REFERENCES
1. Willet, S. G.; Mills, J. C. Stomach organ and cell lineage differentiation: from embryogenesis to adult homeostasis. Cell. Mol. Gastroenterol. Hepatol. 2016, 2, 546-59.
2. Hunt, R. H.; Camilleri, M.; Crowe, S. E.; et al. The stomach in health and disease. Gut 2015, 64, 1650-68.
3. Malfertheiner, P.; Camargo, M. C.; El-Omar, E.; et al. Helicobacter pylori infection. Nat. Rev. Dis. Primers. 2023, 9, 19.
4. Bray, F.; Laversanne, M.; Sung, H.; et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA. Cancer. J. Clin. 2024, 74, 229-63.
5. Khatoon, A.; Sachan, V.; Kori, P.; Khushtar, M.; Pujari, N. M. Current practices and emerging technologies in animal models for gastric ulcer research. JDDHS 2024, 1, 153-60.
6. Hou, N.; Du, X.; Wu, S. Advances in pig models of human diseases. Animal. Model. Exp. Med. 2022, 5, 141-52.
7. Ansari, S.; Yamaoka, Y. Animal models and Helicobacter pylori Infection. J. Clin. Med. 2022, 11, 3141.
8. Weingarden, A. R. Strengths and limitations of in vitro and animal models to advance understanding of human diet-microbiome interactions. Gut. Microbes. Rep. 2026, 3, 2636336.
9. Pan, Y.; Zhao, L.; Fang, J. Animal models and pathogenesis of gastric cancer: from premalignant conditions-to-metastasis. Cancer. Biol. Med. 2026, 23, 637-56.
10. Barranco, S. C.; Weintraub, B.; MacLean, K. K.; Beasley, E. G.; Jenkins, V. K.; Jr Townsend, C. M. Relationship between glutathione levels and drug or radiation sensitivities in human gastric cancer cell lines in vitro. Invest. New. Drugs. 1991, 9, 29-36.
11. Kim, K. J.; Zhong, H.; Tai, D.; et al. Microbiome signatures in advanced gastric cancer: emerging biomarkers for risk stratification, therapy guidance, and prognostic insight. Int. J. Mol. Sci. 2026, 27, 1452.
12. Seidlitz, T.; Koo, B. K.; Stange, D. E. Gastric organoids-an in vitro model system for the study of gastric development and road to personalized medicine. Cell. Death. Differ. 2021, 28, 68-83.
13. Lee, S.; Choi, J. H.; Park, S. Y.; Kim, J. Gastric organoid, a promising modeling for gastric stem cell homeostasis and therapeutic application. Int. J. Stem. Cells. 2024, 17, 337-46.
14. Mu, X.; Wang, L.; Pang, M.; et al. Exploring the applications of gastric organoids in disease modeling and personalized medicine. Gastrointestinal. Tumors. 2025, 12, e013.
16. Chang, Y.; Chen, T.; Geng, S.; et al. A scenario-adaptive microfluidic chip for constructing in vitro models of biological barriers. Anal. Chem. 2025, 97, 3816-21.
17. Jantaree, P.; Bakhchova, L.; Steinmann, U.; Naumann, M. From 3D back to 2D monolayer stomach organoids-on-a-chip. Trends. Biotechnol. 2021, 39, 745-8.
18. Carvalho, M. R.; Yan, L. P.; Li, B.; et al. Gastrointestinal organs and organoids-on-a-chip: advances and translation into the clinics. Biofabrication 2023, 15, 042004.
19. Barker, N.; Huch, M.; Kujala, P.; et al. Lgr5(+ve) stem cells drive self-renewal in the stomach and build long-lived gastric units in vitro. Cell. Stem. Cell. 2010, 6, 25-36.
20. McCracken, K. W.; Catá, E. M.; Crawford, C. M.; et al. Modelling human development and disease in pluripotent stem-cell-derived gastric organoids. Nature 2014, 516, 400-4.
21. Yan, H. H. N.; Siu, H. C.; Law, S.; et al. A comprehensive human gastric cancer organoid biobank captures tumor subtype heterogeneity and enables therapeutic screening. Cell. Stem. Cell. 2018, 23, 882-897.e11.
22. Lee, K. K.; McCauley, H. A.; Broda, T. R.; Kofron, M. J.; Wells, J. M.; Hong, C. I. Human stomach-on-a-chip with luminal flow and peristaltic-like motility. Lab. Chip. 2018, 18, 3079-85.
23. Jeong, H. J.; Park, J. H.; Kang, J. H.; Sabaté, Del. Río. J.; Kong, S. H.; Park, T. E. Organoid-based human stomach micro-physiological system to recapitulate the dynamic mucosal defense mechanism. Adv. Sci. (Weinh). 2023, 10, e2300164.
