State-of-the-art of 3D cultures (organs-on-a-chip) in safety testing and pathophysiology

Abstract

Integrated approaches using different in vitro methods in combination with bioinformatics can (i) increase the success rate and speed of drug development; (ii) improve the accuracy of toxicological risk assessment; and (iii) increase our understanding of disease. Three-dimensional (3D) cell culture models are important building blocks of this strategy which has emerged during the last years. The majority of these models are organotypic, i.e., they aim to reproduce major functions of an organ or organ system. This implies in many cases that more than one cell type forms the 3D structure, and often matrix elements play an important role. This review summarizes the state of the art concerning commonalities of the different models. For instance, the theory of mass transport/metabolite exchange in 3D systems and the special analytical requirements for test endpoints in organotypic cultures are discussed in detail. In the next part, 3D model systems for selected organs--liver, lung, skin, brain--are presented and characterized in dedicated chapters. Also, 3D approaches to the modeling of tumors are presented and discussed. All chapters give a historical background, illustrate the large variety of approaches, and highlight up- and downsides as well as specific requirements. Moreover, they refer to the application in disease modeling, drug discovery and safety assessment. Finally, consensus recommendations indicate a roadmap for the successful implementation of 3D models in routine screening. It is expected that the use of such models will accelerate progress by reducing error rates and wrong predictions from compound testing.

3D models of the hematopoietic stem cell niche under steady-state and active conditions

“…The maximum size of 3D constructs containing living cells is limited by the distance over which diffusion allows efficient nutrition/supply of the cells. Without perfusion the relative concentration of molecules within the biomaterial drops quickly with increasing distance from the biomaterial–media interface 85 . Perfusion provides the possibility to overcome this limitation of insufficient medium supply in the central parts of larger biomaterials and allows, therefore, upscaling the scaffold size.…”

Comparative human and rat neurospheres reveal species differences in chemical effects on neurodevelopmental key events

“…For one, ex vivo NPCs seem to maintain their properties after taking them out of the whole organism, which was shown by compound effects in in vivo-ex vivo comparisons (Foti et al 2013;Go et al 2012;L'Episcopo et al 2013). Secondly, the 3D format of cultures with cell-cell communication and interaction supports physiological cellular functions and thus in vivo-relevant responses toward xenobiotics (Alépée et al 2014;Yamada and Cukierman 2007). Thus, we expected neurospheres to react only at compound concentrations relevant for interfering with signaling pathways necessary for the tested endpoints.…”

Reference compounds for alternative test methods to indicate developmental neurotoxicity (DNT) potential of chemicals: example lists and criteria for their selection and use

“…Clear quality control procedures would be required for in vitro models to produce results comparable across laboratories, and with the ultimate goal to use data for regulatory purposes. To address biological relevance, several different approaches may be combined (Alepee et al, 2014; Hartung et al, 2013; Smirnova et al, 2015; van Vliet et al, 2014). One approach is directly related to the selection of test compounds: the understanding of the response to tool compounds, and mechanistically consistent responses to chemically-related compounds would be helpful to evaluate the biological relevance of the test system.…”