Abstract:Non-clinical models to study metabolism including animal models and cell assays are often limited in terms of species translatability and predictability of human biology. This field urgently requires a push towards more physiologically accurate recapitulations of drug interactions and disease progression in the body. Organ-on-chip systems, specifically multi-organ chips (MOCs), are an emerging technology that is well suited to providing a species-specific platform to study the various types of metabolism (gluc… Show more
“…Multi-organ chips, for instance, liver-, adipose-, and gut-on-a-chip connected, may be particularly suitable to understand organ-crosstalk in chronic liver disease (CLD), such as NAFLD/NASH or cholangiopathies. 5 Figure 2 From single cells to liver-on-a-chip and body on-a-chip. …”
Section: Liver-on-a-chip and Microfluidic Devicesmentioning
“…Multi-organ chips, for instance, liver-, adipose-, and gut-on-a-chip connected, may be particularly suitable to understand organ-crosstalk in chronic liver disease (CLD), such as NAFLD/NASH or cholangiopathies. 5 Figure 2 From single cells to liver-on-a-chip and body on-a-chip. …”
Section: Liver-on-a-chip and Microfluidic Devicesmentioning
“…Other literature reviews described relevant in vitro models for the study of NAFLD in other organs. 7 …”
Section: Defining the Hallmarks Of The Human Nafld Spectrum For Effec...mentioning
confidence: 99%
“…Intriguingly, organ-on-chip systems have been developed to mimic the consequences of overweight in organs such as adipose tissue or the potentials of multiorgan chips as discussed elsewhere. 7 , 79 , 80 , 81 As such, the possibility of connecting several organ-on-a-chip systems represents a largely untapped potential to investigate NAFLD under the influence of metabolic and inflammatory crosstalk between the liver, blood, adipose tissue, and other organs.…”
“…Microphysiological systems (MPS) and organ-on-chips as well as 3D organoids hold great promise to address more complex in vitro ADME, toxicology and pharmacology questions offering miniature, biomimetic systems that replicate key aspects of human organ physiology [10, 11, 12]. These technologies create an environment where human cells can grow and interact in an organ-specific context, providing insights into human biology and disease that were previously unattainable in conventional in vitro models or animal studies.…”
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 on a liver-on-chip as a digital twin that closely mimics the clearance functionality of the human liver. Our approach involves the creation of a compartmental physiological model of the liver using ordinary differential equations (ODEs) to estimate pharmacokinetic (PK) parameters related to on-chip liver clearance. The objectives of this study were twofold: first, to predict human clearance values, and second, to propose a framework for bridging the gap between in vitro findings and their clinical relevance. The methodology integrated quantitative Organ-on-Chip (OoC) and cell-based assay analyses of drug depletion kinetics and is further enhanced by incorporating an OoC-digital twin model to simulate drug depletion kinetics in humans. The in vitro liver clearance for 32 drugs was predicted using a digital-twin model of the liver-on-chip and in vitro to in vivo extrapolation (IVIVE) was assessed using time series PK data. Three ODEs in the model define the drug concentrations in media, interstitium and intracellular compartments based on biological, hardware, and physicochemical information. A key issue in determining liver clearance appears to be the insufficient drug concentration within the intracellular compartment. The digital twin establishes a connection between the hardware chip structure and an advanced mapping of the underlying biology, specifically focusing on the intracellular compartment. Our modelling offers the following benefits: i) better prediction of intrinsic liver clearance of drugs compared to the state-of-the-art model and ii) explainability of behaviour based on physiological parameters. Finally, we illustrate the clinical significance of this approach by applying the findings to humans, utilising propranolol as a proof-of-concept example. This study stands out as the biggest cross-organ-on-chip platform investigation to date, systematically analysing and predicting human clearance values using data obtained from various in vitro liver-on-chip systems.
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