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cell-cell interactions. Hydrogels can effectively replicate found that intestinal organoids grown in decellularized
the microenvironment of the lungs, providing necessary intestine-derived ECM (IEM) hydrogels showed comparable
structural scaffolding and facilitating interactions between expression of core matrix protein-coding genes (Col4a2,
cells, thereby allowing a more accurate reconstruction of the Nid1, and Lama3), cytoskeleton-related genes (Flna, Gsn,
3D structure and function of lung tissue. However, while and Tuba1a), and intestinal epithelial genes involved in
hydrogels can promote the formation of organoids, further thiamine uptake (Tm4sf4) to those of the original intestinal
studies are needed to determine whether they can maintain tissues. In addition, IEM organoids expressed genes
the functional integrity and viability of alveolar epithelial associated with wound healing, inflammation, and immune
cells after transplantation into animal models. This involves response (Procr, Mcpt2, Icam1, Cxcl10, Cxcl16, and Timp3)
investigating the biodegradability of hydrogels in vivo and at levels similar to the original intestinal tissue (Figure 4B),
their ability to provide long-term support to the cells. helping to maintain intestinal barrier homeostasis under
physiological conditions. Overall, gastrointestinal tissue-
4.3. Digestive system
derived ECM hydrogels can effectively replace Matrigel
4.3.1. Gastrointestinal tract in gastrointestinal organoid culture. This alternative has
The primary functions of the gastrointestinal tract are similar properties to native gastrointestinal tissue, providing
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digestion, absorption, excretion, and protection. It a more reliable and repeatable experimental platform for
develops from the endoderm into the foregut, midgut, gastrointestinal research. This work, through proteomic
and hindgut. The foregut develops into the pharynx, analysis, has identified key matrix components necessary for
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esophagus, and stomach, the midgut develops into the small the development of organoids, providing novel insights into
intestine and part of the colon, and the hindgut develops the hydrogels required for organoid cultivation. In addition,
into the colon, rectum, and anus. 108,109 The stomach begins it has addressed the issues of batch-to-batch variation,
forming around week 4, with differentiation of its upper safety concerns, and high costs associated with traditional
and lower regions. Its curvature and rotation establish its Matrigel, paving the way for potential commercialization
final morphology. By the 8 week, the basic structures and clinical applications in humans.
th
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of the small and large intestines are established, followed
by the differentiation of glands and mucosa. The immune 4.3.2. Liver
system of the gastrointestinal tract, including gut-associated The liver is primarily composed of hepatocytes and biliary
lymphoid tissue, continues to develop post-natal to protect epithelial cells working in conjunction with stromal cells,
the body from pathogens. The intestinal epithelium endothelial cells, and mesenchymal cells to perform vital
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undergoes multiple cycles of cell turnover in the crypts metabolic and endocrine functions. Hepatocytes and
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and villi of the small intestine. Sato et al. pioneered the biliary epithelial cells are differentiated from hepatic
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use of Lgr5 ISCs, cultivated on a laminin-enriched matrix progenitor cells (embryonic liver pre-cursors) during
+
and supplemented with EGF, Wnt agonist R-spondin 1, organ development. Different cell types are strategically
and Notch agonist peptides. This approach led to the self- organized at specific locations along the liver lobules,
renewing epithelial structures formation, marking the essential for their individual functions and those of other
inception of organoid technology for the intestine. 23 cell types. 114,115 Hepatocytes are arranged in cord-like
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Kim et al. utilized gastrointestinal tissue ECM structures radiating from the central vein toward the portal
hydrogels as an alternative to cultured gastrointestinal vein. These polarized epithelial cells possess tight junctions
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organoids (Figure 4A). By analyzing the composition and distinct polarity structures critical for their function.
and proteomics of ECM, the researchers found that Bile is collected by tightly connected bile canaliculi, flowing
gastrointestinal tissue-derived ECM hydrogels have highly in the opposite direction to blood and draining through the
similar properties compared to non-gastrointestinal bile ducts. Given this complexity, in vivo, the generation
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Matrigel. They also compared the morphology, formation of organized lobular structures with multiple liver functions
efficiency, organ-specific gene expression levels, and is challenging, particularly the long-standing issue of
functionality of gastrointestinal organoids cultured in ECM culturing and expanding primary hepatocytes (PHs) while
hydrogels versus Matrigel. The results showed that when maintaining liver functions. 117
examining expression levels of gastric epithelial cell markers
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(main cell markers Pgc and parietal cell markers Atp4a and Wang et al. introduced a novel method for the one-
Atp4b) from organoid tissues cultured in decellularized step fabrication of composite hydrogel capsules, based
stomach-derived ECM (SEM) hydrogel, the expression of Pgc on interfacial complexation between oppositely charged
and Atp4a was comparable to that of organoids in Matrigel, sodium alginate and chitosan, for engineering stem cell-
while the expression of Atp4b was higher in organoids derived organoids in an oil-free microfluidic system
cultured in SEM hydrogels. Furthermore, the researchers (Figure 4C). This system enables continuous 3D culture,

Volume 1 Issue 2 (2025) 12 doi: 10.36922/or.8262