24. Hofer, M.; Kim, Y.; Broguiere, N.; et al. Accessible homeostatic gastric organoids reveal secondary cell type-specific host-pathogen interactions in Helicobacter pylori infections. Nat. Commun. 2025, 16, 2767.
25. Karam, S. M.; Leblond, C. P. Identifying and counting epithelial cell types in the “corpus” of the mouse stomach. Anat. Rec. 1992, 232, 231-46.
26. Lee, E. R.; Trasler, J.; Dwivedi, S.; Leblond, C. P. Division of the mouse gastric mucosa into zymogenic and mucous regions on the basis of gland features. Am. J. Anat. 1982, 164, 187-207.
27. Karam, S. M.; Leblond, C. P. Dynamics of epithelial cells in the corpus of the mouse stomach. I. Identification of proliferative cell types and pinpointing of the stem cell. Anat. Rec. 1993, 236, 259-79.
28. Karam, S. M.; Leblond, C. P. Dynamics of epithelial cells in the corpus of the mouse stomach. II. Outward migration of pit cells. Anat. Rec. 1993, 236, 280-96.
29. Karam, S. M.; Leblond, C. P. Dynamics of epithelial cells in the corpus of the mouse stomach. III. Inward migration of neck cells followed by progressive transformation into zymogenic cells. Anat. Rec. 1993, 236, 297-313.
30. Karam, S. M.; Leblond, C. P. Dynamics of epithelial cells in the corpus of the mouse stomach. V. Behavior of entero-endocrine and caveolated cells: general conclusions on cell kinetics in the oxyntic epithelium. Anat. Rec. 1993, 236, 333-40.
31. Lee, E. R.; Leblond, C. P. Dynamic histology of the antral epithelium in the mouse stomach: II. Ultrastructure and renewal of isthmal cells. Am. J. Anat. 1985, 172, 205-24.
32. Tsai, H. F.; Hsu, P. N. Interplay between Helicobacter pylori and immune cells in immune pathogenesis of gastric inflammation and mucosal pathology. Cell. Mol. Immunol. 2010, 7, 255-9.
33. Malfertheiner, P.; Link, A.; Selgrad, M. Helicobacter pylori: perspectives and time trends. Nat. Rev. Gastroenterol. Hepatol. 2014, 11, 628-38.
34. Yuan, Y.; Padol, I. T.; Hunt, R. H. Peptic ulcer disease today. Nat. Clin. Pract. Gastroenterol. Hepatol. 2006, 3, 80-9.
35. Watanabe, T.; Higuchi, K.; Tanigawa, T.; Tominaga, K.; Fujiwara, Y.; Arakawa, T. Mechanisms of peptic ulcer recurrence: role of inflammation. Inflammopharmacology 2002, 10, 291-302.
36. Almadi, M. A.; Lu, Y.; Alali, A. A.; Barkun, A. N. Peptic ulcer disease. Lancet 2024, 404, 68-81.
37. Polk, D. B.; Peek, R. M. Jr. Helicobacter pylori: gastric cancer and beyond. Nat. Rev. Cancer. 2010, 10, 403-14.
38. Wizenty, J.; Sigal, M. Helicobacter pylori, microbiota and gastric cancer - principles of microorganism-driven carcinogenesis. Nat. Rev. Gastroenterol. Hepatol. 2025, 22, 296-313.
39. Zavros, Y.; Merchant, J. L. The immune microenvironment in gastric adenocarcinoma. Nat. Rev. Gastroenterol. Hepatol. 2022, 19, 451-67.
40. Tan, Y.; Matsuzaki, J.; Saito, Y.; Suzuki, H. Environmental factors in gastric carcinogenesis and preventive intervention strategies. Genes. Environ. 2025, 47, 5.
41. Bartfeld, S.; Bayram, T.; van, de. Wetering. M.; et al. In vitro expansion of human gastric epithelial stem cells and their responses to bacterial infection. Gastroenterology 2015, 148, 126-136.e6.
42. Gifford, G. B.; Demitrack, E. S.; Keeley, T. M.; et al. Notch1 and Notch2 receptors regulate mouse and human gastric antral epithelial cell homoeostasis. Gut 2017, 66, 1001-11.
43. McCracken, K. W.; Aihara, E.; Martin, B.; et al. Wnt/β-catenin promotes gastric fundus specification in mice and humans. Nature 2017, 541, 182-7.
44. Broda, T. R.; McCracken, K. W.; Wells, J. M. Generation of human antral and fundic gastric organoids from pluripotent stem cells. Nat. Protoc. 2019, 14, 28-50.
