Abstract
The regeneration of the mucosal interface of the human intestine is critical in the host–gut microbiome crosstalk associated with gastrointestinal diseases. The biopsy-derived intestinal organoids provide genetic information of patients with physiological cytodifferentiation. However, the enclosed lumen and static culture condition substantially limit the utility of patient-derived organoids for microbiome-associated disease modeling. Here, we report a patient-specific three-dimensional (3D) physiodynamic mucosal interface-on-a-chip (PMI Chip) that provides a microphysiological intestinal milieu under defined biomechanics. The real-time imaging and computational simulation of the PMI Chip verified the recapitulation of non-linear luminal and microvascular flow that simulates the hydrodynamics in a living human gut. The multiaxial deformations in a convoluted microchannel not only induced dynamic cell strains but also enhanced particle mixing in the lumen microchannel. Under this physiodynamic condition, an organoid-derived epithelium obtained from the patients diagnosed with Crohn’s disease, ulcerative colitis, or colorectal cancer independently formed 3D epithelial layers with disease-specific differentiations. Moreover, co-culture with the human fecal microbiome in an anoxic–oxic interface resulted in the formation of stochastic microcolonies without a loss of epithelial barrier function. We envision that the patient-specific PMI Chip that conveys genetic, epigenetic, and environmental factors of individual patients will potentially demonstrate the pathophysiological dynamics and complex host–microbiome crosstalk to target a patient-specific disease modeling.
Highlights
The gastrointestinal (GI) epithelial barrier is a physical interface that undergoes constant exposures to the exogenous molecules and antigens
The recreation of an intestinal mucosal interface in vitro is important to demonstrate pathophysiological responses at various GI diseases to predict the immunomodulatory effect of the gut microbiome [2] or validate drug effectiveness [3]
We report a 3D physiodynamic mucosal interface-on-a-chip (PMI Chip) that provides a technical foundation to build the patient-specific models of major human chronic GI disease such as inflammatory bowel disease (IBD), including Crohn’s disease (CD), ulcerative colitis (UC), and colorectal cancer (CRC)
Summary
The gastrointestinal (GI) epithelial barrier is a physical interface that undergoes constant exposures to the exogenous molecules and antigens (i.e., pathogens, nutrients, or toxins). The implementability of the gut-on-a-chip has been improved by integrating human intestinal organoids that reflect the patient’s genetic heritage [17,18], disease pathophysiology [19], and host–gut microbiome interactions [20] This integrative strategy is important for disease modeling because the recreation of mucosal tissue interface using patient’s samples allows us to deploy individual disease factors (e.g., dysbiotic gut microbiome, activated immune cells) in a defined space and time. It has been challenging to standardize and disseminate the microphysiological system (MPS)-based disease modeling, because the culture protocol and device manufacturing are technically nascent [21,22] Advanced features such as in vivo-like hydrodynamic flow [23,24,25], multiaxial mechanical deformations [26,27], controlled oxygen gradient in a mucosal interface [28], and robust co-culture with anaerobic gut bacteria [29] are essentially required
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