The application of organ-on-chip models for the prediction of human pharmacokinetic profiles during drug development

Organ-on-chip (OoC) technology has led to in vitro models with many new possibilities compared to conventional in vitro and in vivo models. In this review, the potential of OoC models to improve the prediction of human oral bioavailability and intrinsic clearance is discussed, with a focus on the functionality of the models and the application in current drug development practice. Multi-OoC models demonstrating the application for pharmacokinetic (PK) studies are summarized and existing challenges are identified. Physiological parameters for a minimal viable platform of a multi-OoC model to study PK are provided, together with PK specific read-outs and recommendations for relevant reference compounds to validate the model. Finally, the translation to in vivo PK profiles is discussed, which will be required to routinely apply OoC models during drug development

Microphysiological Systems to Recapitulate the Gut–Kidney Axis

Chronic kidney disease (CKD) typically appears alongside other comorbidities, highlighting an underlying complex pathophysiology that is thought to be vastly modulated by the bidirectional gut–kidney crosstalk. By combining advances in tissue engineering, biofabrication, microfluidics, and biosensors, microphysiological systems (MPSs) have emerged as promising approaches for emulating the in vitro interconnection of multiple organs, while addressing the limitations of animal models. Mimicking the (patho)physiological states of the gut–kidney axis in vitro requires an MPS that can simulate not only this direct bidirectional crosstalk but also the contributions of other physiological participants such as the liver and the immune system. We discuss recent developments in the field that could potentially lead to in vitro modeling of the gut–kidney axis in CKD

Microphysiological Systems to Recapitulate the Gut–Kidney Axis

Chronic kidney disease (CKD) typically appears alongside other comorbidities, highlighting an underlying complex pathophysiology that is thought to be vastly modulated by the bidirectional gut–kidney crosstalk. By combining advances in tissue engineering, biofabrication, microfluidics, and biosensors, microphysiological systems (MPSs) have emerged as promising approaches for emulating the in vitro interconnection of multiple organs, while addressing the limitations of animal models. Mimicking the (patho)physiological states of the gut–kidney axis in vitro requires an MPS that can simulate not only this direct bidirectional crosstalk but also the contributions of other physiological participants such as the liver and the immune system. We discuss recent developments in the field that could potentially lead to in vitro modeling of the gut–kidney axis in CKD

The potential of multi-organ-on-chip models for assessment of drug disposition as alternative to animal testing

The development of new medicines suffers from attrition, especially in the development pipeline. Eight out of nine drug candidates entering the clinical testing phase fail, mostly due to poor safety and efficacy. The low predictive value of animal models, used in earlier phases of drug development, for effects in humans poses a major problem. In particular, drug disposition can markedly differentiate in experimental animals versus humans. Meanwhile, classic in vitro methods can be used but these models lack the complexity to mimic holistic physiological processes occurring in the human body, especially organ–organ interactions. Therefore, better predictive methods to investigate drug disposition in the preclinical phase are needed, for which recent developments in multiorgan-on-chip methods are very promising. To be able to capture human physiology as good as possible, multiorgan-on-chips should feature 1) human cells endogenously expressing main transporters and metabolizing enzymes; 2) organ models relevant for exposure route; 3) individual organs-on-chip connected in a physiologically relevant manner; 4) a tight cellular barrier between the compartments; 5) organ models properly polarized in 3D; 6) allow for sampling in all major compartments; 7) constructed from materials that do not absorb or adsorb the compound of interest; 8) cells should grow in absence of fetal calf serum and Matrigel; 9) validated with a panel of compounds with known characteristics in humans; 10) an integrated computer model translating concentrations to the human situation. Here, an overview of available systems is presented and the difficult route towards a fully validated system is discussed

The potential of multi-organ-on-chip models for assessment of drug disposition as alternative to animal testing

The development of new medicines suffers from attrition, especially in the development pipeline. Eight out of nine drug candidates entering the clinical testing phase fail, mostly due to poor safety and efficacy. The low predictive value of animal models, used in earlier phases of drug development, for effects in humans poses a major problem. In particular, drug disposition can markedly differentiate in experimental animals versus humans. Meanwhile, classic in vitro methods can be used but these models lack the complexity to mimic holistic physiological processes occurring in the human body, especially organ–organ interactions. Therefore, better predictive methods to investigate drug disposition in the preclinical phase are needed, for which recent developments in multiorgan-on-chip methods are very promising. To be able to capture human physiology as good as possible, multiorgan-on-chips should feature 1) human cells endogenously expressing main transporters and metabolizing enzymes; 2) organ models relevant for exposure route; 3) individual organs-on-chip connected in a physiologically relevant manner; 4) a tight cellular barrier between the compartments; 5) organ models properly polarized in 3D; 6) allow for sampling in all major compartments; 7) constructed from materials that do not absorb or adsorb the compound of interest; 8) cells should grow in absence of fetal calf serum and Matrigel; 9) validated with a panel of compounds with known characteristics in humans; 10) an integrated computer model translating concentrations to the human situation. Here, an overview of available systems is presented and the difficult route towards a fully validated system is discussed

