profound paradigm shift in the field of drug research and development.This policy direction not only addresses the requirements of ethics and technological advancement but may also reshape the entire new drug development industrial chain.
基金The project was supported by the departmental start-up funds of Indiana University Bloomington,and in part by NSF grants(CCF-1909509,and CMMI-2025434)NIH awards(DP2AI160242,DA056242,and DA047858).
文摘pioids are commonly used for treating chronic pain.However,with continued use,they may induce tolerance and/or hyperalgesia,which limits therapeutic efficacy.The human mechanisms of opioid-induced tolerance and hyperalgesia are significantly understudied,in part,because current models cannot fully recapitulate human pathology.Here,we engineered novel human spinal microphysiological systems(MPSs)integrated with plug-and-play neural activity sensing for modeling human nociception and opioid-induced tolerance.Each spinal MPS consists of a flattened human spinal cord organoid derived from human stem cells and a 3D printed organoid holder device for plug-and-play neural activity measurement.We found that the flattened organoid design of MPSs not only reduces hypoxia and necrosis in the organoids,but also promotes their neuron maturation,neural activity,and functional development.We further demonstrated that prolonged opioid exposure resulted in neurochemical correlates of opioid tolerance and hyperalgesia,as measured by altered neural activity,and downregulation ofμ-opioid receptor expression of human spinal MPSs.The MPSs are scalable,cost-effective,easy-to-use,and compatible with commonly-used well-plates,thus allowing plug-and-play measurements of neural activity.We believe the MPSs hold a promising translational potential for studying human pain etiology,screening new treatments,and validating novel therapeutics for human pain medicine.
文摘Microphysiological systems(MPS)created with human-derived cells and biomaterial scaffolds offer a potential in vitro alternative to in vivo animal models.The adoption of three-dimensional MPS models has economic,ethical,regulatory,and scientific implications for the fields of regenerative medicine,metabolism/obesity,oncology,and pharmaceutical drug discovery.Key opinion leaders acknowledge that MPS tools are uniquely positioned to aid in the objective to reduce,refine,and eventually replace animal experimentation while improving the accuracy of the finding’s clinical translation.Adipose tissue has proven to be an accessible and available source of human-derived stromal vascular fraction(SVF)cells,a heterogeneous population available at point of care,and adipose-derived stromal/stem cells,a relatively homogeneous population requiring plastic adherence and culture expansion of the SVF cells.The adipose-derived stromal/stem cells or SVF cells,in combination with human tissue or synthetic biomaterial scaffolds,can be maintained for extended culture periods as three-dimensional MPS models under angiogenic,stromal,adipogenic,or osteogenic conditions.This review highlights recent literature relating to the versatile use of adipose-derived cells as fundamental components of three-dimensional MPS models for discovery research and development.In this context,it compares the merits and limitations of the adipose-derived stromal/stem cells relative to SVF cell models and considers the likely directions that this emerging field of scientific discovery will take in the near future.
基金National Natural Science Foundation of China(Grant No.82373840)Jiangsu Key Laboratory of Neuropsychiatric Diseases(Grants BM2013003 and ZZ2009).
文摘Physiological supporting systems,such as the vascular network and excretion system,are crucial for the effective functioning of organs.This study demonstrates that when a body-on-a-chip microdevice is coupled with miniaturized physiological support systems,it can create a multi-organ microphysiological system capable of more accurately mimicking the physiological complexity of a body,thereby offering potential for preclinical drug testing.To exemplify this concept,we have developed a model system comprising 18 types of microtissues interconnected by a vascular network that replicates the in vivo blood distribution among the organs.Furthermore,this system includes an excretory system with a micro-stirrer that ensures elimination efficiency akin to in vivo conditions.Our findings indicate that this system can:(1)survive and function for almost two months;(2)achieve two-compartment pharmacokinetics of a drug;(3)investigate the dynamic relationship between the tissue distribution and toxicity of a drug;(4)establish the multimorbidity model and evaluate the effectiveness of polypharmacy,challenging tasks with traditional animal models;(5)reduce animal usage in drug evaluations.Notably,features from points(2)to(4)are capabilities not achievable by other in vitro models.The strategy proposed in this study can also be applied to the development of multi-organ microphysiological systems that mimic the physiological complexity of human organs or the entire body.
基金supported by the National Key R&D Program of China(No.2022YFA1104700)to Zhang XNational Key R&D Program of China(2024YFA0919800)to Liu H+3 种基金National Key R&D Program of China(2022YFA1205000)to Zhang MNational Natural Science Foundation of China(No.32171406)to Qin JDMU-1&DICP(DMU-1&DICP UN202202)to Qin JInnovation Program of Science and Research from the DICP,CAS(DICP I202435)to Qin J.