45. Miao, Z. F.; Adkins-Threats, M.; Burclaff, J. R.; et al. A metformin-responsive metabolic pathway controls distinct steps in gastric progenitor fate decisions and maturation. Cell. Stem. Cell. 2020, 26, 910-925.e6.
46. Li, X.; Lin, F.; Cui, Q.; et al. Human gastroids to model regional patterning in early stomach development. Nature 2025, 646, 893-902.
47. Stange, D. E.; Koo, B. K.; Huch, M.; et al. Differentiated Troy+ chief cells act as reserve stem cells to generate all lineages of the stomach epithelium. Cell 2013, 155, 357-68.
48. Wroblewski, L. E.; Piazuelo, M. B.; Chaturvedi, R.; et al. Helicobacter pylori targets cancer-associated apical-junctional constituents in gastroids and gastric epithelial cells. Gut 2015, 64, 720-30.
49. Bertaux-Skeirik, N.; Feng, R.; Schumacher, M. A.; et al. CD44 plays a functional role in Helicobacter pylori-induced epithelial cell proliferation. PLoS. Pathog. 2015, 11, e1004663.
50. Holokai, L.; Chakrabarti, J.; Broda, T.; et al. Increased programmed death-ligand 1 is an early epithelial cell response to Helicobacter pylori infection. PLoS. Pathog. 2019, 15, e1007468.
51. Tan, P.; Yeoh, K. G. Genetics and molecular pathogenesis of gastric adenocarcinoma. Gastroenterology 2015, 149, 1153-1162.e3.
52. Zhao, H.; Cheng, Y.; Kalra, A.; et al. Generation and multiomic profiling of a TP53/CDKN2A double-knockout gastroesophageal junction organoid model. Sci. Transl. Med. 2022, 14, eabq6146.
53. Lo, Y. H.; Horn, H. T.; Huang, M. F.; et al. Large-scale CRISPR screening in primary human 3D gastric organoids enables comprehensive dissection of gene-drug interactions. Nat. Commun. 2025, 16, 7566.
54. Genome Atlas Research Network. Comprehensive molecular characterization of gastric adenocarcinoma. Nature 2014, 513, 202-9.
55. Seidlitz, T.; Merker, S. R.; Rothe, A.; et al. Human gastric cancer modelling using organoids. Gut 2019, 68, 207-17.
56. Vlachogiannis, G.; Hedayat, S.; Vatsiou, A.; et al. Patient-derived organoids model treatment response of metastatic gastrointestinal cancers. Science 2018, 359, 920-6.
57. Ma, J.; Liu, X.; Xu, H.; Jiang, C. Patient-derived organoids in gastric cancer: bridging the tumor microenvironment to functional precision oncology. Front. Bioeng. Biotechnol. 2026, 14, 1790902.
58. Nanki, K.; Toshimitsu, K.; Takano, A.; et al. Divergent routes toward Wnt and R-spondin niche independency during human gastric carcinogenesis. Cell 2018, 174, 856-869.e17.
59. Xu, Z. Y.; Tang, J. N.; Xie, H. X.; et al. 5-fluorouracil chemotherapy of gastric cancer generates residual cells with properties of cancer stem cells. Int. J. Biol. Sci. 2015, 11, 284-94.
60. Ukai, S.; Honma, R.; Sakamoto, N.; et al. Molecular biological analysis of 5-FU-resistant gastric cancer organoids; KHDRBS3 contributes to the attainment of features of cancer stem cell. Oncogene 2020, 39, 7265-78.
61. Wong, T. L.; Loh, J. J.; Lu, S.; et al. ADAR1-mediated RNA editing of SCD1 drives drug resistance and self-renewal in gastric cancer. Nat. Commun. 2023, 14, 2861.
62. Zhao, Y.; Li, S.; Zhu, L.; et al. Personalized drug screening using patient-derived organoid and its clinical relevance in gastric cancer. Cell. Rep. Med. 2024, 5, 101627.
63. McDonald, H. G.; Harper, M. M.; Hill, K.; et al. Creation of EGD-derived gastric cancer organoids to predict treatment responses. Cancers. (Basel). 2023, 15, 3036.
64. Jones, B. C.; Benedetti, G.; Calà, G.; et al. Human gastric multi-regional assembloids for functional parietal maturation and patient-specific modelling of antral foveolar hyperplasia. Nat. Biomed. Eng. 2026.
66. Zhang, B.; Korolj, A.; Lai, B. F. L.; Radisic, M. Advances in organ-on-a-chip engineering. Nat. Rev. Mater. 2018, 3, 257-78.
67. Zhao, Y.; Landau, S.; Okhovatian, S.; et al. Integrating organoids and organ-on-a-chip devices. Nat. Rev. Bioeng. 2024, 2, 588-608.
