In Vitro Models of the Blood-Brain Barrier

Abstract

Knowledge about the transport of active compounds across the blood-brain barrier is of essential importance for drug development. Systemically applied drugs for the central nervous system (CNS) must be able to cross the blood-brain barrier in order to reach their target sites, whereas drugs that are supposed to act in the periphery should not permeate the blood-brain barrier so that they do not trigger any adverse central adverse effects. A number of approaches have been pursued, and manifold in silico, in vitro, and in vivo animal models were developed in order to be able to make a better prediction for humans about the possible penetration of active substances into the CNS. In this particular case, however, in vitro models play a special role, since the data basis for in silico models is usually in need of improvement, and the predictive power of in vivo animal models has to be checked for possible species differences. The blood-brain barrier is a dynamic, highly selective barrier formed by brain capillary endothelial cells. One of its main tasks is the maintenance of homeostasis in the CNS. The function of the barrier is regulated by cells of the microenvironment and the shear stress mediated by the blood flow, which makes the model development most complex. In general, one could follow the credo “as easy as possible, as complex as necessary” for the usage of in vitro BBB models for drug development. In addition to the description of the classical cell culture models (transwell, hollow fiber) and guidance how to apply them, the latest developments (spheroids, microfluidic models) will be introduced in this chapter, as it is attempted to get more in vivo-like and to be applicable for high-throughput usage with these models. Moreover, details about the development of models based on stem cells derived from different sources with a special focus on human induced pluripotent stem cells are presented.