RT Journal Article SR Electronic T1 Organotypic and Microphysiological Human Tissue Models for Drug Discovery and Developmentā€”Current State-of-the-Art and Future Perspectives JF Pharmacological Reviews JO Pharmacol Rev FD American Society for Pharmacology and Experimental Therapeutics SP 141 OP 206 DO 10.1124/pharmrev.120.000238 VO 74 IS 1 A1 Sonia Youhanna A1 Aurino M. Kemas A1 Lena Preiss A1 Yitian Zhou A1 Joanne X. Shen A1 Selgin D. Cakal A1 Francesco S. Paqualini A1 Sravan K. Goparaju A1 Reza Zandi Shafagh A1 Johan Ulrik Lind A1 Carl M. Sellgren A1 Volker M. Lauschke A2 Gunnar Schulte YR 2022 UL http://pharmrev.aspetjournals.org/content/74/1/141.abstract AB The number of successful drug development projects has been stagnant for decades despite major breakthroughs in chemistry, molecular biology, and genetics. Unreliable target identification and poor translatability of preclinical models have been identified as major causes of failure. To improve predictions of clinical efficacy and safety, interest has shifted to three-dimensional culture methods in which human cells can retain many physiologically and functionally relevant phenotypes for extended periods of time. Here, we review the state of the art of available organotypic culture techniques and critically review emerging models of human tissues with key importance for pharmacokinetics, pharmacodynamics, and toxicity. In addition, developments in bioprinting and microfluidic multiorgan cultures to emulate systemic drug disposition are summarized. We close by highlighting important trends regarding the fabrication of organotypic culture platforms and the choice of platform material to limit drug absorption and polymer leaching while supporting the phenotypic maintenance of cultured cells and allowing for scalable device fabrication. We conclude that organotypic and microphysiological human tissue models constitute promising systems to promote drug discovery and development by facilitating drug target identification and improving the preclinical evaluation of drug toxicity and pharmacokinetics. There is, however, a critical need for further validation, benchmarking, and consolidation efforts ideally conducted in intersectoral multicenter settings to accelerate acceptance of these novel models as reliable tools for translational pharmacology and toxicology.Significance Statement Organotypic and microphysiological culture of human cells has emerged as a promising tool for preclinical drug discovery and development that might be able to narrow the translation gap. This review discusses recent technological and methodological advancements and the use of these systems for hit discovery and the evaluation of toxicity, clearance, and absorption of lead compounds.