In Vitro Models of the Small Intestine: Engineering Challenges and Engineering Solutions

Abstract

Pathologies affecting the small intestine contribute significantly to the disease burden of both the developing and the developed world, which has motivated investigation into the disease mechanisms through in vitro models. Although existing in vitro models recapitulate selected features of the intestine, various important aspects have often been isolated or omitted due to the anatomical and physiological complexity. The small intestine's intricate microanatomy, heterogeneous cell populations, steep oxygen gradients, microbiota, and intestinal wall contractions are often not included in in vitro experimental models of the small intestine, despite their importance in both intestinal biology and pathology. Known and unknown interdependencies between various physiological aspects necessitate more complex in vitro models. Microfluidic technology has made it possible to mimic the dynamic mechanical environment, signaling gradients, and other important aspects of small intestinal biology. This review presents an overview of the complexity of small intestinal anatomy and bioengineered models that recapitulate some of these physiological aspects.

Keywords: gut-on-a-chip; microfluidic models of intestine; small intestine model; tissue engineered intestine.

FIG. 1.

Cross section of the small intestine. Color images are available online.

FIG. 2.

The crypt-villus axis. Color images are available online.

FIG. 3.

(A–E) Small intestinal cells growing on microfabricated crypt-villus structures. Reproduced with permission from Wang et al. Copyright 2017 Elsevier Ltd. Color images are available online.

FIG. 4.

(A) Three-dimensional printed villi in collagen using Caco-2 cells with HUVECs in the mesenchyme. Adapted and reprinted with permission from Kim and Kim. Copyright 2018 American Chemical Society. (B) Tube-shaped silk scaffold model containing intestinal myofibroblasts in the bulk gel and HIE-derived epithelial monolayer on the inner surface. Adapted and reproduced with permission from Chen et al. Copyright 2017 PLoS One. (C) Gut-on-a-chip device featuring two perfusable channels separated an epithelial monolayer on a permeable membrane that can be stretched by pressurizing adjacent chambers. Adapted and reproduced with permission from Kim and Ingber. Copyright 2013 Royal Society of Chemistry. (D) Human-microbial crosstalk (HuMiX) system for culturing aerobic and anaerobic bacteria in close proximity to epithelial monolayers and studying human–microbe interactions. Adapted and reproduced with permission from Shah et al. Copyright 2018 Nature. HIE, human intestinal enteroids; HUVEC, human umbilical vein endothelial cells. Color images are available online.