Development of a Gut-on-a-Chip Model for High Throughput Disease Modeling and Drug Discovery

Abstract

A common bottleneck in any drug development process is finding sufficiently accurate models that capture key aspects of disease development and progression. Conventional drug screening models often rely on simple 2D culture systems that fail to recapitulate the complexity of the organ situation. In this study, we show the application of a robust high throughput 3D gut-on-a-chip model for investigating hallmarks of inflammatory bowel disease (IBD). Using the OrganoPlate platform, we subjected enterocyte-like cells to an immune-relevant inflammatory trigger in order to recapitulate key events of IBD and to further investigate the suitability of this model for compound discovery and target validation activities. The induction of inflammatory conditions caused a loss of barrier function of the intestinal epithelium and its activation by increased cytokine production, two events observed in IBD physiopathology. More importantly, anti-inflammatory compound exposure prevented the loss of barrier function and the increased cytokine release. Furthermore, knockdown of key inflammatory regulators RELA and MYD88 through on-chip adenoviral shRNA transduction alleviated IBD phenotype by decreasing cytokine production. In summary, we demonstrate the routine use of a gut-on-a-chip platform for disease-specific aspects modeling. The approach can be used for larger scale disease modeling, target validation and drug discovery purposes.

Drug Toxicity Evaluation Based on Organ-on-a-chip Technology: A Review

“…They used the device to test the metabolic capacity of verapamil and isofluamide, and the results showed that intestinal cells had high levels of CYP450 enzyme expression, which enhanced the metabolism of oral drugs. Claudia et al constructed a high-throughput intestinal chip device to mimic inflammatory bowel disease (IBD) in vitro ( Figure 5A) [122]. Inhibition of crucial inflammation regulators RELA and MYD88 by on-chip adenovirus short hairpin RNA (shRNA) transduction can reduce the IBD phenotype by reducing cytokine production.…”

“…Some other-organ-on-a-chip systems for drug toxicity testing. (A) Schematic representation of the 3-lane OrganoPlate gut-on-a-chip model[122]. (B) A microengineered model of human pulmonary edema[127].…”

Direct On-Chip Differentiation of Intestinal Tubules from Induced Pluripotent Stem Cells

“…In-vitro models that closely mimic the human intestinal epithelium and its physiology are important tools for drug development processes [ 1 , 2 , 3 ]. As oral drug delivery is the preferred route of administration [ 4 ], such models have enormous potential to improve and speed up studies of absorption [ 5 ], disease modelling [ 6 ], drug metabolism and interactions as well as associated toxicity [ 7 , 8 ]. Therefore, patient-specific absorption models that take the gut complexity, passive and active transport and patient variability into consideration could be highly valuable in the evaluation of candidate drugs [ 9 ].…”

3D bioprinted breast tumor model for structure–activity relationship study

“…Adoption of new techniques in the drug discovery pipeline has been regarded as a solution to this serious issue. Typically, artificial intelligence [1], cell spheroid model [2], organ-on-a-chip [3], organoid [4], 3D bioprinting [5], and similar techniques have been gradually merged into the pharmaceutical industry to increase the efficiency of drug discovery. Among them, the 3D bioprinting technique offers highly biomimetic in vitro models and has attracted considerable attention.…”