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

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Abstract

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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Abbreviations

2D:

Two-dimensional

3D:

Three-dimensional

SI:

Small intestine

LI:

Large intestine

CBC:

Crypt base columnar cells

TA:

Transit-amplifying

M cell:

Microfold cell

UV:

Ultraviolet

PDMS:

Polydimethylsiloxane

PTFE:

Polytetrafluoroethylene

PEG:

Poly(ethylene glycol)

AA:

Acrylic acid

ECM:

Extracellular matrix

UV-LIGA:

Ultraviolet-lithography, electroplating, and molding

PLA:

Poly(lactic acid)

CVD:

Chemical vapor deposition

PMMA:

Poly(methyl methacrylate)

PLGA:

Poly(lactic-co-glycolic acid)

PEVA:

Poly-ethylene-co-vinyl-acetate

CAD:

Computer-aided design

PEGDA:

Poly(ethylene glycol) diacrylate

VMEPS:

Vertically moving extrusion-based printing system

HUVECs:

Human umbilical vein endothelial cells

TEER:

Transepithelial electrical resistance

MUC17:

Mucin 17

RT-PCR:

Reverse transcription polymerase chain reaction

FITC:

Fluorescein isothiocyanate

PCL:

Poly-ε-caprolactone

ZO-1:

Zonula occludens-1

P-gp:

P-Glycoprotein

ALP:

Alkaline phosphatase

CYP3A4:

Cytochrome P450 3A4

EdU:

5-Ethynyl-2′-deoxyuridine

Olfm4:

Olfactomedin 4

CK20:

Keratin 20

MUC2:

Mucin 2

E-cad:

E-cadherin

ISC:

Intestinal stem cell

RGD:

Arginine-glycine-aspartate

GAGs:

Glycosaminoglycans

Wnt:

Wingless-related integration site

TGF-β:

Transforming growth factor beta

FGF:

Fibroblast growth factors

LGR5:

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

IFN-γ:

Interferon gamma

TNF-α:

Tumor necrosis factor alpha

YAP:

Yes-associated protein 1

BCRP:

Breast cancer resistance protein

MRP2:

Multidrug resistance protein 2

iPSCs:

Induced pluripotent stem cells

STAT1:

Signal transducer and activator of transcription 1

ENS:

Enteric nervous system

MIP-2:

Macrophage inflammatory protein 2

IL-10:

Interleukin 10

ISEMFs:

Intestinal subepithelial myofibroblasts

SCFAs:

Short-chain fatty acids

ELCs:

Enterocytes-like cells

DELCs:

Definite endodermal-like cells

IPLCs:

Intestinal progenitor-like cells

HLCs:

Hindgut-like cells

EGF:

Epidermal growth factor

5-aza:

5-Aza-2′-deoxycytidine

BIO:

6-Bromoindirubin-3′-oxime

DAPT:

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

WRN:

Wnt3A,R-spondin,Noggin

PEPT1:

Peptide transporter 1

SIOs:

Small intestinal organoids

Cos:

Colonic organoids

BMPs:

Bone morphogenetic proteins

SATB2:

Special AT-rich sequence-binding protein 2

HOX:

Homeobox

WDR43:

WD Repeat Domain 43

TALEN:

Transcription activator-like effector nuclease

CFTR:

Cystic fibrosis transmembrane conductance regulator

IBD:

Inflammatory bowel disease

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Acknowledgements

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

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Authors and Affiliations

  1. Department of Biotechnology, Indian Institute of Technology Kharagpur, Kharagpur, West Bengal, 721302, India

    Tarun Agarwal & Tapas K. Maiti

  2. Center for Advanced Biomaterials for Health Care, Istituto Italiano di Tecnologia (IIT@CRIB), 80125, Naples, Italy

    Valentina Onesto

  3. National Engineering Research Center for Nano-Medicine, Department of Biomedical Engineering, College of Life Science and Technology, Huazhong University of Science and Technology, 1037 Luoyu Road, Wuhan, 430074, People’s Republic of China

    Lallepak Lamboni & Guang Yang

  4. Laboratoire de Biologie Moléculaire, Institut National d’Hygiène-Togo, 26 Rue Nangbéto, Quartier Administratif- PO. Box 1396, Lomé, Togo

    Lallepak Lamboni

  5. Department of Biotechnology and Medical Engineering, National Institute of Technology Rourkela, Rourkela, Orissa, 769008, India

    Aafreen Ansari

  6. Institute for Polymers, Composites and Biomaterials (IPCB), National Research Council (CNR), Naples, Italy

    Pooyan Makvandi

  7. Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran

    Massoud Vosough

  8. Department of Regenerative Medicine, Cell Science Research Centre, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran

    Massoud Vosough

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  1. Tarun Agarwal
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Contributions

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. 4, 568–595 (2021). https://doi.org/10.1007/s42242-020-00120-5

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