Functional coupling of human pancreatic islets and liver spheroids on-a-chip: Towards a novel human ex vivo type 2 diabetes model

Abstract

Human in vitro physiological models studying disease and drug treatment effects are urgently needed as more relevant tools to identify new drug targets and therapies. We have developed a human microfluidic two-organ-chip model to study pancreatic islet–liver cross-talk based on insulin and glucose regulation. We have established a robust co-culture of human pancreatic islet microtissues and liver spheroids maintaining functional responses up to 15 days in an insulin-free medium. Functional coupling, demonstrated by insulin released from the islet microtissues in response to a glucose load applied in glucose tolerance tests on different days, promoted glucose uptake by the liver spheroids. Co-cultures maintained postprandial glucose concentrations in the circulation whereas glucose levels remained elevated in both single cultures. Thus, insulin secreted into the circulation stimulated glucose uptake by the liver spheroids, while the latter, in the absence of insulin, did not consume glucose as efficiently. As the glucose concentration fell, insulin secretion subsided, demonstrating a functional feedback loop between the liver and the insulin-secreting islet microtissues. Finally, inter-laboratory validation verified robustness and reproducibility. Further development of this model using tools inducing impaired glucose regulation should provide a unique in vitro system emulating human type 2 diabetes mellitus.

Investigation of the hepatic respiration and liver zonation on rat hepatocytes using an integrated oxygen biosensor in a microscale device

“…3,4 Concerning the liver, the features of those bioreactors mimic the liver physiology as much as possible. Thus, the additional integration of progress in tissue engineering, 5,6 including liver cell co-cultures, three dimensional cultures, or organ-to-organ cocultures, [7][8][9] contribute to propose a wide range of liver-on-chip devices. The knowledge of liver organ-on-chip contributed to the proposal of even stem cell-based culture methods 10 or complex human primary cell-based models.…”

A robotic platform for fluidically-linked human body-on-chips experimentation

“…Furthermore, the direct contact of parenchymal tissues with a shared medium not only poses a significant technical challenge for developing a universal blood substitute that all cell types can tolerate, but it may hinder normal tissue function by forcing parenchymal cells of different organs to interact directly, which does not occur in vivo. Several microphysiological systems have incorporated tissue culture well inserts with semi-permeable membranes lined by both parenchymal cells and endothelial cells to develop a more physiological shared medium for linked organs 11,19,20 . Yet others have demonstrated 3D culture of endothelial cells with a parenchymal tissue in single organ configurations 56 , which facilitates a shared medium but presents additional variability in vasculature area for PBPK calculations.…”

“…In particular, these systems offer limited ability to sample the different biological compartments or the capacity to reconfigure the system so that the same platform can be used for multiple experimental designs. Other HuBoC systems have used manual or automated transfer of fluid flow between multiple microfluidic culture systems using gravity feed 10,16 or they relied on perfusion through integrated microfluidic networks controlled by microvalve pumps 14,19,20 . But in these systems the shared medium containing drugs was transferred directly from one parenchymal tissue type to another without passing across a vascular endothelium as normally occurs in vivo.…”

Harnessing the Potential of Stem Cells for Disease Modeling: Progress and Promises

“…The possibility of harnessing stem cells versatility, differentiated cells specific properties and microfluidic control allowed to build disease models with unprecedented features, as it made possible to reproduce in vitro complex biological structures that could not be obtained with previous cell culturing technologies such as the blood-brain barrier [204] (Table 6). As a matter of fact, in the past five years many disease models have been developed, such as lung-on-a-chip for cancer [205] or coupled-OOCs of liver and pancreas spheroids able to maintain glucose homeostasis for modeling type 2 diabetes [206] (Table 6). Of note, different OOC models can be linked to build an ideal 'human-on-a-chip' which could theoretically serve as the ultimate alternative to animal models for its capacity to predict multiorgan biological interactions and response to therapeutic treatments [202,207].…”