Microphysiological Systems to Recapitulate the Gut–Kidney Axis

Chronic kidney disease (CKD) typically appears alongside other comorbidities, highlighting an underlying complex pathophysiology that is thought to be vastly modulated by the bidirectional gut–kidney crosstalk. By combining advances in tissue engineering, biofabrication, microfluidics, and biosensors, microphysiological systems (MPSs) have emerged as promising approaches for emulating the in vitro interconnection of multiple organs, while addressing the limitations of animal models. Mimicking the (patho)physiological states of the gut–kidney axis in vitro requires an MPS that can simulate not only this direct bidirectional crosstalk but also the contributions of other physiological participants such as the liver and the immune system. We discuss recent developments in the field that could potentially lead to in vitro modeling of the gut–kidney axis in CKD

Microphysiological Systems to Recapitulate the Gut–Kidney Axis

Chronic kidney disease (CKD) typically appears alongside other comorbidities, highlighting an underlying complex pathophysiology that is thought to be vastly modulated by the bidirectional gut–kidney crosstalk. By combining advances in tissue engineering, biofabrication, microfluidics, and biosensors, microphysiological systems (MPSs) have emerged as promising approaches for emulating the in vitro interconnection of multiple organs, while addressing the limitations of animal models. Mimicking the (patho)physiological states of the gut–kidney axis in vitro requires an MPS that can simulate not only this direct bidirectional crosstalk but also the contributions of other physiological participants such as the liver and the immune system. We discuss recent developments in the field that could potentially lead to in vitro modeling of the gut–kidney axis in CKD

Integrating extracellular matrix-mimicking layers in microfluidic devices: More control over the tumor microenvironment

A challenge in studying cancer invasion is to understand the interaction between cancer cells and the extracellular matrix (ECM). Although the ECM influences cancer invasion, it is still unclear how its properties contribute to the process. Here, we present a new microfabrication method to integrate ECM-mimicking matrix layers between two microchannels. Using this chip, we have observed that the invasion distance of MDA-MB-231 breast cancer cells into 3D Polycaprolactone matrices and the general cell morphology are not affected by the ECM fiber diameter. The cells however produce longer and more protrusions in the matrix with smaller fiber size

Metastasis in context:modeling the tumor microenvironment with cancer-on-a-chip approaches

\u3cp\u3eMost cancer deaths are not caused by the primary tumor, but by secondary tumors formed through metastasis, a complex and poorly understood process. Cues from the tumor microenvironment, such as the biochemical composition, cellular population, extracellular matrix, and tissue (fluid) mechanics, have been indicated to play a pivotal role in the onset of metastasis. Dissecting the role of these cues from the tumor microenvironment in a controlled manner is challenging, but essential to understanding metastasis. Recently, cancer-on-a-chip models have emerged as a tool to study the tumor microenvironment and its role in metastasis. These models are based on microfluidic chips and contain small chambers for cell culture, enabling control over local gradients, fluid flow, tissue mechanics, and composition of the local environment. Here, we review the recent contributions of cancer-on-a-chip models to our understanding of the role of the tumor microenvironment in the onset of metastasis, and provide an outlook for future applications of this emerging technology.\u3c/p\u3

The potential of multi-organ-on-chip models for assessment of drug disposition as alternative to animal testing

The development of new medicines suffers from attrition, especially in the development pipeline. Eight out of nine drug candidates entering the clinical testing phase fail, mostly due to poor safety and efficacy. The low predictive value of animal models, used in earlier phases of drug development, for effects in humans poses a major problem. In particular, drug disposition can markedly differentiate in experimental animals versus humans. Meanwhile, classic in vitro methods can be used but these models lack the complexity to mimic holistic physiological processes occurring in the human body, especially organ–organ interactions. Therefore, better predictive methods to investigate drug disposition in the preclinical phase are needed, for which recent developments in multiorgan-on-chip methods are very promising. To be able to capture human physiology as good as possible, multiorgan-on-chips should feature 1) human cells endogenously expressing main transporters and metabolizing enzymes; 2) organ models relevant for exposure route; 3) individual organs-on-chip connected in a physiologically relevant manner; 4) a tight cellular barrier between the compartments; 5) organ models properly polarized in 3D; 6) allow for sampling in all major compartments; 7) constructed from materials that do not absorb or adsorb the compound of interest; 8) cells should grow in absence of fetal calf serum and Matrigel; 9) validated with a panel of compounds with known characteristics in humans; 10) an integrated computer model translating concentrations to the human situation. Here, an overview of available systems is presented and the difficult route towards a fully validated system is discussed