Metabolic syndrome refers to a complex disorder involving several tissues and organs and their interactions possibly resulting in diabetes, obesity, non-alcoholic fatty liver disorder (NAFLD), insulin resistance and cardiac failure (Lara Castro and Garvey, 2008; Ginsberg and MacCallum, 2009; Shin et al., 2013; Gaggini et al., 2013; Fornari and Maffeis, 2019). The state of art of metabolic syndrome has documented the organ crosstalk's only in a few papers based on “classical” 2D culture and mainly in animal models (Wong et al., 2016). The research strategy based on those 2D in vitro models and the animal models failed to translate pertinent solutions up to patients. Furthermore, although food was identified as one source of the metabolic syndrome onset (Moreno-Fernández et al., 2018; Rodríguez-Correa et al., 2020; de la Iglesia et al., 2016), as well as the epigenetic and genetic background (Fornari and Maffeis, 2019), the sequence of the development of the metabolic syndrome is still controversial (McMillen and Robinson, 2005; Kassi et al., 2011; Fornari and Maffeis, 2019). The systemic complications and the lack of pertinent human model led to bottlenecks in risk evaluations (Fornari and Maffeis, 2019), diagnosis, therapy and thus to clinical and to industries (pharmaceutical, food industry) demands (Lillich et al., 2021).

Because the metabolic syndrome is systemic disease, the in vitro technological challenges are to consider the interactions between the different organs. Therefore, reproducing a model that includes complex multi organ interaction is mandatory for the disease's description but also for the drug screening. To solve this problem, the organ-on-chip (OoC) technology is one of the potential strategies. This approach is based on the conviction that the reproduction of the human physiological relevant microenvironment is a key feature in obtaining in-vivo-like cell responses. OoC systems can be tuned to emulate the in vivo cells/organs microenvironment, including 3D organization, cell-to-cell/matrix interactions, concentration gradients (oxygen, molecules), shear force, continuous nutrients and waste exchange/removing (Yokoi et al., 2023; Messelmani et al., 2022; Moradi et al., 2020). Furthermore, thanks to OoC technology, two or more organs can be connected using fluidic tubing or integrated in a single device to mimic physiological organs' crosstalk (Picollet-D'hahan et al., 2021).

Focussing on metabolic syndrome, liver and pancreas are among the two key organs. Several examples of liver-on-chip (Deng et al., 2019; Ehrlich et al., 2019) and pancreas-on-chip (Essaouiba et al., 2020a; Abadpour et al., 2020) technologies were reported in the literature. In order to investigate the synergy between liver and pancreas, few liver-pancreas coculture OoC models were also previously developed. Bauer and her colleagues combined ex vivo human islets of Langerhans with human liver aggregates generated from HepaRG cell line to investigate type 2 diabetes metillus (Bauer et al., 2017). Essaouiba et al. (2020b) also established a model with freshly isolated rat primary hepatocytes and rat Langehrans islets and confirmed the organ-to-organ synergy and crosstalks.

In the last decades, due to the limited availability of human primary cells and the lack of functionality of cell lines, human induced pluripotent stem cells (hiPSCs) have emerged as a promising cell-source for the development of relevant in vitro models. In this context, our group has proposed an OoC protocol suitable for maturation of hiPSCs into hepatocyte like cells (HLCs). The liver tissue displayed hepatic regeneration profiles and functional patterns including CYP450 activity (Danoy et al., 2021a, 2021b, 2022). Furthermore, the model also presented several CK7 and CK19 positive cells illustrating the presence of still immature cells and cholangiocyte-like cells in the biochips (Danoy et al., 2023; Scheidecker et al., 2024; Wang et al., 2025). We also proposed a technology allowing the maturation of hiPSCs up to pancreatic like tissue (PLTs) using 3D honeycombs technology (Essaouiba et al., 2021; Morisseau et al. 2023, 2024). In the 3D honeycomb model, the pancreatic tissue displayed several bihormonal β−cells subtypes (Morisseau et al., 2023). In addition, the pancreatic tissues were successfully cultivated in pancreas organ on chip and they were positive to insulin and glucagon. They also responded to glucose and GLP1 stimulated insulin secretion (Essaouiba et al., 2021). Following those preliminary works, we propose in this study an advanced organ on chip solution suitable for human derived induced pluripotent stem cells to investigate human liver and pancreas interactions.