Managing the challenge of drug-induced liver injury: a roadmap for the development and deployment of preclinical predictive models

Nature Reviews Drug Discovery, Journal Year: 2019, Volume and Issue: 19(2), P. 131 - 148

Published: Nov. 20, 2019

Language: Английский

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Engineering Multi‐Cellular Spheroids for Tissue Engineering and Regenerative Medicine

Advanced Healthcare Materials, Journal Year: 2020, Volume and Issue: 9(23)

Published: July 30, 2020

Abstract Multi‐cellular spheroids are formed as a 3D structure with dense cell–cell/cell–extracellular matrix interactions, and thus, have been widely utilized implantable therapeutics various ex vivo tissue models in engineering. In principle, spheroid culture methods maximize cell–cell cohesion induce spontaneous cellular assembly while minimizing interactions substrates by using physical forces such gravitational or centrifugal forces, protein‐repellant biomaterials, micro‐structured surfaces. addition, biofunctional materials including magnetic nanoparticles, polymer microspheres, nanofiber particles combined cells to harvest composite spheroids, accelerate formation, increase the mechanical properties viability of direct differentiation stem into desirable cell types. Biocompatible hydrogels developed produce microgels for fabrication size‐controlled high efficiency. Recently, further engineered fabricate structurally functionally reliable vitro artificial tissues desired shape enhanced specific biological functions. This paper reviews overall characteristics general/advanced techniques. Significant roles functional biomaterials advanced engineering emphasis on use reconstruction also thoroughly discussed.

Language: Английский

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Bioprinting of Multiscaled Hepatic Lobules within a Highly Vascularized Construct

Small, Journal Year: 2020, Volume and Issue: 16(13)

Published: Feb. 20, 2020

Abstract Highly vascularized complex liver tissue is generally divided into lobes, lobules, hepatocytes, and sinusoids, which can be viewed under different types of lens from the micro‐ to macro‐scale. To engineer multiscaled heterogeneous tissues, a sophisticated rapid engineering approach required, such as advanced 3D bioprinting. In this study, preset extrusion bioprinting technique, create heterogeneous, multicellular, multimaterial structures simultaneously, utilized for creating hepatic lobule (≈1 mm) array. The fabricated lobules include cells, endothelial lumen. cells surround exterior lumen, finally, become interconnected with each other. Compared cell/endothelial cell mixtures, shows higher albumin secretion, urea production, albumin, MRP2, CD31 protein levels, well as, cytochrome P450 enzyme activity. It found that type spatial patterning in bioink accelerates cellular organization, could preserve structural integrity improve functions. conclusion, extruded within highly construct are successfully constructed, enabling both macro‐scale fabrication, support creation large constructs multiscale engineering.

Language: Английский

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3D cell culture models: Drug pharmacokinetics, safety assessment, and regulatory consideration

Clinical and Translational Science, Journal Year: 2021, Volume and Issue: 14(5), P. 1659 - 1680

Published: May 13, 2021

Abstract Nonclinical testing has served as a foundation for evaluating potential risks and effectiveness of investigational new drugs in humans. However, the current two‐dimensional (2D) vitro cell culture systems cannot accurately depict simulate rich environment complex processes observed vivo, whereas animal studies present significant drawbacks with inherited species‐specific differences low throughput increased demands. To improve nonclinical prediction drug safety efficacy, researchers continue to develop novel models evaluate promote use improved cell‐ organ‐based assays more accurate representation human susceptibility response. Among others, three‐dimensional (3D) physiologically relevant cellular microenvironment offer great promise assessing disposition pharmacokinetics (PKs) that influence efficacy from an early stage development. Currently, there are numerous different types 3D systems, simple spheroids complicated organoids organs‐on‐chips, single‐cell type static co‐culture equipped microfluidic flow control well hybrid combine 2D biomedical microelectromechanical systems. This article reviews application challenges PKs, safety, assessment, provides focused discussion regulatory perspectives on liver‐, intestine‐, kidney‐, neuron‐based models.

Language: Английский

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A 3D microfluidic liver model for high throughput compound toxicity screening in the OrganoPlate®

Toxicology, Journal Year: 2021, Volume and Issue: 450, P. 152667 - 152667

Published: Jan. 8, 2021

We report the development, automation and validation of a 3D, microfluidic liver-on-a-chip for high throughput hepatotoxicity screening, OrganoPlate LiverTox™. The model is comprised aggregates induced pluripotent stem cell (iPSC)-derived hepatocytes (iHep) seeded in an extracellular matrix organ channel co-cultured with endothelial cells THP-1 monoblasts differentiated to macrophages vascular 96 well Mimetas 2-lane. A key component screening we protocol seed, dose, collect replenish media add assay reagents 2-lane using standard laboratory liquid handling robot. combination secretome measurements image-based analysis was used demonstrate stable 15 day viability, albumin urea secretion. Over same time-period, CYP3A4 activity increased alpha-fetoprotein secretion decreased suggesting further maturation iHeps. Troglitazone, clinical hepatotoxin, chosen as control compound studies. Albumin, urea, hepatocyte nuclear size viability staining provided Robust Z'factors > 0.2 plates treated 72 h 180 μM troglitazone compared vehicle control. most robust statistic Z' factor = 0.6. small library 159 compounds known liver effects added LiverTox at 50 Toxicological Prioritization scores were calculated. follow up dose-response evaluation select hits revealed be sensitive calculating TC50 values. This platform provides robust, novel which can screening.