68. Li, L.; Lieleg, O.; Jang, S.; Ribbeck, K.; Han, J. A microfluidic in vitro system for the quantitative study of the stomach mucus barrier function. Lab. Chip. 2012, 12, 4071-9.
69. Bakhchova, L.; Jantaree, P.; Gupta, A.; Isermann, B.; Steinmann, U.; Naumann, M. On-a-chip-based sensitive detection of drug-induced apoptosis in polarized gastric epithelial cells. ACS. Biomater. Sci. Eng. 2021, 7, 5474-83.
70. Hofer, M.; Duque-Correa, M. A.; Lutolf, M. P. Patterned gastrointestinal monolayers with bilateral access as observable models of parasite gut infection. Nat. Biomed. Eng. 2025, 9, 1075-85.
71. Ferreira, D. A.; Conde, J. P.; Rothbauer, M.; Ertl, P.; Granja, P. L.; Oliveira, C. Bioinspired human stomach-on-a-chip with in vivo like function and architecture. Lab. Chip. 2023, 23, 495-510.
72. Xiang, H.; Chen, F.; Dong, Z.; et al. A microfluidic tumor-on-chip platform deciphers hypoxia-driven FOXO3a/PD-L1 signaling in gastric cancer immunotherapy resistance. Mater. Today. Bio. 2025, 33, 101925.
73. Kim, J.; Kim, J.; Gao, G.; et al. Bioprinted organoids platform with tumor vasculature for implementing precision personalized medicine targeted towards gastric cancer. Adv. Funct. Mater. 2024, 34, 2306676.
74. Jin, Y.; Kim, J.; Lee, J. S.; et al. Vascularized liver organoids generated using induced hepatic tissue and dynamic liver-specific microenvironment as a drug testing platform. Adv. Funct. Mater. 2018, 28, 1801954.
75. Laine, L.; Takeuchi, K.; Tarnawski, A. Gastric mucosal defense and cytoprotection: bench to bedside. Gastroenterology 2008, 135, 41-60.
76. Sáenz, J. B.; Mills, J. C. Acid and the basis for cellular plasticity and reprogramming in gastric repair and cancer. Nat. Rev. Gastroenterol. Hepatol. 2018, 15, 257-73.
78. Niikura, R.; Hayakawa, Y.; Nagata, N.; et al. Non-Helicobacter pylori gastric microbiome modulates prooncogenic responses and is associated with gastric cancer risk. Gastro. Hep. Adv. 2023, 2, 684-700.
79. Meng, L.; Fan, L.; Rao, S.; et al. Primary human gastric cancer cells integrated hydrogel microcapsules for personalized drug screening. ACS. Appl. Mater. Interfaces. 2026, 18, 7900-9.
80. Ingber, D. E. Human organs-on-chips for disease modelling, drug development and personalized medicine. Nat. Rev. Genet. 2022, 23, 467-91.
81. Huang, Y.; Liu, T.; Huang, Q.; Wang, Y. From organ-on-a-chip to human-on-a-chip: a review of research progress and latest applications. ACS. Sens. 2024, 9, 3466-88.
82. Pan, F. C.; Evans, T.; Chen, S. Modeling endodermal organ development and diseases using human pluripotent stem cell-derived organoids. J. Mol. Cell. Biol. 2020, 12, 580-92.
83. Berthier, E.; Young, E. W.; Beebe, D. Engineers are from PDMS-land, biologists are from Polystyrenia. Lab. Chip. 2012, 12, 1224-37.
84. van, Meer. B. J.; de, Vries. H.; Firth, K. S. A.; et al. Small molecule absorption by PDMS in the context of drug response bioassays. Biochem. Biophys. Res. Commun. 2017, 482, 323-8.
85. Vandereyken, K.; Sifrim, A.; Thienpont, B.; Voet, T. Methods and applications for single-cell and spatial multi-omics. Nat. Rev. Genet. 2023, 24, 494-515.
86. Deng, S.; Li, C.; Cao, J.; et al. Organ-on-a-chip meets artificial intelligence in drug evaluation. Theranostics 2023, 13, 4526-58.
87. Yong, Q.; Chen, C.; Zhang, X.; et al. The synergy of artificial intelligence and organ-on-a-chip: building a next-generation intelligent engine for drug development. Int. J. Pharm. 2026, 703, 127339.
88. Liu, Y.; Chen, X.; Tang, T.; Chen, X.; Fang, X. Smart delivery system based on microfluidic Nanomaterials. Prog. Mater. Sci. 2027, 163, 101771.
89. Hong, F.; Tan, R.; Wang, T.; et al. Standard: human gastric organoids. Cell. Regen. 2025, 14, 2.
