Complex in vitro models positioned for impact to drug testing in pharma: a review DOI Creative Commons
Michael S. Kang, Eugene C. Chen, Helen Cifuentes

et al.

Biofabrication, Journal Year: 2024, Volume and Issue: 16(4), P. 042006 - 042006

Published: Aug. 27, 2024

Abstract Recent years have seen the creation and popularization of various complex in vitro models (CIVMs), such as organoids organs-on-chip, a technology with potential to reduce animal usage pharma while also enhancing our ability create safe efficacious drugs for patients. Public awareness CIVMs has increased, part, due recent passage FDA Modernization Act 2.0. This visibility is expected spur deeper investment adoption models. Thus, end-users model developers alike require framework both understand readiness current enter drug development process, assess upcoming same. review presents selection based on comparative -omics data (which we term model-omics), metrics qualification specific test assays that may support context-of-use (COU) assays. We surveyed existing healthy tissue ten development-critical organs body, provide evaluations suggestions improving model-omics COU each. In whole, this comes from perspective, seeks an evaluation where are poised maximum impact roadmap realizing potential.

Language: Английский

Organs-on-chips: into the next decade DOI
Lucie A. Low, Christine L. Mummery, Brian R. Berridge

et al.

Nature Reviews Drug Discovery, Journal Year: 2020, Volume and Issue: 20(5), P. 345 - 361

Published: Sept. 10, 2020

Language: Английский

Citations

697
In vitro models replicating the human intestinal epithelium for absorption and metabolism studies: A systematic review DOI Creative Commons
Arianna Fedi, Chiara Vitale,

Giulia Ponschin

et al.

Journal of Controlled Release, Journal Year: 2021, Volume and Issue: 335, P. 247 - 268

Published: May 24, 2021

Absorption, distribution, metabolism and excretion (ADME) studies represent a fundamental step in the early stages of drug discovery. In particular, absorption orally administered drugs, which occurs at intestinal level, has gained attention since poor oral bioavailability often led to failures for new approval. this context, several vitro preclinical models have been recently developed optimized better resemble human physiology lab serve as an animal alternative accomplish 3Rs principles. However, numerous are ineffective recapitulating key features small intestine epithelium lack prediction potential during stage. review, we provide overview aimed mimicking barrier pharmaceutical screening. After briefly describing how works, present i) conventional 2D synthetic cell-based systems, ii) 3D replicating main architecture, iii) micro-physiological systems (MPSs) reproducing dynamic stimuli cells exposed native microenvironment. will highlight benefits drawbacks leading used studies.

Language: Английский

Citations

149
3D cell culture models: Drug pharmacokinetics, safety assessment, and regulatory consideration DOI Creative Commons
Hongbing Wang, Paul C. Brown, Edwin C.Y. Chow

et al.

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

Citations

142
Towards in vitro models for reducing or replacing the use of animals in drug testing DOI
David M. Stresser, Anna K. Kopec, Philip Hewitt

et al.

Nature Biomedical Engineering, Journal Year: 2023, Volume and Issue: 8(8), P. 930 - 935

Published: Dec. 27, 2023

Language: Английский

Citations

47
Introduction to a manuscript series on the characterization and use of microphysiological systems (MPS) in pharmaceutical safety and ADME applications DOI

Kristin Fabre,

Brian R. Berridge, William R. Proctor

et al.

Lab on a Chip, Journal Year: 2020, Volume and Issue: 20(6), P. 1049 - 1057

Published: Jan. 1, 2020

Opportunities in the drug discovery/development process for potential MPS incorporation.

Language: Английский

Citations

91
Exploration and application of a liver-on-a-chip device in combination with modelling and simulation for quantitative drug metabolism studies DOI Creative Commons

Luca Docci,

Nicoló Milani, Thomas Ramp

et al.

Lab on a Chip, Journal Year: 2022, Volume and Issue: 22(6), P. 1187 - 1205

Published: Jan. 1, 2022

Microphysiological systems (MPS) are complex and more physiologically realistic cellular in vitro tools that aim to provide relevant human data for quantitative prediction of clinical pharmacokinetics while also reducing the need animal testing.

Language: Английский

Citations

44
Organotypic and Microphysiological Human Tissue Models for Drug Discovery and Development—Current State-of-the-Art and Future Perspectives DOI Creative Commons
Sonia Youhanna, Aurino M. Kemas,

Lena C. Preiss

et al.