Language: Английский

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A Review of CYP-Mediated Drug Interactions: Mechanisms and In Vitro Drug-Drug Interaction Assessment

Biomolecules, Journal Year: 2024, Volume and Issue: 14(1), P. 99 - 99

Published: Jan. 12, 2024

Drug metabolism is a major determinant of drug concentrations in the body. Drug-drug interactions (DDIs) caused by co-administration multiple drugs can lead to alteration exposure victim drug, raising safety or effectiveness concerns. Assessment DDI potential starts with vitro experiments determine kinetic parameters and identify risks associated use comedication that inform future clinical studies. The diverse range experimental models techniques has significantly contributed examination DDIs. Cytochrome P450 (CYP) enzymes are responsible for biotransformation many on market, making them frequently implicated Consequently, there been growing focus assessment risk CYPs. This review article provides mechanistic insights underlying CYP inhibition/induction an overview CYP-mediated

Language: Английский

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Prediction of Drug-Induced Hepatotoxicity Using Long-Term Stable Primary Hepatic 3D Spheroid Cultures in Chemically Defined Conditions

Toxicological Sciences, Journal Year: 2018, Volume and Issue: 163(2), P. 655 - 665

Published: March 23, 2018

High failure rates of drug candidates in the clinics, restricted-use warnings as well withdrawals drugs postmarketing stages are substantial concern for pharmaceutical industry and drug-induced liver injury (DILI) constitutes one most frequent reasons such safety failures. Importantly, DILI cannot be accurately predicted using animal models, tests commonly complemented with assessments human vitro systems. 3D spheroid cultures primary hepatocytes chemically defined conditions, hereafter termed CD-spheroids, have recently emerged a microphysiological model system which retain their molecular phenotypes hepatic functions multiple weeks culture. However, predictive power detection hepatotoxic liabilities has not been systematically assessed. Therefore, we here evaluated hepatotoxicity 123 or without direct implication clinical events. ATP quantifications single endpoint, distinguished between nontoxic structural analogues exceeded both sensitivity specificity all previously published assays at substantially lower exposure levels, successfully detecting 69% compounds producing any false positive results (100% specificity). Furthermore, platform supports culture spheroids from preclinical thereby allowing identification animal-specific toxicity We anticipate that CD-spheroids represent powerful versatile tool discovery development can reliably flag provide guidance selection suitable models.

Language: Английский

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3D Primary Hepatocyte Culture Systems for Analyses of Liver Diseases, Drug Metabolism, and Toxicity: Emerging Culture Paradigms and Applications

Biotechnology Journal, Journal Year: 2019, Volume and Issue: 14(7)

Published: April 8, 2019

Recent research has shown that the maintenance of relevant liver functions ex vivo requires models in which cells exhibit an vivo-like phenotype, often achieved by reconstitution appropriate cellular interactions. Multiple different have been presented differ utilized, media, and culture conditions. Furthermore, several technologically approaches including bioreactors, chips, plate-based systems fluidic or static media constituting chemically diverse materials. Using such models, ability to predict drug metabolism, toxicity, functionality increased tremendously as compared conventional vitro are cultured 2D monolayers. Here, authors highlight important considerations for microphysiological primary hepatocyte culture, review current paradigms, discuss their opportunities studies hepatotoxicity, biology, disease.

Language: Английский

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Human soluble ACE2 improves the effect of remdesivir in SARS‐CoV‐2 infection

EMBO Molecular Medicine, Journal Year: 2020, Volume and Issue: 13(1)

Published: Nov. 12, 2020

There is a critical need for safe and effective drugs COVID-19. Only remdesivir has received authorization COVID-19 been shown to improve outcomes but not decrease mortality. However, the dose of limited by hepatic kidney toxicity. ACE2 cell surface receptor SARS-CoV-2. Here, we investigated additive effect combination therapy using with recombinant soluble (high/low dose) on Vero E6 organoids, targeting two different modalities SARS-CoV-2 life cycle: entry via its intracellular viral RNA replication. This treatment markedly improved their therapeutic windows against in both models. By single amino-acid resolution screening haploid ES cells, report singular pathway required toxicity, namely, Adenylate Kinase 2. The data provided here demonstrate that combining targets, common strategy HIV treatment, exhibit strong effects at sub-toxic concentrations. Our lay groundwork study combinatorial regimens future clinical trials.

Language: Английский

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In vitro and ex vivo models of adipocytes

AJP Cell Physiology, Journal Year: 2021, Volume and Issue: 320(5), P. C822 - C841

Published: Jan. 13, 2021

Adipocytes are specialized cells with pleiotropic roles in physiology and pathology. Several types of fat distinct metabolic properties coexist various anatomically defined depots mammals. White, beige, brown adipocytes differ their handling lipids thermogenic capacity, promoting differences size morphology. Moreover, release proteins paracrine endocrine functions. The intrinsic pose specific challenges culture. Mature float suspension culture due to high triacylglycerol content fragile. a fully differentiated state, notably acquirement the unilocular lipid droplet white adipocyte, has so far not been reached two-dimensional Cultures mouse human-differentiated preadipocyte cell lines primary have established mimic white, adipocytes. Here, we survey models mature adipocyte survival describing main characteristics, conditions, advantages, limitations. An important development is advent three-dimensional culture, adipose spheroids that recapitulate vivo function morphology depots. Challenges for future include isolation adipose-derived stem from different anatomic location animal humans differing sex, age, mass, pathophysiological conditions. Further understanding dysfunction will be achieved through genetic manipulation, CRISPR-mediated gene editing. Capturing heterogeneity at single-cell level within single depot key diversities cardiometabolic parameters among lean obese individuals.

Language: Английский

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