Human stomach-on-a-chip with luminal flow and peristaltic-like motility

Abstract

Current in vitro approaches and animal models have critical limitations for modeling human gastrointestinal diseases because they may not properly represent multicellular human primary tissues. Therefore, there is a need for model platforms that recapitulate human in vivo development, physiology, and disease processes to validate new therapeutics. One of the major steps toward this goal was the generation of three-dimensional (3D) human gastric organoids (hGOs) via the directed differentiation of human pluripotent stem cells (hPSCs). The normal functions and diseases of the stomach occur in the luminal epithelium, however accessing the epithelium on the inside of organoids is challenging. We sought to develop a bioengineered platform to introduce luminal flow through hGOs to better model in vivo gastric functions. Here, we report an innovative microfluidic imaging platform housing hGOs with peristaltic luminal flow in vitro. This human stomach-on-a-chip allows robust, long-term, 3D growth of hGOs with the capacity for luminal delivery via a peristaltic pump. Organoids were cannulated and medium containing fluorescent dextran was delivered through the lumen using a peristaltic pump. This system also allowed us to rhythmically introduce stretch and contraction to the organoid, reminiscent of gastric motility. Our platform has the potential for long-term delivery of nutrients or pharmacological agents into the gastric lumen in vitro for the study of human gastric physiology, disease modeling, and drug screening, among other possibilities.

Spatiotemporal Gradient and Instability of Wnt Induce Heterogeneous Growth and Differentiation of Human Intestinal Organoids

“…Indeed, there has been a report that suggests making multiple Matrigel drops ( Stewart et al, 2020 ), where our study explains why this approach is important. A microphysiological system may be also contemplated to maintain the steady-state Wnt concentration to the organoids introduced in the microdevice, which may, in part, resolve the diffusion limitation issue ( Jin et al., 2014 ; Lee et al., 2018 ).…”

Biomedical Application of Functional Materials in Organ-on-a-Chip

“…Microfluidic technology provides a way to simulate spatiotemporal chemical gradients, dynamic mechanical forces, and critical tissue interfaces by manipulation of fluids at micro levels. OOC systems that can recreate key aspects of the complex physiological microenvironment of human lung (Huh et al, 2010), heart (Maoz et al, 2017), stomach (Lee K. K. et al, 2018), intestine (Kim et al, 2016), liver (Weng et al, 2017), kidney (Sateesh et al, 2018), blood vessels (Wang et al, 2015), etc., have been developed. Moreover, multi-organs-on-a-chip or body-on-a-chip systems have been proposed (Sung et al, 2019;Zhao et al, 2019a).…”

Long-term flow through human intestinal organoids with the gut organoid flow chip (GOFlowChip)

“…Short-term luminal flow has been established through human gastric organoids (HGOs) for tens of minutes; 19 however, to perform physiologically relevant experiments such as real-time monitoring and control of luminal contents, luminal flow must be established for multiple days, and extending flow time by more than two orders of magnitude presents significant engineering challenges. For example, the flow of biological media in millifluidic devices is plagued by the formation of bubbles, which disrupt the luminal space and interfere with organoid imaging.…”

“…82,83 The use of intact, preformed organoids precludes the use of artificial scaffolding and allows the tissue culture to form in an environment more representative of in vitro conditions before integration into the chip; however, for gastrointestinal organoids, access to the luminal space remains challenging. Short-term luminal flow has been established through human gastric organoids (HGOs), 19 but the time scale of flow has been limited, and the impact of luminal flow on organoid viability is not clear. A fluidic device capable of establishing long-term flow through gastrointestinal organoids is still needed.…”