Organotypic and Microphysiological Human Tissue Models for Drug Discovery and Development—Current State-of-the-Art and Future PerspectivesShow others and affiliations
2022 (English)In: Pharmacological Reviews, ISSN 0031-6997, E-ISSN 1521-0081, Vol. 74, no 1, p. 141-206Article in journal (Refereed) Published
Abstract [en]
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.
Place, publisher, year, edition, pages
American Society for Pharmacology & Experimental Therapeutics (ASPET) , 2022. Vol. 74, no 1, p. 141-206
Keywords [en]
4 aminohippuric acid, ABC transporter, ABC transporter subfamily B, alkene, aquaporin, bile salt export pump, breast cancer resistance protein, cytochrome P450, diclofenac, dimeticone, elastomer, G protein coupled receptor, glutathione transferase, heme oxygenase 1, microRNA, neutrophil gelatinase associated lipocalin, organic anion transporter, paracetamol, poly(methyl methacrylate), polycarbonate, polystyrene, reactive oxygen metabolite, sodium glucose cotransporter 1, solute carrier protein, tolcapone, troglitazone, WT1 protein, action potential, amyotrophic lateral sclerosis, Article, autism, blood brain barrier, cardiotoxicity, cell activation, coculture, coronavirus disease 2019, drug absorption, drug clearance, drug disposition, drug distribution, drug efficacy, drug excretion, drug metabolism, drug research, drug response, drug safety, drug screening, Duchenne muscular dystrophy, electric resistance, electron beam, embryoid body, embryonic stem cell, engineered heart tissue, extracellular matrix, gene expression, gene identification, gene targeting, hepatic stellate cell, Hepatitis B virus, human, induced pluripotent stem cell, inflammatory bowel disease, intrinsic clearance, liver sinusoidal endothelial cell, liver toxicity, metabolomics, microchip analysis, microfluidics, mitochondrial membrane potential, molecular biology, nephrotoxicity, neuromuscular junction, neurotoxicity, nonalcoholic fatty liver, nonalcoholic steatohepatitis, organotypic culture, pharmacodynamics, pharmacokinetic parameters, phenotype, reperfusion injury, spheroid cell, stellate cell, three dimensional printing, tissue culture, tissue engineering, transwell assay, two dimensional cell culture, adverse drug reaction, drug development, multicenter study (topic), preclinical study, Drug Discovery, Drug Evaluation, Preclinical, Drug-Related Side Effects and Adverse Reactions, Humans, Multicenter Studies as Topic
National Category
Immunology in the medical area Endocrinology and Diabetes Gastroenterology and Hepatology
Identifiers
URN: urn:nbn:se:kth:diva-319972DOI: 10.1124/PHARMREV.120.000238ISI: 000958526200001PubMedID: 35017176Scopus ID: 2-s2.0-85123461685OAI: oai:DiVA.org:kth-319972DiVA, id: diva2:1704157
Note
QC 20221017
2022-10-172022-10-172025-02-11Bibliographically approved