Engineering biomimetic intestinal topological features in 3D tissue models: retrospects and prospects


Conventional 2D intestinal models cannot precisely recapitulate biomimetic features in vitro and thus are unsuitable for various pharmacokinetic applications, development of disease models, and understanding the host-microbiome interactions. Thus, recently, efforts have been directed toward recreating in vitro models with intestine-associated unique 3D crypt-villus (for small intestine) or crypt-lumen (for large intestine) architectures. This review comprehensively delineates the current advancements in this research area in terms of the different microfabrication technologies (photolithography, laser ablation, and 3D bioprinting) employed and the physiological relevance of the obtained models in mimicking the features of native intestinal tissue. A major thrust of the manuscript is also on highlighting the dynamic interplay between intestinal cells (both the stem cells and differentiated ones) and different biophysical, biochemical, and mechanobiological cues along with interaction with other cell types and intestinal microbiome, providing goals for the future developments in this sphere. The article also manifests an outlook toward the application of induced pluripotent stem cells in the context of intestinal tissue models. On a concluding note, challenges and prospects for clinical translation of 3D patterned intestinal tissue models have been discussed.

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Fig. 1
Fig. 2
Fig. 3
Fig. 4







Small intestine


Large intestine


Crypt base columnar cells



M cell:

Microfold cell








Poly(ethylene glycol)


Acrylic acid


Extracellular matrix


Ultraviolet-lithography, electroplating, and molding


Poly(lactic acid)


Chemical vapor deposition


Poly(methyl methacrylate)


Poly(lactic-co-glycolic acid)




Computer-aided design


Poly(ethylene glycol) diacrylate


Vertically moving extrusion-based printing system


Human umbilical vein endothelial cells


Transepithelial electrical resistance


Mucin 17


Reverse transcription polymerase chain reaction


Fluorescein isothiocyanate




Zonula occludens-1




Alkaline phosphatase


Cytochrome P450 3A4




Olfactomedin 4


Keratin 20


Mucin 2




Intestinal stem cell






Wingless-related integration site


Transforming growth factor beta


Fibroblast growth factors


Leucine-rich repeat-containing G-protein coupled receptor 5


Interferon gamma


Tumor necrosis factor alpha


Yes-associated protein 1


Breast cancer resistance protein


Multidrug resistance protein 2


Induced pluripotent stem cells


Signal transducer and activator of transcription 1


Enteric nervous system


Macrophage inflammatory protein 2


Interleukin 10


Intestinal subepithelial myofibroblasts


Short-chain fatty acids


Enterocytes-like cells


Definite endodermal-like cells


Intestinal progenitor-like cells


Hindgut-like cells


Epidermal growth factor






N-[(3,5-difluorophenyl)acetyl]-L-alanyl-2-phenyl-1,1-dimethylethyl ester-glycine




Peptide transporter 1


Small intestinal organoids


Colonic organoids


Bone morphogenetic proteins


Special AT-rich sequence-binding protein 2




WD Repeat Domain 43


Transcription activator-like effector nuclease


Cystic fibrosis transmembrane conductance regulator


Inflammatory bowel disease


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TA would like to acknowledge the INSPIRE scheme, Department of Science and Technology, Government of India, for providing the fellowship.

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TA was involved in conceptualization, writing–original draft, writing–reviewing and editing; VO was involved in writing–original draft; LL was involved in writing–original draft; AA was involved in writing–original draft; TKM was involved in conceptualization, writing–reviewing and editing; PM was involved in writing–reviewing and editing; MV was involved in writing–reviewing and editing; GY was involved in writing–reviewing and editing.

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Correspondence to Tapas K. Maiti.

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This article does not contain any studies with human or animal subjects performed by any of the authors.

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Valentina Onesto and Lallepak Lamboni are equal contribution to this work.

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Agarwal, T., Onesto, V., Lamboni, L. et al. Engineering biomimetic intestinal topological features in 3D tissue models: retrospects and prospects. Bio-des. Manuf. (2021).

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  • Intestine tissue models
  • Microfabrication
  • Biophysicochemical and biomechanical cues
  • Coculture
  • Induced pluripotent stem cells