Gut-on-a-chip for disease models

Abstract

The intestinal tract is a vital organ responsible for digestion and absorption in the human body and plays an essential role in pathogen invasion. Compared with other traditional models, gut-on-a-chip has many unique advantages, and thereby, it can be considered as a novel model for studying intestinal functions and diseases. Based on the chip design, we can replicate the in vivo microenvironment of the intestine and study the effects of individual variables on the experiment. In recent years, it has been used to study several diseases. To better mimic the intestinal microenvironment, the structure and function of gut-on-a-chip are constantly optimised and improved. Owing to the complexity of the disease mechanism, gut-on-a-chip can be used in conjunction with other organ chips. In this review, we summarise the human intestinal structure and function as well as the development and improvement of gut-on-a-chip. Finally, we present and discuss gut-on-a-chip applications in inflammatory bowel disease (IBD), viral infections and phenylketonuria. Further improvement of the simulation and high throughput of gut-on-a-chip and realisation of personalised treatments are the problems that should be solved for gut-on-a-chip as a disease model.

Keywords: Gut-on-a-chip; SARS-CoV-2; disease model; inflammatory bowel disease; phenylketonuria.

Figure 1.

Schematic diagram of the intestinal mucosa. The intestinal structure can be divided into mucus, villi, crypt, lamina propria, muscularis mucosae and submucosa from the outside to the inside. Symbiotic bacteria in mucus play an essential role in intestinal barrier function. The epithelium includes many types of cells, including enterocytes, goblet cells, enteroendocrine cells, tuft cells, Paneth cells and intestinal stem cells. Similar to many vital parts, the lamina propria also contains many immune cells. Tight junctions, adherent junctions and desmosomes are the main components of the apical junction complex. The ENS resides in the submucosa, consisting of two major plexuses: the myenteric plexus and submucosal plexus.

Figure 2.

Schematic diagram showing the current development of gut-on-a-chip. (a) The process of making an organ-on-a-chip generally includes: Design, fabrication of parts, assembly and examination. (b) Gut-on-a-chip can be architecturally classified into three types, the first type one contains porous membrane, and the last two use other materials (extracellular matrix and collagen gel) as opposed to porous membrane. (c) The development of a single gut-on-a-chip. Initially, gut-on-a-chip was only able to simply culture monolayer cells. Gradually, gut-on-a-chip was able to co-culture a variety of cells and bacteria. Currently, there are a lot of sensors embedded in gut-on-a-chip, which can be analysed in real time. (d) Schematic diagram of the application of gut-on-a-chip at present. The gut-on-a-chip model is designed according to the anatomical knowledge and then applied to evaluate whether the flow velocity and shear force are in line with the physiological conditions in the human body. To make the experimental process more in line with human physiological conditions, gut-on-a-chip has been used in conjunction with other organ chips (including lung-on-a-chip, liver-on-a-chip and brain-on-a-chip). Simultaneously, each organ chip can use embedded sensors to analyse various metabolites in real time.

Figure 3.

Schematic diagram of the mechanism of three diseases related to the gut. (a) Changes in intestinal structure and composition in IBD patients. The type and quantity of intestinal microorganisms in patients change. Compared with earlier, mucus secretion decreases; on the contrary, the number of immune cells increases. (b) A schematic diagram of invasion of two types of epidemic coronaviruses of the human body. These coronaviruses recognise angiotensin-converting enzyme 2 (ACE2) receptor to infect human cells. Given that rodents do not possess this receptor, they are not suitable for applications involving the infection of these viruses. (c) A schematic diagram of the primary mechanism of Phenylketonuria (PKU). Gene mutation reduces the activity of phenylalanine hydroxylase, resulting in a large accumulation of phenylalanine in the liver. Eventually, these physiological processes will have toxic effects on the nervous system.