Abstract
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.
Highlights
Discovery and development of safe and effective medicines critically depends on the accurate translation of robust preclinical findings
There has been tremendous progress in the development of organotypic and microphysiological 3D human models of tissues with relevance for drug response and toxicity. These activities have resulted in a multitude of methodologically distinct culture paradigms, including spheroid cultures, transwell cultures, micropatterned coculture (MPCC), and perfused microchips
The use of primary human liver cells constitutes the gold standard and has mostly replaced cell lines for studies of hepatotoxicity, pharmacokinetic profiling, and liver disease modeling
Summary
Discovery and development of safe and effective medicines critically depends on the accurate translation of robust preclinical findings To this end, a multitude of enabling technologies have been developed, including combinatorial chemistry that allows for more efficient generation of chemically diverse screening libraries, omics technologies that provide accurate and comprehensive phenotypic profiling data, and gene editing tools, which enable the rapid generation of mechanistically relevant in vitro and in vivo models. Organotypic and microphysiological cell culture of human cells using spheroids, organoids, or microfluidic devices aspires to facilitate result translation, opening up exciting opportunities for drug discovery and development In some of these systems, human cells can be cultured with relevant molecular phenotypes and functions for extended periods of time—often weeks to months— enabling the study of long-term human drug absorption, distribution, metabolism, and excretion (ADME) as well as of chronic toxicity. The model should have been benchmarked using a standardized set of mechanistically distinct hepatotoxic and nontoxic training compounds that allow for comparisons with other liver systems
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