The liver is the largest internal organ of the human body and it has a central role in maintaining homeostasis, metabolic functionality, and drug metabolism. In fact, hepatocytes are responsible for over 500 functions among which synthesis of proteins, the metabolism of fats, proteins, and carbohydrates.  They allow glycogen and lipids storage beside the detoxification of endogenous (e.g., bilirubin) and exogenous (e.g., drugs) substrates. Furthermore, hepatocytes produce bile which is useful for fats digestion and absorption [1].

Hepatic artery and portal vein supply the liver respectively with oxygenated and nutrient-rich blood. Hepatocytes are organized in fundamental and microscopic units called lobules. Lobules have a hexagonal structure with a central vein that collects the blood flowing from the portal triad along the sinusoids. Sinusoids are capillaries that consist of particular endothelial cells, known as liver sinusoidal endothelial cells (LSECs) [2]. These cells have peculiar characteristics that make them considered as a scavenger system that clear the blood from waste product and as a selective filter for substances passing from the sinusoid lumen to the parenchyma (hepatocytes, fat-cells) and vice versa. In fact, LSECs contain several structures such as micropinocytoticvescicles and lysosome vacuoles, which allow a high endocytotic activity.

Moreover, LSECs are devoid of the basal lamina and present nanopores through their surface. These nanopores, also called fenestrations (from Latin, fenestrae), have a 150 to 175 nm diameter and are grouped forming sieve plates that enable the passage of several molecules (e.g., metabolites, plasma proteins, drugs, lipoproteins, viruses, exosomes). LSECs are involved in many liver processes such as the initiation and progression of chronic liver diseases, liver regeneration, and the regulation of hepatic vascular tone. Although the relevance of the alteration in the number of fenestrations is demonstrated for all these processes, many aspects of fenestration’s behavior are still not elucidated [3, 4]. The understanding of unresolved aspects like this latter would be crucial in order to make out fundamentals of liver biology and elaborate new therapeutic approaches.

Unfortunately, cells like LSECs or hepatocytes are difficult to grow in standard 2D cultures and often they early dedifferentiate losing their characteristic functionalities. For this reason, liver on a chip technology could be extremely helpful since it facilitates cell growth by mimicking the structure of native hepatic units (e.g., lobule, sinusoid).