Pharmacological Reviews, Journal Year: 2022, Volume and Issue: 74(1), P. 141 - 206

Published: Jan. 1, 2022

The number of successful drug development projects has been stagnant for decades despite major breakthroughs in chemistry, molecular biology, and genetics. Unreliable target identification poor translatability preclinical models have identified as causes failure. To improve predictions clinical efficacy safety, interest shifted to three-dimensional culture methods which human cells can retain many physiologically functionally relevant phenotypes extended periods time. Here, we review the state art available organotypic techniques critically emerging tissues with key importance pharmacokinetics, pharmacodynamics, toxicity. In addition, developments bioprinting microfluidic multiorgan cultures emulate systemic disposition are summarized. We close by highlighting important trends regarding fabrication platforms choice platform material limit absorption polymer leaching while supporting phenotypic maintenance cultured allowing scalable device fabrication. conclude that microphysiological tissue constitute promising systems promote discovery facilitating improving evaluation toxicity pharmacokinetics. There is, however, a critical need further validation, benchmarking, consolidation efforts ideally conducted intersectoral multicenter settings accelerate acceptance these novel reliable tools translational pharmacology toxicology.

Significance Statement

Organotypic emerged tool might be able narrow translation gap. This discusses recent technological methodological advancements use hit toxicity, clearance, lead compounds.

Language: Английский

Citations

39
Progress in developing microphysiological systems for biological product assessment DOI Creative Commons
Mona Mansouri, Johnny Lam, Kyung E. Sung

et al.

Lab on a Chip, Journal Year: 2024, Volume and Issue: 24(5), P. 1293 - 1306

Published: Jan. 1, 2024

This review delves into microphysiological systems, miniature physiological environments used to evaluate biological products, reducing the need for animal experimentation. We consider their benefits as well persistent challenges in material selection/fabrication and reproducibility.

Language: Английский

Citations

11
Liver-on-chips for drug discovery and development DOI Creative Commons
Viraj Mehta,

Guruswamy Karnam,

Vamsi Madgula

et al.

Materials Today Bio, Journal Year: 2024, Volume and Issue: 27, P. 101143 - 101143

Published: July 2, 2024

Recent FDA modernization act 2.0 has led to increasing industrial R&D investment in advanced

Language: Английский

Citations

10
DigiLoCS: A leap forward in predictive organ-on-chip simulations DOI Creative Commons
Manoja Rajalakshmi Aravindakshan, Chittaranjan Mandal, Alex Pothen

et al.

PLoS ONE, Journal Year: 2025, Volume and Issue: 20(1), P. e0314083 - e0314083

Published: Jan. 9, 2025

Digital twins, driven by data and mathematical modelling, have emerged as powerful tools for simulating complex biological systems. In this work, we focus on modelling the clearance a liver-on-chip digital twin that closely mimics functionality of human liver. Our approach involves creation compartmental physiological model liver using ordinary differential equations (ODEs) to estimate pharmacokinetic (PK) parameters related on-chip clearance. The objectives study were twofold: first, predict values, second, propose framework bridging gap between in vitro findings their clinical relevance. methodology integrated quantitative Organ-on-Chip (OoC) cell-based assay analyses drug depletion kinetics is further enhanced incorporating an OoC-digital simulate humans. 32 drugs was predicted digital-twin vivo extrapolation (IVIVE) assessed time series PK data. Three ODEs define concentrations media, interstitium intracellular compartments based biological, hardware, physicochemical information. A key issue determining appears be insufficient concentration within compartment. establishes connection hardware chip structure advanced mapping underlying biology, specifically focusing offers following benefits: i ) better prediction intrinsic compared conventional ii )explainability behaviour parameters. Finally, illustrate significance applying humans, utilising propranolol proof-of-concept example. This stands out biggest cross-organ-on-chip platform investigation date, systematically analysing predicting values obtained from various Accurate important inadequate understanding compound can lead unexpected undesirable outcomes trials, ranging underdosing toxicity. Physiologically (PBPK) estimation explored. aim develop twins capable predictions outcomes, ultimately reducing time, cost, patient burden associated with development. Various hepatic systems are effectiveness investigated. developed tool, DigiLoCs, focuses explicitly accurately describing processes liver-chip ODE-constrained optimisation applied compounds. DigiLoCs enable differentiation active (metabolism) passive (permeability partitioning) detailed information compound-specific characteristics hardware-specific These signify significant stride towards more accurate efficient development methodologies.

Language: Английский

Citations

1