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International Journal of Bioprinting Coronavirus-infected bioprinted intestine

For example, the pH and oxygen gradients generated along on-chip models have been used to investigate hepatitis B
the crypt–villus connection give rise to different microbial virus life cycle and immune responses, while kidney distal
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compositions and distributions at the crypt and the villus tubule-on-chip models have been utilized to explore renal
tip, resulting in locally different signaling outcomes dysfunction induced by Pseudorabies virus. In light of the
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and physiology. Introducing villi structures to in vitro ability of SARS-CoV-2 to infect multiple organs and cause
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platforms induces significant changes in the physiological diverse symptoms, organ-on-chip models have been
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traits of cultured epithelial cells, ultimately impacting employed to replicate SARS-CoV-2 infection in relevant
pathogen–host cell interactions. We have previously human tissues. Lung-on-chip models demonstrated the
shown that gut epithelial cells cultured on 3D villi protect efficacy of remdesivir in inhibiting viral replication and
themselves against the bacterial pathogen Salmonella preserving alveolar barrier integrity, while liver-on-chip
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typhimurium infections through increased production models shed light on liver pathophysiology in COVID-19
of mucin 17 (MUC17), which is not observed in 2D patients. Additionally, organ-on-chip models have been
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cultured cells. By incorporating 3D villi structures into utilized to study other human coronavirus infections such
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intestine-on-chip models, researchers can better mimic as HCoV-NL63 and its impact on endothelial barrier
the physiological characteristics of the human intestine function, VE–cadherin junctions, and pro-inflammatory
and gain insights into the complex interactions between cytokine levels. These findings highlight the immense
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pathogens and the intestinal epithelium. potential of organ-on-chip models in advancing our
Mechanical stress is pivotal in replicating the dynamics understanding of viral infections in the intestine and
of pathogen infections on an intestine-on-chip platform. other organs.
The gastrointestinal tract is continuously subjected to a Intestine-on-chip models have shown promising
myriad of mechanical forces, such as strains and shear stress potential in studying viral infections in the intestinal
due to gut motility. Such forces have profound implications context, although the number of studies remains limited
on the physiology and functionality of in vitro intestinal (Figure 3B). Villenave et al. conducted an investigation
epithelial cells. 50-55 Influences extend to aspects like mucus using a human gut-on-chip model infected with Coxsackie
secretion, barrier fortitude, cytoskeletal arrangement, B1 virus, an enterovirus strain, revealing polarized
mitochondrial operations, drug processing, and the infection dynamics (Figure 3C). The study demonstrated
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development of microvilli—all of which can potentially that viral infection primarily occurred on the apical side
modulate pathogen–host dynamics. For instance, Kim of polarized intestinal epithelial cells, while the basolateral
et al. exposed gut epithelial cells to mechanical stimuli, side exhibited reduced viral titers, diminished cytopathic
encompassing cyclic strain and fluidic shear. This exposure effects, and delayed caspase-3 activation. Notably, virus
culminated in the emergence of villi structures, creating release and cytokine release were predominantly observed
an environment that mirrored in vivo gut conditions. on the apical side, underscoring the relevance of the
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Capitalizing on this device with primary human cells, they intestine-on-chip model for studying viral behaviors and
further unveiled that an upsurge in certain microbiome infection mechanisms in the intestinal context.
metabolites heightens the human susceptibility to infections Although the number of studies incorporating human
from enterohemorrhagic Escherichia coli (EHEC). Such coronavirus strains in intestine-on-chip models remains
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revelations underscore the value of the intestine-on-chip limited, recent efforts have aimed to fill this gap (Figure
approach, asserting its capability to emulate a setting 3D and E). Bein et al. infected an intestine-on-chip model
where bacterial interactions with intestinal epithelial cells with HCoV-NL63, a surrogate for SARS-CoV-2, and
are physiologically akin to real-life scenarios.
tested drug candidates while assessing their effects on the
In the future, intestine-on-chip platforms incorporated inflammatory responses induced by infection. They also
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with multiple cell types, including epithelial cells, immune demonstrated a significant increase in the expression of
cells, and microbiota, hold promise for investigating ACE2, the binding receptor for SARS-CoV-2, in intestine-
host–pathogen interactions, understanding the effects on-chip conditions, which closely resembles the in vivo
of parasitic infections on barrier integrity and immune environment for viral infection. Similarly, Guo et al.
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responses, and exploring the modulation of the gut infected an intestine-on-chip model with SARS-CoV-2
microbiota during infection. and employed transcriptomic analysis to investigate
abnormal RNA and protein metabolism, as well as activated
4.2. Intestine-on-chip for human immune responses in intestinal epithelial and endothelial
coronavirus infection cells following infection. These studies illustrate the
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Organ-on-chip platforms have been extensively used to ongoing progress in utilizing intestine-on-chip models
study viral infections in various human organs. 58,59 Liver- for studying viral infections, including those caused by

Volume 10 Issue 2 (2024) 171 doi: 10.36922/ijb.1704