Fungal brain infection modelled in a human-neurovascular-unit-on-a-chip with a functional blood–brain barrier

Kim, Jin; Lee, Kyung Tae; Lee, Jong Seung; Shin, Jisoo; Cui, Baofang; Yang, Kisuk; Choi, Yi Sun; Choi, Nakwon; Lee, Soo Hyun; Lee, Jae Hyun; Bahn, Yong-Sun; Cho, Seung Woo

doi:10.1038/s41551-021-00743-8

Cited by 107 publications

(87 citation statements)

References 92 publications

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“…In a recent study, the human neurovascular unit was modelled in a microfluidic chip containing a perfused channel lined by endothelium interfaced with pericytes adjacent to a 3D ECM gel containing astrocytes and neurons derived by in situ differentiation of human neural stem cells 91 . This chip was used to model brain infection by the fungus Cryptococcus neoformans and revealed that clusters of the fungal cells penetrate the BBB without altering tight junctions, suggesting a transcytosis-mediated mechanism as well as providing a testbed in which to develop novel therapeutics.…”

Section: Clinical Mimicry In Organ Chipsmentioning

confidence: 99%

Human organs-on-chips for disease modelling, drug development and personalized medicine

2022

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The failure of animal models to predict therapeutic responses in humans is a major problem that also brings into question their use for basic research. Organ-on-a-chip (organ chip) microfluidic devices lined with living cells cultured under fluid flow can recapitulate organ-level physiology and pathophysiology with high fidelity. Here, I review how single and multiple human organ chip systems have been used to model complex diseases and rare genetic disorders, to study host–microbiome interactions, to recapitulate whole-body inter-organ physiology and to reproduce human clinical responses to drugs, radiation, toxins and infectious pathogens. I also address the challenges that must be overcome for organ chips to be accepted by the pharmaceutical industry and regulatory agencies, as well as discuss recent advances in the field. It is evident that the use of human organ chips instead of animal models for drug development and as living avatars for personalized medicine is ever closer to realization.

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Section: Clinical Mimicry In Organ Chipsmentioning

confidence: 99%

Human organs-on-chips for disease modelling, drug development and personalized medicine

2022

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“…Therefore, if a safety decision cannot be reached using this protective approach further targeted investigations or refinements will be needed. These may include the use of higher-tier approaches, such as hiPSC derived embryos combined with single cell omics techniques ( Shahbazi et al, 2019 ; Zheng et al, 2019 ; Xiang et al, 2020 ; Sozen et al, 2021 ), bespoke microphysiological systems (MPS) and conceptual or agent-based or dynamic models ( Kleinstreuer et al, 2013 ; Villeneuve et al, 2014 ; Capone et al, 2018 ; Thomas et al, 2019 ; Richards et al, 2020 ; Kim et al, 2021 ; Wiedenmann et al, 2021 ), to make a more explicit link between the cellular changes observed and an adverse outcome (a quantitative AOP). Such a bespoke approach will require a significant investment that may not be practical for day-to-day decision making.…”

Section: Discussionmentioning

confidence: 99%

Beyond AOPs: A Mechanistic Evaluation of NAMs in DART Testing

et al. 2022

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New Approach Methodologies (NAMs) promise to offer a unique opportunity to enable human-relevant safety decisions to be made without the need for animal testing in the context of exposure-driven Next Generation Risk Assessment (NGRA). Protecting human health against the potential effects a chemical may have on embryo-foetal development and/or aspects of reproductive biology using NGRA is particularly challenging. These are not single endpoint or health effects and risk assessments have traditionally relied on data from Developmental and Reproductive Toxicity (DART) tests in animals. There are numerous Adverse Outcome Pathways (AOPs) that can lead to DART, which means defining and developing strict testing strategies for every AOP, to predict apical outcomes, is neither a tenable goal nor a necessity to ensure NAM-based safety assessments are fit-for-purpose. Instead, a pragmatic approach is needed that uses the available knowledge and data to ensure NAM-based exposure-led safety assessments are sufficiently protective. To this end, the mechanistic and biological coverage of existing NAMs for DART were assessed and gaps to be addressed were identified, allowing the development of an approach that relies on generating data relevant to the overall mechanisms involved in human reproduction and embryo-foetal development. Using the knowledge of cellular processes and signalling pathways underlying the key stages in reproduction and development, we have developed a broad outline of endpoints informative of DART. When the existing NAMs were compared against this outline to determine whether they provide comprehensive coverage when integrated in a framework, we found them to generally cover the reproductive and developmental processes underlying the traditionally evaluated apical endpoint studies. The application of this safety assessment framework is illustrated using an exposure-led case study.

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“…Current in vitro model designs capture different aspects of these microenvironmental cues (Fig. 2 A) [ 37 ], and can be broadly categorized as: (1) 2D microfluidic chip membrane-based models that incorporate shear flow and other cell types [ 30 , 38 ], (2) parallel channel microfluidic models will hybrid 2D/3D cell culture [ 39 , 40 ], (3) parallel channel microfluidic models with self-organized microvascular networks [ 20 , 31 ], and (4) templating based devices which generate cylindrical microvessels in an extracellular matrix [ 41 , 42 ]. Self-organization and templating approaches enable incorporation of a wide repertoire of microenvironmental cues including cylindrical geometry, cell-ECM interactions, and direct cell–cell interactions.…”

Section: Accuracy Of the Microenvironmentmentioning

confidence: 99%

Next-generation in vitro blood–brain barrier models: benchmarking and improving model accuracy

Linville

Searson

2021

Fluids Barriers CNS

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With the limitations associated with post-mortem tissue and animal models, In vitro BBB models enable precise control of independent variables and microenvironmental cues, and hence play an important role in studying the BBB. Advances in stem cell technology and tissue engineering provide the tools to create next-generation in vitro BBB models with spatial organization of different cell types in 3D microenvironments that more closely match the human brain. These models will be capable of assessing the physiological and pathological responses to different perturbations relevant to health and disease. Here, we review the factors that determine the accuracy of in vitro BBB models, and describe how these factors will guide the development of next-generation models. Improving the accuracy of cell sources and microenvironmental cues will enable in vitro BBB models with improved accuracy and specificity to study processes and phenomena associated with zonation, brain region, age, sex, ethnicity, and disease state.

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Fungal brain infection modelled in a human-neurovascular-unit-on-a-chip with a functional blood–brain barrier

Cited by 107 publications

References 92 publications

Human organs-on-chips for disease modelling, drug development and personalized medicine

Human organs-on-chips for disease modelling, drug development and personalized medicine

Beyond AOPs: A Mechanistic Evaluation of NAMs in DART Testing

Next-generation in vitro blood–brain barrier models: benchmarking and improving model accuracy

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