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Frey O.,ETH Zurich | Misun P.M.,ETH Zurich | Fluri D.A.,InSphero | Hengstler J.G.,TU Dortmund | Hierlemann A.,ETH Zurich
Nature Communications | Year: 2014

Integration of multiple three-dimensional microtissues into microfluidic networks enables new insights in how different organs or tissues of an organism interact. Here, we present a platform that extends the hanging-drop technology, used for multi-cellular spheroid formation, to multifunctional complex microfluidic networks. Engineered as completely open, 'hanging' microfluidic system at the bottom of a substrate, the platform features high flexibility in microtissue arrangements and interconnections, while fabrication is simple and operation robust. Multiple spheroids of different cell types are formed in parallel on the same platform; the different tissues are then connected in physiological order for multi-tissue experiments through reconfiguration of the fluidic network. Liquid flow is precisely controlled through the hanging drops, which enable nutrient supply, substance dosage and inter-organ metabolic communication. The possibility to perform parallelized microtissue formation on the same chip that is subsequently used for complex multi-tissue experiments renders the developed platform a promising technology for 'body-on-a-chip'- related research. © 2014 Macmillan Publishers Limited. All rights reserved. Source

Agency: Cordis | Branch: FP7 | Program: CP | Phase: ICT-2011.9.2 | Award Amount: 1.92M | Year: 2012

High attrition and failures rates in pharmaceutical and biotechnological drug development require a paradigm change towards more physiological human cell-based assays at an early time point in the process. The central idea of this proposal is to develop a versatile and reconfigurable pharmaceutical screening technology platform that relies on organotypic three-dimensional spherical microtissues. This platform will accommodate different types of human microtissues (tumor, brain, liver, heart etc.) and feature microfluidic interconnection between these tissues, thus mimicking the physiological context and conditions in a human body. Dosage of components or candidate drugs to, e.g., liver tissue will lead to the generation of metabolic products in the respective tissue compartment. These products then can be routed via the microfluidics to, e.g., connective tissue to assess the efficacy of the candidate drug and related adverse toxicological effects on the target tissue and functionally related tissues. This way, functional connectivity in a real body can be mimicked at the desired level of complexity, and the effects of drugs can be comprehensively assessed.

Agency: Cordis | Branch: H2020 | Program: RIA | Phase: PHC-16-2015 | Award Amount: 5.12M | Year: 2016

Self-renew and multilineage potential characterize stem cells. We have recently described that pancreas progenitor cells extracted from adult donors can be expanded long-term in vitro into 3D structures, which we have termed organoids. Pancreas organoids reproduce in vitro all the features of pancreas ductal epithelia, and have a limitless expansion potential. Thus, pancreas organoids promise to boost cell therapy of type 1 diabetes. We have recently observed that progenitor cells organoids preserve their genetic stability over a long time in culture. That represents an advantage, when compared to iPS or hES derived approaches, where genetic instability raises concerns for their future therapeutic applications. While progenitor organoids are promising for the future of cell therapy, bringing stem cell-based therapies to patients requires a reliable characterization (knowing what the cells do and how they do it, i.e. a phenotypic and molecular biology characterization), chemically well-defined culture media, and the capacity of mass-production under GLP/GMP conditions. The LSFM4LIFE consortium aims to the mass production of pancreas organoids for the cellular therapy of type 1 diabetes. The goals of the project are: (1) optimize growth and differentiation of human pancreas stem-cell organoids by employing phenotypic and molecular high-throughput screening (2) standardize the growth and differentiation of the organoids under well-defined biochemical conditions, and (3) achieve GLP/GMP-production of the human organoids for preclinical studies and phase I clinical studies. The close collaboration in the consortium between academic researchers and industry, as well as its cross-disciplinary composition, are essential to realize the goals of the project. The work packages of the project will have a technological impact in the form of patents and first market replication.

Thoma C.R.,ETH Zurich | Zimmermann M.,ETH Zurich | Agarkova I.,InSphero | Kelm J.M.,InSphero | Krek W.,ETH Zurich
Advanced Drug Delivery Reviews | Year: 2014

Phenotypic heterogeneity of cancer cells, cell biological context, heterotypic crosstalk and the microenvironment are key determinants of the multistep process of tumor development. They sign responsible, to a significant extent, for the limited response and resistance of cancer cells to molecular-targeted therapies. Better functional knowledge of the complex intra- and intercellular signaling circuits underlying communication between the different cell types populating a tumor tissue and of the systemic and local factors that shape the tumor microenvironment is therefore imperative. Sophisticated 3D multicellular tumor spheroid (MCTS) systems provide an emerging tool to model the phenotypic and cellular heterogeneity as well as microenvironmental aspects of in vivo tumor growth. In this review we discuss the cellular, chemical and physical factors contributing to zonation and cellular crosstalk within tumor masses. On this basis, we further describe 3D cell culture technologies for growth of MCTS as advanced tools for exploring molecular tumor growth determinants and facilitating drug discovery efforts. We conclude with a synopsis on technological aspects for on-line analysis and post-processing of 3D MCTS models. © 2014 Elsevier B.V. Source

Agency: Cordis | Branch: H2020 | Program: RIA | Phase: PHC-33-2015 | Award Amount: 30.12M | Year: 2016

The vision of EU-ToxRisk is to drive a paradigm shift in toxicology towards an animal-free, mechanism-based integrated approach to chemical safety assessment. The project will unite all relevant disciplines and stakeholders to establish: i) pragmatic, solid read-across procedures incorporating mechanistic and toxicokinetic knowledge; and ii) ab initio hazard and risk assessment strategies of chemicals with little background information. The project will focus on repeated dose systemic toxicity (liver, kidney, lung and nervous system) as well as developmental/reproduction toxicity. Different human tiered test systems are integrated to balance speed, cost and biological complexity. EU-ToxRisk extensively integrates the adverse outcome pathway (AOP)-based toxicity testing concept. Therefore, advanced technologies, including high throughput transcriptomics, RNA interference, and high throughput microscopy, will provide quantitative and mechanistic underpinning of AOPs and key events (KE). The project combines in silico tools and in vitro assays by computational modelling approaches to provide quantitative data on the activation of KE of AOP. This information, together with detailed toxicokinetics data, and in vitro-in vivo extrapolation algorithms forms the basis for improved hazard and risk assessment. The EU-ToxRisk work plan is structured along a broad spectrum of case studies, driven by the cosmetics, (agro)-chemical, pharma industry together with regulators. The approach involves iterative training, testing, optimization and validation phases to establish fit-for-purpose integrated approaches to testing and assessment with key EU-ToxRisk methodologies. The test systems will be combined to a flexible service package for exploitation and continued impact across industry sectors and regulatory application. The proof-of-concept for the new mechanism-based testing strategy will make EU-ToxRisk the flagship in Europe for animal-free chemical safety assessment.

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