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.
Highlights
1.1 BackgroundSpecific tissue function and physiology may be lost in 2D systems. 3D culture models were created to better mimic the in vivo situation and to maintain such functions (Haycock, 2011)
The use of more complex models may improve this situation, as their underlying basic biological functions may be used as readouts, without necessitating exact knowledge of the upstream modes of action of potential toxicants. 3D models are expected to contribute to this progress by allowing the modelling of more biological processes that are essential for the functioning of the brain and nervous systems
To provide human cellular material, which is currently seen as the new gold standard in toxicology of the 21st century (Leist et al, 2008b; NRC, 2007), new technologies are emerging that allow differentiation of human embryonic stem cells, human induced pluripotent stem cells or fetal neural progenitor cells (NPCs) into neurons and glial cells (Bal-Price et al, 2012; Fritsche et al, 2011; Leist et al, 2008a)
Summary
Specific tissue function and physiology may be lost in 2D systems. 3D culture models were created to better mimic the in vivo situation and to maintain such functions (Haycock, 2011). Differences in artificial organ design are a result of the desired endpoint: for instance, a model for skin irritation can potentially be achieved using a simpler strategy than, perhaps, the more complex endpoint of developmental delay of the formation of the nervous system Both endpoints are important in testing of drug candidates and chemicals. When discussing the transition from animal models to in vitro models, it is important to remember that test systems need not recapitulate every aspect of an animal model (or human disease), but they should provide predictive data for a particular question Another common theme is linked to technical limitations of model construction: at present, few models, such as the MCTS (multicellular tumour spheroids), have the potential to be produced at a large scale according to stringent standards required for toxicity testing and drug development. This important theme is covered in a dedicated chapter on mass transport
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