Gut bioengineering promotes gut repair and pharmaceutical research: a review

Abstract

The gastrointestinal (GI) tract has a diverse set of physiological functions, including peristalsis, immune defense, and nutrient absorptions. These functions are mediated by various intestinal cells such as epithelial cells, interstitial cells, smooth muscle cells, and neurocytes. The loss or dysfunction of specific cells directly results in GI disease, while supplementation of normal cells promotes gut healing. Gut bioengineering has been developing for this purpose to reconstruct the damaged tissues. Moreover, GI tract provides an accessible route for drug delivery, but the collateral damages induced by side effects cannot be ignored. Bioengineered intestinal tissues provide three-dimensional platforms that mimic the in vivo environment to study drug functions. Given the importance of gut bioengineering in current research, in this review, we summarize the advances in the technologies of gut bioengineering and their applications. We were able to identify several ground-breaking discoveries in our review, while more work is needed to promote the clinical translation of gut bioengineering.

Keywords: Gut bioengineering; gut repair; lab on a chip; organoids; pharmaceutical research; stem cells.

Figure 1.

Techniques of gut bioengineering. (a) Three main types of tissue scaffolds: decellularized scaffolds, biologically derived hydrogels, and synthetic scaffolds. (b) Decellularized scaffolds promote healing of damaged gut based on their cell recruitment ability. (c) Specific cells can be laden by tissue scaffolds to repair injured gut. (d) Intestinal organoids that mimic gut anatomy and physiology are constructed to treat defects in intestinal tissues. (e) The application methods of intestinal organoids in gut repair. ESCs: embryonic stem cells; ISCs: intestinal stem cells; PSC: pluripotent stem cells.

Figure 2.

Regulation of intestinal organoid formation by different growth factors. (a) The biomolecule-signaling pathway-effect axis during construction of intestinal organoids. Arrows show activation of signaling pathway. Lines without arrowheads show inhibition of the signaling pathway. (b) Integration of several specific growth factors determines the differentiation direction of stem cells by regulating Wnt and Notch signaling pathways. For example, activation of Wnt and Notch signaling pathways causes self-renewal of stem cells. Inhibition of Wnt signaling pathway by IWP-2 leads to differentiation of enterocytes (VIL1+), while inhibition of Notch signaling pathway by DAPT leads to differentiation of other cell types such as goblet cells (MUC2+), enteroendocrine cells (CHGA+), and Paneth cells (DEFA5+) depending on the subsequent switch of Wnt signaling pathway. CHIR: CHIR99021; IL-2: interleukin-2; VPA: valproic acid.

Figure 3.

Existing cellular microdevices for drug screening and their features. (a) The traditional Transwell plate for 2D culture of Caco-2 cells. (b) The modified Transwell plate containing villus-shaped hydrogels for 3D culture of Caco-2 cells. (c) The 3D culture of intestinal organoids. (d) The Caco-2 cells can polarize and differentiate into a columnar epithelium with the appearance of intestinal villi when cultured on the mechanically relevant chip. (e) The modified gut-on-a-chip containing villus-shaped hydrogels for 3D culture of Caco-2 cells. (f) The various cells from intestinal organoids can polarize and assemble as the finger-like villi when cultured on the chip. Arrows in the same color represent the in vitro intestinal models before and after integration of microfluidic chip (the schematic diagram of microfluidic chip was from Kasendra et al.).