文摘Organs-on-chips are microphysiological systems designed to replicate key functions of human organs,thereby accelerating innovation in life sciences,such as disease modeling,drug development,and precision medicine.However,the lack of standardized defnitions,structural designs,cell sources,model constructions,and functional validations has posed challenges to their widespread translational applications.On April 29,2024,the Chinese Society of Biotechnology introduced"Organs-on-chips:Liver",China’s frst group standard for human liver-on-a-chip technology.This pioneering standard provides comprehensive guidelines,including scope,terminology,defnitions,technical requirements,detection methods,and quality control measures for developing liver models on chips.The introduction of this standard is set to facilitate the establishment of institutional protocols,promote widespread adoption,and drive the international standardization of liver-on-a-chip technologies.
基金National Key R&D Program of China(No.2022YFA1104700)to Zhang XNational Natural Science Foundation of China(No.32171406)to Qin JInnovation Program of Science and Research from the DICP,CAS(DICP I202435)to Qin J.
文摘Organs-on-chips are microphysiological systems that allow to replicate the key functions of human organs and accel-erate the innovation in life sciences including disease modeling,drug development,and precision medicine.How-ever,due to the lack of standards in their definition,structural design,cell source,model construction,and functional validation,a wide range of translational application of organs-on-chips remains a challenging.“Organs-on-chips:Intestine”is the first group standard on human intestine-on-a-chip in China,jointly agreed and released by the experts from the Chinese Society of Biotechnology on 29th April 2024.This standard specifies the scope,terminology,definitions,technical requirements,detection methods,and quality control in building the human intestinal model on a chip.The publication of this group standard will guide the institutional establishment,acceptance and execution of proper practical protocols and accelerate the international standardization of intestine-on-a-chip for translational applications.
基金supported by the Strategic Priority Research Program of the Chinese Academy of Sciences(XDB29050301,XDB32030200,and XDA16020900)the National Key R&D Program of China(2017YFB0405404)+6 种基金the National Science and Technology Major Project(2018ZX09201017-001-001)Yunnan Key Research and Development Program(202003AD150009)the National Natural Science Foundation of China(31671038,31971373,8170347081803492)China Postdoctoral Science Foundation(2019M660065)Innovation Program of Science and Research from the Dalian Institute of Chemical PhysicsChinese Academy of Sciences(DICP I201934)。
文摘Coronavirus disease 2019(COVID-19), caused by severe acute respiratory syndrome coronavirus 2(SARSCo V-2), has become a global pandemic. Clinical evidence suggests that the intestine is another high-risk organ for SARS-Co V-2 infection besides the lungs. However, a model that can accurately reflect the response of the human intestine to the virus is still lacking. Here, we created an intestinal infection model on a chip that allows the recapitulation of human relevant intestinal pathophysiology induced by SARSCo V-2 at organ level. This microengineered gut-on-chip reconstitutes the key features of the intestinal epithelium-vascular endothelium barrier through the three-dimensional(3 D) co-culture of human intestinal epithelial, mucin-secreting, and vascular endothelial cells under physiological fluid flow. The intestinal epithelium showed permissiveness for viral infection and obvious morphological changes with injury of intestinal villi, dispersed distribution of mucus-secreting cells, and reduced expression of tight junction(E-cadherin), indicating the destruction of the intestinal barrier integrity caused by virus.Moreover, the vascular endothelium exhibited abnormal cell morphology, with disrupted adherent junctions. Transcriptional analysis revealed abnormal RNA and protein metabolism, as well as activated immune responses in both epithelial and endothelial cells after viral infection(e.g., upregulated cytokine genes), which may contribute to the injury of the intestinal barrier associated with gastrointestinal symptoms. This human organ system can partially mirror intestinal barrier injury and the human response to viral infection, which is not possible in existing in vitro culture models. It provides a unique and rapid platform to accelerate COVID-19 research and develop novel therapies.
基金financial support from the National Key R&D Program of China (2019YFA0709200)the National Natural Science Foundation of China (21874066, and 61804076)+3 种基金the Key Research and Development Program of Jiangsu Province (BE2021373, China)the Natural Science Foundation of Jiangsu Province (BK20180700, and BK20200336, China)the Fundamental Research Funds for Central Universities (China)the Program for Innovative Talents and Entrepreneur in Jiangsu (China)。
文摘New drug discovery is under growing pressure to satisfy the demand from a wide range of domains, especially from the pharmaceutical industry and healthcare services. Assessment of drug efficacy and safety prior to human clinical trials is a crucial part of drug development, which deserves greater emphasis to reduce the cost and time in drug discovery. Recent advances in microfabrication and tissue engineering have given rise to organ-on-a-chip, an in vitro model capable of recapitulating human organ functions in vivo and providing insight into disease pathophysiology, which offers a potential alternative to animal models for more efficient pre-clinical screening of drug candidates. In this review, we first give a snapshot of general considerations for organ-on-a-chip device design. Then, we comprehensively review the recent advances in organ-on-a-chip for drug screening. Finally, we summarize some key challenges of the progress in this field and discuss future prospects of organ-on-a-chip development. Overall,this review highlights the new avenue that organ-on-a-chip opens for drug development, therapeutic innovation, and precision medicine.
