Organotypic and Microphysiological Human Tissue Models for Drug Discovery and Development—Current State-of-the-Art and Future Perspectives

• 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. 

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper -- Immunologi inom det medicinska området (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Immunology in the medical area (hsv//eng)

MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin -- Endokrinologi och diabetes (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine -- Endocrinology and Diabetes (hsv//eng)

MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin -- Gastroenterologi (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine -- Gastroenterology and Hepatology (hsv//eng)

Nyckelord

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

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