The rapid progress in combinatorial chemistry continues to yield a myriad of potentially bioactive compounds every day. With thousands of pharmaceutically valuable drugs at hand, there is an urgent need for engineered tissue equivalents that could serve as in-vitro model systems during the initial stages ofdrug discovery, specifically during the preclinical stages of cell/tissue-based high-throughput screening (HTS). Given the well-known problematics of using two-dimensional (2D) cell cultures as pharmacological test-beds, more realistic three-dimensional (3D) tissue constructs are required. Generation of high-fidelity engineered tissuelike constructs is based on the targeted interactions of organ-specific cells and "intelligent" biomimetic scaffolds, emulating the complex natural environment, the extracellular matrix (ECM) in which these cells develop/differentiate and function.

In this chapter, we will begin by introducing the most common natural and synthetic materials and platform biotechnologies for creating scaffolds that are in use for engineering tissue constructs, and which might be useful for pharmaceutical purposes, as models for drug discovery and in-vitro testing. A variety of approaches for modifying the chemistry and geometry of these materials towards rendering them useful as intelligent biomatrices for 3D tissue engineering will be presented. We then will discuss, both paradigmatically and critically, the fabrication principles and potential use of engineered constructs in cardiac, hepatic, and pulmonary tissue engineering. Finally, we will explore in more detail the current and future use of engineered models of the blood-brain barrier (BBB), where the use of novel "intelligent" biomaterials and scaffolds promises to break the current impasse in engineering high-fidelity in-vitro models of the BBB and thus facilitate reliable and predictive HTS of central nervous system (CNS)-active compounds during early stages of drug discovery.

Although the application of bioengineered 3D in-vitro tissue models in pharmaceutical research is in its infancy, the interdisciplinary approach and the achievements described in this chapter provide an encouraging first step towards the accelerated development of such models for drug discovery.

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